Precision Nutrition Ebook Genetics The Universe Within

Genetics:
The Universe Within

Can knowing more about your genes
help you eat, move, and live better?
By Krista Scott-Dixon, PhD

With John Berardi, Phd, Alaina Hardie, and Helen Kollias, PhD
Genetics: The Universe Within
By Krista Scott-Dixon, PhD
WITH
John Berardi, PhD Alaina Hardie Helen Kollias, PhD
PE E R RE VIE WE D BY
Ryan Andrews Dr. Victor Pea

Cam DePutter Alex Picot-Annand
Dr. Trevor Kashey Jennifer Petrosino
Kenny Manson Dr. Jennifer Zantinge
2017 Precision Nutrition. All Rights Reserved.

Genetics: The Universe Within
CHAPTER 1 CHAPTER 2 CHAPTER 3

Introduction The basics of genetics Introduction to
A brief introduction to genetics An overview of how genetics works, genetic testing
and what youll learn in this book. and an introduction to some of the What does genetic testing involve?
key ideas youll need to understand What are some of the general
genetic testing and its implications. issues to think about while deciding
if genetic testing is right for you?

Specific genetic What we found: Heredity What we found: Metabolism
testing services How does heredity work? Why In this chapter, we explore
What should you think about when dont we all share the same some of the basic metabolic
considering particular genetic genetic variations? How might our processes, such as how we
testing services? Which services ethnic background and ancestry regulate our blood sugar or thyroid
did we choose, and why? affect our overall health? output, and how they might be
affected by genetic factors.

What we found: Body What we found: Food What we found: Food
weight and body comp preferences intolerances
In this chapter, we look at Why we might dislike some Why dont some foods dont agree
some genetic factors related foods, like others, and really like with you? And how much of that
to energy balance, what makes others? In this chapter, we'll cover may be due to genetic factors?
our bodies naturally bigger or how genetics influence how we
smaller, and how much lean or experience the taste of food.
fat mass were likely to have.

What we found: Nutrient What we found: Exercise What does this
absorption and use and muscle performance mean for you?
In this chapter, well examine some In this chapter, we look at some of Now that you've learned more
genetic factors that may affect the genetic factors that may shape about genetic testing, or
how our bodies digest, absorb, our response to (and recovery from) even gathered your own data,
and use particular nutrients. exercise and training, and whether what should you do next?
we have a natural athletic type.

Glossary of terms References Contributors and
Confused by codons? Mystified by Dont believe us? Want to learn acknowledgments
mutations? No worries, weve got a more? Enjoy the hundreds of Science is a collaborative endeavor.
handy glossary for all the technical references weve collected. We are most grateful to all of those
terms weve used in this book. who contributed their data and
expertise to help us write this book.
CHAPTER 1
Introduction
Our fate cannot be taken from us. It is a gift.

Dante Alighieri, Inferno (1472)
Oh, I am fortunes fool!

William Shakespeare, Romeo and Juliet (1595)
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GENETICS: THE UNIVERSE WITHIN
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1
What if you could know your future?
If you could know how you would live? How you might die? Where your path
might take you in the meantime?
Would you do anything differently?
Would you try to fight fate? Or just let yourself be swept along in the river leading
to the inevitable waterfall of your ending?
Human beings have wondered about destiny for

a long time.
Is our life course pre-determined? Is there some kind of plan?
Do we have free will? Can we do anything we like? Or are there limits?
If theres a plan, who or what creates it?
In 2017 BC, we might have said: The gods. The stars. The spirits. The same
powerful, invisible forces that create gusts of wind also push and pull us along
the path of our lives.
In 2017, we might say: Genetics.
Human beings have also wondered about who

they are, and why they are that way.
Why is one person tall, and another one short? Why is one person quick to
anger, and one calm? Why did this person get sick when the plague hit, and not
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that one?
Why is so much of ourselves often hidden from us?
Why dont we know why we do things?
Are we really just like our fathers, or mothers, or second cousins? Are we
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basically just carbon copies of our ancestors, or are we a blank slate?

Again, in 2017, we often try to answer these questions with: Genetics.

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2
Genetics seems like the answer to
everything.
But is it really?
For instance:
What can we really know about ourselves using the tools of genetic
analysis, and what is just speculation, wishing, and guessing?
How much certainty can we really gain from knowing about our genome?
Are genetic data a for sure, a maybe, or I dunno?
If we find something we dont like, how much can we change? How

negotiable is the expression of our genes?
Whats important and whats not? Our genome has a lot of information. Is
all of it relevant to our concerns and interests? Do we really care about the
genetic program that makes the third eyelash from the left?
Even if we can get all the knowledge we want, what should we do with it?
Genetics is an exciting area of

exploration.
In 2000, scientists mapped out a rough draft of the human genome our
genetic code.
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In 2003, the National Human Genome Research Institute (NHGRI) in the U.S.
announced that they had successfully completed the Human Genome Project.
Now we had a map of ourselves in theory, the code for all human beings on
earth.
And not just humans. Some form of this code is in every living thing on Earth.
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You are directly related to the bacteria that live on your body.
Yes, you might have diverged a billion years ago, and dont really plan to get
together at Thanksgiving, but theres a part of your genome, and a part of their
genome, that came from the same place.
This system of coding created all life from mushrooms, to dolphins, to oak
trees, to us.
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3
In 2007, commercial genetic testing services like 23andMe became available to
the general public. Anyone could have their genome scanned and read.
Since then, the field of genetic testing and genetic counseling has exploded. Its
now cheaper, faster, and easier to get your genome examined.
Genetic testing looks to answer Big Questions like:
What if we could know not just speculate, or guess, or wonder, but

know for sure how we work at the most basic level? What, exactly, our
bodies are doing?
What key opens which lock? What exact set of genetic instructions makes
us a sprinter, or have heart disease, or have a funny-looking baby toe?
What does our future hold? What diseases might we get (or avoid)? How
might we grow and develop?
How can we be better? Is there something in our genetic code that could
tell us what to eat or how to exercise? What supplements to take to function
better, or lower our risk of disease?
Some advocates of genetic testing suggest that they also have the Big Answers.
Do this genetic test, and well tell

you exactly what health, fitness,
and nutrition plan you need.
Its an exciting promise. PRECISION NUTRITION

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What if we could have a complete plan for everything that we wanted to do,
change, or improve?
A plan based on our unique, special blueprint? A one-in-seven-billion program,

just for us?
Wow. That would be amazing. Wouldnt it?

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4
Take a back seat, horoscopes! See ya, metabolic typing! Later, random trial
and error!
Theres a new plan in town! And its gonna tell me everything I would ever
need to know about what to do!
Well
Were not quite there yet.
But we are at a thrilling crossroads in human

knowledge and understanding.
Imagine you are standing outside a toy store. It has a small window.
You can see in the window. You get a glimpse of what the store contains.
But the window is too small to show you everything.
If you squint and peer inside, and crane your neck, you can see tiny bits and
pieces. An action figure here. A train set there.
You know the toy store is full of cool, fun, interesting stuff to play with.
You just cant see it all
Yet.
Thats where were at with understanding genetics and how we might use it.
In this book, well peek into the toy
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store.
Well tell you:
What genetic testing is, and how it works.

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What genetic testing can do and not do.

What genetic testing can tell you and not tell you.
What you can learn about your health, fitness, and nutrition through
genetic testing.
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5
Which tests might be better, more accurate, or more useful than others.
What you might do with any information you get from genetic testing.
Why we think this is exciting and cool, and full of potential but not quite
a magic solution to anything yet.
All of this is right now.
As in, heres what we can realistically do or know right now. Heres what tools
are available right now.
Of course, right now will change.
We want to dream, and we also want to be

scientists.
Well tell you what possibilities genetic testing can offer, and what the actual
research says.
We encourage you to read this book with the following mindset:
There is stuff we know, and stuff we dont know.
Thats how science works.
This is cool.
Imagine the possibilities. Its not magic yet but it could be.
This is complex.
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There are no simple answers. There are no hacks, appealing as that idea might
be.
Get excited, but keep it real.
We may all look like ignorant idiots in 200 years as knowledge and research
progresses. (Well, assuming we havent lit the planet on fire by then.)
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So bear in mind that any scientific claims are subject to critical scrutiny and
revision. And try not to write a check that your science cant cash.
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6
Were personally invested.
Science is not individual geniuses laboring alone in a lab.
Science is a collaborative endeavor.
This project is no different.
We shared our own genetic data.

18 members of the Precision Nutrition team plus 15 of their family and friends
agreed to share their genetic data for this project.
Throughout this book, well look at what they discovered in their genes, and
what that might mean for them and you.
At times, with their consent, we share some personal details about them. (Youll
find out, for instance, whos a sugar monster, whos the most Neanderthal, and
who had an ancestry surprise.)
At other times, well present their data in anonymous aggregate.
Heres our team.

For more about the people who wrote and reviewed this book, see Chapter 15:
Contributors and acknowledgments.
Thanks to everyone who contributed a little part of themselves for their

openness and contribution to scientific exploration.
We need to look at this from many angles.
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For example, we need to understand such things as:
the molecular biology of genes and how they work;

how scientists collect, process, and store genetic data;
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how genetic testing relates to nutrition and exercise physiology;

how probability and risk work;

how we might feel about any genetic test results we get; and
whether knowing about our genes will actually inspire us to change and if
so, how?
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7
So, well look at the topic from different viewpoints to give you depth and
context.
The science is neat. But this isnt

just about science.
Its not just about buzzwords like bio-hacking, personalized medicine, or gene
editing.
Its also about psychology and behavior. How we think about ourselves. What
were prepared to do to potentially change our fate.
As you read this book, remember an important caution:
As with most preferences, health risks, and genetic traits, there are many complex,
interrelated factors.
There is almost never one single gene that inevitably leads to a given result.
Any genetic data we share are simply clues for further exploration.
Heres what the rest of this book

will cover.
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Getting started with the fundamentals
CHAPTER 2
The basics of genetics
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An overview of how genetics works, and an introduction to some of the

key ideas youll need to understand genetic testing and its implications. We
recommend you review this chapter if youre new to the topic, or if youre looking
for a refresher. If youre already running your own biotech lab, feel free to skip it.
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8
Genetic testing
CHAPTER 3
Introduction to genetic testing
What does genetic testing involve? What are some of the general issues to think
about while deciding if genetic testing is right for you? This chapter includes
a description of the basic process of a genetic test from sample collection to
discovering youre related to Marie Antoinette.
CHAPTER 4
Specific genetic testing services
What should you think about when considering particular genetic testing
services? Which services did we choose, and why?
Specific topics of interest

CHAPTER 5
What we found: Heredity
How does heredity work? Why dont we all share the same genetic variations?
How might our ethnic background and ancestry affect our overall health?
CHAPTER 6
What we found: Metabolism
In this chapter, we explore some of the basic metabolic processes, such as how
we regulate our blood sugar or thyroid output, and how they might be affected
by genetic factors.
CHAPTER 7
What we found: Body weight and body comp
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In this chapter, we look at some genetic factors related to energy balance, what
makes our bodies naturally bigger or smaller, and how much lean or fat mass
were likely to have.
CHAPTER 8
What we found: Food preferences
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Why we might dislike some foods, like others, and really like others? In this
chapter, well cover how genetics influence how we experience the taste of food,
and how they shape our food preferences.
CHAPTER 9
What we found: Food intolerances
Why dont some foods dont agree with you? And how much of that may be due
to genetic factors?
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CHAPTER 10
What we found: Nutrient absorption and use
In this chapter, well examine some genetic factors that may affect how our
bodies digest, absorb, and use particular nutrients.
CHAPTER 11
What we found: Exercise and muscle performance
In this chapter, we look at some of the genetic factors that may shape our
response to (and recovery from) exercise and training, as well as whether we
have a natural athletic type.
What this all means and what to do next

CHAPTER 12
What does this mean for you?
Now that youve learned all about genetic testing, some of the data that you
can discover with it, and some of the traits that might affect your general health,
nutrition, and/or fitness, this chapter gives you some realistic next actions to
consider.
References
CHAPTER 13
Glossary of terms
Confused by codons? Mystified by mutations? No worries, weve got a handy
glossary for all the technical terms weve used in this book.
CHAPTER 14
References
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Dont believe us? Want to learn more? Enjoy the hundreds of references weve
collected.
CHAPTER 15
Contributors and acknowledgments
Science is a collaborative endeavor. We are most grateful to all of those who
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contributed their data and expertise to help us write this book.

Consider this a buffet.

Take what you like and leave the rest.
Skim and scan chapters. Or dig in.

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We suggest you peek at Chapter 2, even though its kinda heavy-duty. Or check
the glossary in Chapter 13 as needed if you dont recognize a sciencey term.
Think about what you want to get out of this book, and read it accordingly.
Look for the What this means for you sections in each chapter.
There, well give you some practical tips for how to think about a given topic,
and/or what to do next.
Also, check out Chapter 12 for our overall recommendations.
Let questions be there.
We have some answers for you, but not as many as youd probably hoped.
Get comfortable with questions, because thats how science works.
(As the physicist Richard Feynman quipped, Give me questions I cant answer,
not answers I cant question.)
Get curious.
Lets go!
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CHAPTER 2
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An overview of how genetics works,

and an introduction to some of the

key ideas youll need to understand
genetic testing and its implications.
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CHAPTER 2

What youll learn in this chapter
In this chapter, youll learn the basics about:
What genes do, and how;

Why computation and biomedical engineering are important;
The structure of DNA; and
How our genetic code might relate to any traits we express.
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Warning (or challenge): This chapter is heavy.
Its meant to be a reference for the rest of the book. So theres a lot of
information here.
You dont need to understand or remember it all in order to grasp the key
ideas about genetic testing.
Feel free to skim this chapter, skip it, come back to it whatever you like.
If youre new to understanding genetics or just want a refresher, we do suggest

you tackle at least a bit of this material.
If youve already done your graduate work in genetics, go ahead and breeze on
past.
A quick review of key terms

Before we get into this chapter, lets learn a few basic terms.
(Youll also find any bolded term in our glossary.)
DNA is a biological molecule that holds the code for making all living things.
Fun factoid!
Some viruses do not have DNA. Some (like parvovirus) have single-stranded DNA
genomes. Some (such as pox viruses) have double-stranded DNA genomes. Most have
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RNA genomes of some kind.
Genes are regions of DNA that encode instructions for making specific proteins. |
If genes have names, we put those in italics, like this: FGF21. This helps us tell
them apart from their corresponding protein names.
For instance:
The FGF21 gene (written in italics) codes for a protein called fibroblast
growth factor 21, or FGF21 (no italics).
The TAS2R38 gene codes for a protein called taste receptor 2 member 38,
or TAS2R38.
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Variants of the same genes are known as alleles or polymorphisms.
For instance, the type of earwax you have is controlled by a single gene known
as ABCC11 (which is also involved, by the way, in how your sweat smells). If you
have one of two variants / alleles of the gene, youll have wet earwax; if you have
a third variant / allele, your earwax will be dry.
Genetics is the study of genes, how they work, and how particular traits (such as
eye color) are passed from parent to offspring (known as heredity).
The expression of one gene can influence two or more apparently unrelated
processes or traits. Well see examples of this as we look at specific topics, such
as metabolism. This is known as pleiotropy (from the ancient Greek pleion, or
more, and tropos, or way). A variant in one gene may have a wide variety of
effects.
Our genotype is our genetic code; our phenotype is how that code is actually
expressed as it interacts with our environment. The same genotype can have
different phenotypes. Different environments (for instance, our activity, our
nutrition, our exposure to toxins, and so forth) can change our observable traits
(for instance, our physiology or behavior).
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Figure 2.1: Relationship between genotype and expressed traits

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Epigenetics is the study of how activation and inhibition of gene expression

is regulated. The same genetic blueprint may be used to express different
things; for instance, exercising can activate expression of genes involved in the
antioxidant response. We may already have had those genes, but exercising
affects their epigenetic expression.
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A genome is the complete set of an organisms genetic information. For
instance, the Human Genome Project studied the complete genetic code of
human beings.
In this book, well be talking about genetic testing.
Generally, this doesnt mean we are testing the entire genome. As youll learn,
the amount of information in an entire human genome is very, very, very
large. We have about 22,000 genes, and about 3 billion base pairs, or pairs
of nucleotides in our strings of DNA. (Well learn more about nucleotides in a
moment.)
With genetic testing, we usually test a single gene or single nucleotide

polymorphism (SNP), which is just one single point mutation to one nucleotide
within a gene. There can be several SNPs in the same gene; most widely used
SNPs are in noncoding regions.
Noncoding regions are parts of the genetic code that dont code for any
proteins, and theyre known as introns. Regions that do code for proteins are
known as exons. (Well look more at coding and noncoding regions in
Chapter 4, and at splicing more below.)
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Figure 2.2: Introns, exons, and mRNA splicing
Copy number variation (CNV) refers to whether chunks of genetic material

are repeated, kind of like having three or more of the same socks instead of a
single pair.
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CNVs can also affect how genes work. For instance, having multiple copies of
genes that make the enzyme amylase would increase our ability to break down
the carbohydrate amylose. This variation may reflect our ancestral history (for
instance, whether we come from an ethnic group that has traditionally eaten a
high-starch diet) and may be linked to our body weight.
Figure 2.3: Duplication of genetic material Figure 2.4: Copy number variation (CNV)
What do genes do?
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Genes are information.
In the real world, we have to figure out a few things when we use information:
How to transmit and transport information how to get it from one place
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to another without losing it along the way.

How to reproduce information properly and carefully.

How to store information so it doesnt degrade or take up too much space.
How we receive and interpret informational signals that are sent.
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Genes and their associated products and processes do all of this inside our
bodies.
We can think of a gene as a unit of information or a set of instructions for

making something in this case, a specific protein.
In eukaryotic cells (cells that have a nucleus and distinct organelles bound by a
membrane), DNA is organized in chromosomes in the nucleus.
When cells divide, chromosomes are duplicated and DNA is replicated. Once
cells finish dividing, each cell ends up with its own full set of chromosomes.
Eukaryotes store most of their DNA inside the cell nucleus and some of their
DNA in organelles, such as mitochondria or chloroplasts (in plants).
Genetically speaking, we are about half of each of our parents. But were not
exactly like our mom and dad. And were not a precise 50% of each. Were more
like a 49-point-something percentage of each, plus some random mutations that
sneaked in along the way.
Well learn more about mutations in a bit.
For now, the key points are:
Genes store information.

Information is passed from parent to offspring.
Its not a perfect transmission every time.
When we look at our genes, or particular variation in our genes, we can see this
transmission of information. And we can see the variations among ourselves,
even within the same family.
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Why does this happen?
How does this work?
And what does this all mean for your own genetic code?
To explain, lets start with a concept that may be a little new to you.
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Biology is computation.
Most people tend to think of biology as just a bunch of wet squishy bits. We can
also think about biology as being a type of computation.
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Imagine you were trying to program a computer
to do something.
Computers are pretty literal and only do what you tell them, so you want to
make sure youre absolutely clear. Youll also need to give the computer some
structured parameters for making decisions, otherwise they get confused.
For example, you might tell the computer:
IF this is true, THEN do this thing.
IF todays date is July 18, THEN send Dr. John Berardi a birthday card.
IF Dr. JB likes cake, THEN make him some.
Maybe your IF / THEN instructions have conditions:
IF Dr. JB likes cake OR you like cake, THEN make a cake.
IF you are on a desert island AND today is July 18, THEN spell out Happy
birthday using driftwood instead.
Biology works in similar ways.

Lets imagine something simple, like the communication between a cell and the
outside world.
Some cells have receptors (such as a specific type of protein) on their

membranes. These receptors bind to other things, such as other proteins or
simpler molecules.
Each receptor is picky and will only bind to particular things (these specific
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molecules are known as ligands), much like a key will only work in one or two
locks.
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Figure 2.5: Receptors and binding sites

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A receptor acts like a switch. If something binds to a receptor, it triggers another
event, like turning a switch to on.
So, we might imagine a situation where the instructions for our cells biological
computer read something like this:
IF receptor A is on AND receptor B is off, THEN make protein from gene A
IF gene A is active, AND gene B is available, THEN make the protein from
gene B.
Note that this looks very much like the computer code you might have learned in
school:
IF xyz THEN do something.
Computers are still pretty dumb, relative to biology. But at a basic level, the
concept is similar.
Genes encode a series of instructions, like a computer program and

accumulate problems, also like computer programs.
Computers can start from scratch. In theory, you could make a computer that
thinks in a way that nothing ever has before, using components that nobody has
ever used before.
Biological systems dont work that way. They can only use the structures and
systems that they have inherited (along with, of course, any new mutations,
which are only a small part of a much bigger whole).
Sometimes this can mean that biological systems are pretty efficient perhaps
evolution has done a lot of work to tidy things up.
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Sometimes the systems can be less efficient. They have a lot of what computer
folks call cruft: clutter and redundant junk such as old equipment or code that
just hangs around and either does nothing or actively gums up the works.
Biology is engineering.
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Remember high school chemistry with diagrams like this?
Figure 2.6: Simple H20 molecule

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(Thats water.)
Or these?
Figure 2.7: Simple caffeine and nicotine molecules
(Those are caffeine and nicotine, maybe two of your best friends in high school,
you rebel you.)
You might have been left with the impression that molecules are basically flat
polygons and lines.
However, molecules are three-dimensional.

So water actually looks more like this:
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Figure 2.8: 3-dimensional H20 molecule

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And nicotine looks more like this:
Figure 2.9: 3D nicotine molecule
Molecular structures in the body are the same way.
For instance, here is a three-dimensional protein (a Cas9 nuclease, in case

youre wondering) that our co-author Alaina printed in her lab:
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Figure 2.10: 3D protein

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Youll notice that proteins are not abstract line drawings, but actual, tangible
objects.
If you blew that nicotine protein up larger, it would look like this:
Figure 2.11: 3D nicotine protein
The physical shape of the protein would affect how you could interact with it.
The same thing happens at the molecular level.
For instance, lets imagine you have a protein that is shaped like this:
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Figure 2.12: Hook-shaped protein
It has a straight end and a hooked end.
Lets imagine that 3-dimensional J-shaped protein is moving around in your

body.
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Then it finds a protein that looks like this:
Figure 2.13: Eye bolt-shaped protein
What happens? Well, if conditions are right, maybe the hook-shaped part of the
first protein will latch on to the eye-shaped part of the other protein, and stick
there.
Figure 2.14: Hook and eye proteins connected
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The physical shapes of the proteins determine how they will interact.
If you just have this:
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Figure 2.15: Column-shaped protein

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then the J-hook has nothing to connect to.
In other words: Shape matters. The physical characteristics of molecules

determine whether and how they will interact (or react) with other molecules.
And biology is, after all, just a whole lot of reactions with the final result of
making something be alive.
DNA is a 3-dimensional structure.

First: What does the acronym DNA stand for?
Yes, eager student in the front with your hand up, the answer is
deoxyribonucleic acid.
Aside from making you the team champ on trivia night, knowing the full name of
DNA actually gives you clues to how DNA is constructed, and to understanding
how genetics work. Part of that has to do with the physical shape of DNA and
how the molecules fit together.
A DNA strand is shaped like a ladder, and made out of two pieces:
A deoxyribose backbone, i.e., the side rails of the DNA ladder. (RNA has
ribose here.)
Bases or nucleotides, i.e., the ladders rungs.
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Figure 2.16: DNA ladder

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Ribose is a simple sugar. De-oxy means without oxygen, so deoxyribose
means a ribose without an oxygen.
OK, now imagine that the deoxyribose sugar is actually a sort-of T-shaped piece
of Lego, like this:
Figure 2.17: Deoxyribose Lego
And imagine a few of those Legos stacked on top of each other, like this:
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Figure 2.18: Deoxyribose Lego stack

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Then imagine youre getting real fancy with the Lego stack and you want to
indicate which way is up.
So you draw an arrow along the stack, like this.
Figure 2.19: Deoxyribose Lego stack with arrows
Congratulations. You just built the deoxyribose backbone of DNA.
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And, since you have 3 pokey-outy parts to which other things can attach, you
have also built the foundation for a specific unit of DNA, known as a codon (aka
a sequence of three nucleotides).
DNA uses computation.

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Except imagine that in DNA computation, we arent making numbers, but amino
acids.
Remember our Lego structure? We can stick bases, or nucleotides, on it. Bases
are the building blocks of nucleic acids.
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Figure 2.20: Nucleotides on deoxyribose backbone
With DNA, we have 4 options for nucleotides:
Adenine (A)
Cytosine (C)
Guanine (G)
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Thymine (T)
RNA (which well look at in a moment) gives us one more: uracil (U), which
replaces thymine.
Two of these nucleotides (A and G) are long. Two (C and T) are short. So in a full
strand of DNA, short nucleotides pair with long ones, and vice versa.
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Like this:
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Figure 2.21: Short and long pairs of nucleotides
The nucleotide formula for proteins
You can imagine that each nucleotide is like a box that could have 1 of 4 possible
nucleic acids inside: either an A, a C, a G, or a T, like this:
Figure 2.22: Nucleotides in boxes PRECISION NUTRITION

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With 2 boxes, we get 4 x 4 values = 16 possible combinations.
With 3 boxes, we get 4 x 4 x 4 values = 64 possible combinations.
DNA codes for proteins. Proteins are made of amino acids. So part of that DNA
has to code for a particular amino acid.
We need to make about 20 amino acids.

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We cant do that with 1 box (which can only contain 1 of 4 possible nucleotides),
or 2 boxes (which only gives us 16 possible combinations). We need 3 boxes.
Hence, a codon is 3 units. BIO MATH!!
We need many different 3-nucleotide codons to code for these 20 amino acids.
Keeping it all straight can be confusing. Thus, researchers have come up with
some ways to help us catalogue and interpret codons, such as a codon wheel
(shown below).
A codon wheel helps us in both directions: We can decipher what amino acid a
particular codon codes for, and what codons code for a particular amino acid.
To read the wheel, start from the center. Thats one nucleotide. Then go
outwards and pick another one of 4. And outwards again, picking another one
of 4.
For instance:
Starting with C in the middle moving outwards and picking another C

then moving outwards again and picking a U, C, A or G gives you the amino
acid leucine.
Starting with G in the middle moving outwards and picking an A then

moving outwards again and picking an A or a G gives you glutamine.
You might also notice that some amino acids can be made with more than one
combo of nucleotides.
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Figure 2.23: DNA codon wheel

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Well learn more about codons and how they work later.
For now, just remember this structure of DNA:
Figure 2.24: Basic structure of DNA
Genes have geography.

The shape of DNA is not random.
To go back to the idea that genes store information, this shape is not an
accident. Because of the way the DNA Lego blocks fit together:
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The molecule is extremely stable.
Our bodies can copy it with extremely high fidelity and accuracy.
This is good, because as well see later, we dont really want things falling apart
or getting sloppy with reproduction. Errors happen all the time, but we have
biological proofreaders to catch them.
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Remember our little ribose Lego? Deoxyribose is a carbohydrate, which means

it has carbon. In biochem, we number the carbons. Each little Lego block has
one carbon called the 5-prime (written as 5) and another called the 3-prime
(written as 3).
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Our bodies will always read DNA in a certain order (hence the arrow): from
5-prime to 3-prime, and they go in opposite directions. One side will be 5 to 3
reading up, the other 5 to 3 reading down.
Figure 2.25: Directionality of DNA pieces
This directionality of each DNA piece is

important.
Think about how you read. If you read English:
YOU READ FROM LEFT TO RIGHT.
.TFEL OT THGIR MORF DAER TNOD UOY
DNA reading works the same way. It has to go in a particular direction.
Imagine you were making a machine to read DNA. Its a simple computer, so it
can only read one nucleotide at a time. It scans down the strand, reading from 5
to 3, reading the name of each nucleotide, like this:
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ACTTGAATGCATC
and so on. It has to go in that direction, because the reverse (reading from 3 to
5) would be something totally different:
CTACGTAAGTTCA
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Different letters, different meaning.
DNA isnt just floating around randomly in cells. Its packed into highly organized
structures, tightly wrapped around proteins called histones like beads on a
string, so that massive amounts of this genetic material can fit into the tiny space
of a cells nucleus.
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Unspooled, your strands of DNA would be around two meters long. Yet they fit
into a space about 1/1,000 of a millimeter.
This protein-DNA complex is called chromatin, and its what makes up your
bodys chromosomes.
Figure 2.26: Structure of chromosomes
The ways that our chromosomes are folded in space, and physically organized in
the nucleus, can significantly affect how genes are expressed.
For example:
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Factors known as enhancers, which increase the likelihood that a given
gene will be transcribed, need to be located close to the regions that they
act on.
Much of epigenetics (which well look at briefly below), or the regulation

of gene expression, is related to histone modification, or changes to the
physical configuration of the histone proteins that DNA wraps around.
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Recent groundbreaking research at the Salk Institute for Biological Studies

has just revealed that we are now able to see how chromatin is organized in a
living cell. (Previously, we had to pull the cell apart to see this, so we could not
see how chromatin worked in the wild.)
This research revealed that the way in which chromatin was packed into the
nucleus its shape as well as its density affected its function.
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What this means is that:
The shape of molecules is important. Shape affects how molecules work,

and how they interact with other molecules.
Thus, genetic expression is not just about the genes we have, but where
theyre located.
Commercial genetic testing can tell us about some of the specific genes we
have, but not about how theyre physically organized. We cant know the
geography of our genes from a commercial test, which means we cant know
a lot about how those genes may be expressed.
How are proteins made from genes?

The central dogma of molecular biology
All of this adds up to what is sometimes known as the central dogma of
molecular biology: DNA to RNA to proteins.
DNA is read in groups of three nucleotides called codons.

These DNA codons are transcribed to an in-between molecule,
messenger ribonucleic acid (mRNA). (Well look at this in more detail in a
minute.)
The mRNA is read and each mRNA codon is translated to one amino acid.
Amino acids are linked together to make proteins.
Thus, again, DNAs job is to store the information to make proteins.
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All of molecular biology revolves around this basic principle.
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Figure 2.27: DNA to RNA to protein
Gene expression and making proteins

There are two general steps to make a protein. Together, theyre called gene
expression.
1 | RNA synthesis (transcription): Making RNA, using the instructions from

DNA. At this step, double-stranded DNA is unzipped like a zipper by
enzymes called polymerases into single, complementary strands of RNA.
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2 | Protein synthesis (translation): Making proteins, using the instructions from
RNA.
RNA has many jobs, and there are several types, which well look at in a
moment.
For now, well focus on messenger RNA (mRNA). mRNA is the intermediary
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between DNA and proteins.
For a long time, scientists thought that one gene coded for one mRNA, that then
coded for one protein: If you had 100 genes, youd make 100 different mRNAs,
and then 100 different proteins. That way, if you knew all the genes, youd know
all the proteins.
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Its more complicated than that. (Warning: Were going to say this a lot. Like, a
lot.)
RNA splicing
One gene can code for many related proteins through RNA splicing.
RNA splicing is like producing alternative cuts of movies think of directors

cuts, alternative endings, 20 year anniversary edition cut, and what-have-you-
done-to-my-favorite-movie?? cut.
Some cuts could be minor. Some could completely change the movie (i.e., the
protein thats expressed).
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Figure 2.28: DNA to RNA to splicing to proteins

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Now, imagine your movie is also full of commercials. You have to watch the
movie in little bits. This is annoying. So, imagine that you re-cut the movie, take
out the commercials, and stick all the movie bits back together so you get one
uninterrupted full-length feature.
You can think of introns (sometimes known as intervening sequences) as the

commercials. Remember, introns dont code for proteins.
You can think of exons (sometimes known as expressing sequences) as the

movie itself. Since exons code for proteins, theyre like the story of what will
happen, genetically speaking.
Just like a movie with irritating and useless commercials removed, mRNA is
spliced so that all the introns are taken out, and only the exons, the expressing
sequences, remain.
Now, sometimes theres a small problem: Our editor is excellent but not perfect.
So, when our mRNA movie is re-cut during the RNA splicing process:
We might end up with a perfect, commercial-free copy of the original

movie. Just some nice exons all stuck together in an uninterrupted, faithfully
reproduced sequence.
Or, if alternative splicing occurs, we might end up with a few scenes missing
from our movie. A few exons might get cut out.
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Figure 2.29: RNA splicing

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Transporting mRNA in and out of the nucleus
Remember that DNA and RNA live mainly in the nucleus. (In Chapter 6, well talk
about another kind of DNA, mitochondrial DNA, that doesnt.)
Before it can be used to code for protein, mRNA has to clear a couple more
hurdles. Enter mRNA export.
mRNA needs to get out of the nucleus and to ribosomes, the protein-making
factories in the cytoplasm.
It also needs to keep itself from breaking down. If its broken down
(degraded), then it cant be used.
You dont want RNA just randomly escaping the nucleus, just like you dont want
drunken texts to your ex or boss escaping your phone at 3:00 AM.
Thus, you need to regulate mRNA degradation and stability so it can make it to
the ribosome and be translated into a protein.
Nuclear exporting involves nuclear transport receptors that chaperone the

mRNA through a nuclear pore, which means that trying to get the mRNA out of
the nucleus can be a bit of a bottleneck.
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Figure 2:30: RNA movement through nuclear pore
Once precursor mRNA grows up and becomes mature mRNA (via splicing and
some accessories stuck on for stability), its selected and moved out of the
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nucleus.
Mature mRNA has a bunch of extra nucleotides stuck on one end (a 3 poly-A
tail) that acts a bit like the little plastic ends on your shoelaces that keep them
from getting frayed. On the other end of the mRNA (the 5 end), it has a cap (a
7-methylguanosine cap).
The cap and the tail protect the mRNA from being broken down and keep it
stable. The more stable the mRNA is, the more protein it can make.
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Other types of RNA
Besides pre-mRNA and mRNA, there are several other types of RNA we need to
make proteins.
Transfer RNA (tRNA). tRNAs are RNA molecules that carry specific amino
acids to the ribosome. They match mRNA codons with their respective
amino acid.
Ribosomal RNA (rRNA) is an RNA enzyme that links amino acids together
in the ribosome to make a polypeptide chain. Remember that ribosomes
are where the mRNA is read and matched with tRNA that carry amino acids,
which are then assembled to make the protein.
Other RNAs such as small nuclear RNA (snRNA), microRNA (miRNA), and
small interfering RNA (siRNA) regulate how much and what type protein will
be made.
Theres no exam.
Just remember:
Its much more complicated than One gene, one protein.
TYPE OF RNA MAIN FUNCTION
mRNA Codes for protein
rRNA An RNA enzyme that links amino acids together
tRNA Bridges between mRNA codons and the amino acids they code for
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snRNA RNA splicing
miRNA Generally block translation of specific mRNA, though can also

upregulate (increase) it
siRNA Selectively target specific mRNA for degradation

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Controlling gene expression: from
DNA to protein
There are 5 steps going from DNA to protein that are controlled via mRNA
production, processing and transport.
1 | Transcription: making RNA from DNA
2 | RNA processing: splicing RNA
3 | RNA export: exporting mRNA out of the nucleus
4 | Translation: making protein from mRNA
5 | Post-translational processing: getting rid of unwanted or harmful mRNA,

which can happen before proteins are made (kind of like a quality control
mechanism)
Your body doesnt constantly make RNA from DNA. Its a very regulated process.
Only certain genes are transcribed, and only at certain times.
Genes have three control regions:
promoters
enhancers
terminators
Promoters and terminators (basically starters and stoppers) are similar for all
genes.
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But enhancer regions are different. Their variations allow them to match
transcription factors with some specificity, allowing systems to activate and
deactivate transcription of certain genes by the presence and absence of their
transcription factor(s).
How do mutations happen?

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Think about nucleotide pairs like matching pairs of socks. Ideally, you have all
your socks properly sorted and paired after doing laundry. Sometimes, that
happens. Sometimes, not.
Sometimes you lose or mismatch socks maybe one sock, maybe a pair of
socks, maybe a few pairs. Sometimes you even end up with new socks socks
that arent even yours.
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The same can happen with the nucleotide pairs of DNA. This is called a mutation
some type of permanent change to the nucleotide pairing sequence. This can
happen in a few different ways, and for different reasons.
The example of antioxidants and reactive oxygen species
You may have heard the term antioxidant (for instance, as an ingredient in
superfoods, or vitamins C and E).
But why do we need antioxidants in the first place?
In normal metabolism, we create what are called reactive oxygen species (ROS).
ROS are unstable, oxygen-containing molecules that are normal byproducts of
cellular respiration. Oxidative damage happens naturally during cell metabolism
some estimates suggest this occurs 10,000 times a day per cell.
Usually, our cells are able to balance oxidative damage with their own
antioxidant system.
However, under environmental stress (such as exposure to toxins), ROS can build
up faster than the cell can clear them. This can cause mutations by chemically
modifying the nucleotides to become a slightly different molecule.
Types and causes of mutations
Having a lot of ROS hanging around is one cause of mutations.
There are many other ways for oxidative changes to occur, such as:
exposure to ionizing radiation (such as X-rays or radioactive material);

certain types of chemicals (such as heavy metals or pesticides);
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ultraviolet light (two nucleotides cytosine and thymine are particularly
sensitive to UV light); and
spontaneous (and uncorrected) errors in the DNA replication/copying

process.
Mutations can affect anything from only a single nucleotide, to large-scale

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alterations to chromosomes. They can change the structure and function of

genes.
Small mutations can sometimes have big effects that change a proteins amino
acid composition:
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Substitution mutations: In a codon, one nucleotide is exchanged for another
(for instance, an A for a G or a C for a T). These can end up being:
Silent mutations that code for the same or a similar-enough amino acid
(e.g., both CCA and CCT result in proline)
Missense mutations, which code for a different amino acid (e.g., CCA
results in proline, but CTA results in leucine).
Nonsense mutations, which create stop codons and can truncate the
protein (e.g., TAC makes tyrosine, while TAA signals stop). This means
that a cells ribosome (the protein-making factory), will stop producing
the protein before that protein has all of its amino acids. Consequently,
this can affect the way the protein works.
Frameshift mutations: Sometimes, the DNA copying process can insert or

delete one or more nucleotides, which means that the whole reading frame
has shifted. Everything after the frame might now be nonsense, or the gene
may simply be missing some amino acids.
Insertions, as the name implies, add one or more extra nucleotides into
the DNA.
Deletions remove one or more nucleotides from the DNA.
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Figure 2.31: Insertions and deletions

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More significant mutations that can affect one or more entire genes can include:
Amplifications or duplications, or more than one copy of genes or regions

of a chromosome.
Deletions of large parts of a chromosome, which results in losing some

genes in those regions.
Bringing together previously separated chunks of DNA, which may mean

different genes come together to form new ones (known as fusion genes).
An example of this is the unique seaweed-digesting bacterial enzyme in the
gut bacteria of people with Japanese ancestry, which researchers speculate
may originally have come from the genes of marine bacteria that live on
seaweed. This jump of DNA from unicellular organisms (such as bacteria)
to multicellular organisms (such as humans) is known as horizontal gene
transfer.
Chromosomal translocations, which happen when unrelated chromosomes

swap parts.
Terminal and interstitial deletions, which happen when a piece of DNA is

removed from a single chromosome. Large deletions can be severe or even
catastrophic to an organism. Prader-Willi Syndrome, which affects many
aspects of normal growth, development, and metabolism, is a result of an
interstitial deletion.
Chromosomal inversions, which flip the order of a segment of a

chromosome. These mutations are usually benign.
Loss of heterozygosity, or losing an allele from the (possibly different) pair of

genes that you inherit from your parents, so that you only get one regular
allele.
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Figure 2.32: Other mutations

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Sometimes mutations have observable effects, sometimes not.
For instance:
Genes can be partly or completely de-activated. These are known as loss-

of-function mutations, or inactivating mutations. For example, in androgen
insensitivity syndrome (AIS), a mutation inactivates the androgen receptor
and can cause chromosomally XY people to develop physically as female.
The effects of genes can get stronger. If we have extra copies of a gene in
a genome (copy number variation, or CNV), there are more copies of the
gene to be transcribed, and the effect can be more pronounced.
Genes can change their function. For example, a mutation at codon 6 of

HBB, the -globin gene (which changes the amino acid code from glutamic
acid into valine) can mean that hemoglobin cant carry as much oxygen. You
may know of this mutation as sickle-cell anemia.
Sometimes mutations are helpful, perhaps giving us some kind of advantage

in our environment. Sometimes they are harmful. Sometimes they have no
apparent effect at all.
Mutations that gave us an advantage in one environment (such as the ability

to store energy when food was scarce and required lots of effort to get)
might not give us an advantage in a different environment (e.g., now that
food is abundant, cheap, and energy-dense).
However, sometimes mutations kill an organism. These are known as lethal

mutations. While there are some exceptions, if youve made it to adulthood,
youve likely escaped most of the major lethal mutations.
Fixing DNA damage
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How does the body reach that high fidelity we mentioned earlier? By precisely
spotting and quickly repairing some of the more common mutations.
Like the Quality Assurance process of factory production, our bodies carefully
check for DNA damage and quality at various checkpoints in the cell cycle.
If the QA testers spot damage, they (ideally) stop the production line, pause
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cell division, and fix things.

In fact, given how many components our genome has, its quite amazing how
effective and efficient our genetic copying process is as accurate as only one
major error per every 1010 (or 10,000,000,000) nucleotides. Try finding a factory
with that level of precision!
Our bodies can repair DNA damage in several ways:

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Mismatch repair (MMR) happens when a set of genes notices errors in
DNA replication and recombination.
We know of 7 DNA MMR proteins (MLH1, MLH3, MSH2, MSH3, MSH6,

PMS1 and PMS2) that work in an orderly process to find and fix things.
When MMR doesnt happen correctly, we may get what is called

microsatellite instability (MSI), which means that small, variable, highly
mutation-prone chunks of DNA (aka microsatellites) end up as part of
our genetic material. MSI has been linked to many cancers.
Base excision repair (BER) and nucleotide excision repair (NER) processes
fix lesions and physical damage that can lead to DNA mis-pairing or breaks
during replication. Deficiencies in BER / NER have been linked to cancer as
well as neurodegeneration.
Nonhomologous end-joining (NHEJ) and homologous recombination

repair (HRR) are processes that repair double-strand lesions, or breaks. You
can think of double-strand breaks as your DNA ladder being cut between
the rails. These are some of the most dangerous types of DNA damage.
One double-strand break is enough to kill a cell or destroy the integrity of its
genome.
Translesion synthesis (TLS) DNA polymerases let unrepaired lesions get

through the process of DNA replication, to be fixed later.
Sometimes, critical mutations occur not to particular genes that do things like
make body structures, but to the genes involved in finding and fixing mistakes.
So diseases of genetic origin occur from not having a strong enough repair
crew.
You could spend your life studying the details of genetics. (Heck, we had a hard
time keeping this basics chapter under 10,000 words.)
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But you dont need to know all the details if you simply want to grasp the basics
of genetic testing.
Just get the general idea:
Mutations and variations are complex.

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Sometimes mutations take an organism out of the game before it can reproduce.
Or, if the organism does manage to reproduce, the mutation isnt passed to its
offspring.
Sometimes mutations dont affect the reproduction process (for instance, its
something that only affects people over 60, or it gives you a funny-shaped nose
but someone loves you anyway).
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Often, mutations and genetic variations can be inherited, and as a result, they
can affect our health, nutrition, and fitness.
Early in genetic research, scientists often wondered if a single gene could

be responsible for particular diseases. For instance, could there be a cancer
gene?
We now know that most diseases result from combinations of factors.
For instance, the BRCA1 and BRCA2 gene variants play a strong role in the
development of breast and ovarian cancers. Many other genes do too, such as
genes involved in DNA repair.
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Figure 2.33: Genes involved in breast cancer

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Different types of ovarian cancer
TYPE 1 TYPE 2
Mutations TEN, KRAS, BRAF,

P TP53
PIK3CA, ERBB2, CTNNB1, BRCA1
ARID1A, PPP2R1A, and BRCA2
microsatellite instability
Prevalence About 30% About 70%
Tumor type Serous, endometrioid, mucinous, Serous, mixed malignant

and clear-cell tumors mesodermal tumors
carcinosarcomas, and
undifferentiated tumors
Grade & progression Low and borderline, slow and High and aggressive
often isolated to ovary
These variations affect not only the origins of particular types of ovarian cancer,
but also their locations, clinical progressions and outcomes.
Diseases such as cancer are not just one thing.
They are diverse phenomena that result from complex genetic and
environmental interactions.
Well be emphasizing this throughout the text:
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Epigenetics: Environment
matters.
Have you ever met identical twins that were different? Different
personalities, different habits, maybe even different physical traits
despite being genetically the same?
Studies have compared what happens when one identical twin exercises
or eats nutritiously and the other one doesnt. For example, one study
compared 10 pairs of twins. One twin of each pair exercised regularly; the
other twin was sedentary.
The researchers found that the more active twins were leaner and
metabolically healthier. They also had more grey matter in their brains than
their genetically identical but inactive counterparts. Other studies have
found similar results.
Why arent two people with the same genetic blueprint exact copies of one
another?
The answer is epigenetics, the regulation of whether or not our genes are
expressed.
Our environment (such as what we eat, whats around us, our exercise
habits, what happened to us as children, and so forth) affects gene
expression.
There are many ways that this can happen, such as histone modification.
Youll remember that histones are proteins that make up part of the
package of DNA, and can affect how parts of that DNA are activated or
repressed.
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A full discussion of epigenetics is cool, but beyond the scope of this book.
Just get the general ideas here:
Genetic expression depends on more than just the genetic blueprint

we received at conception.
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Just knowing our genetic code (our genotype) is not enough to fully
understand what it means, or how it may shape our phenotype (for
instance, our health, our risk of disease, our physical characteristics
like height, and so forth).
Many other factors can affect how and whether specific genes are
expressed.
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Whats up next
Now that you have some fundamentals under your belt, well explore how
genetic tests work, and what they look for.
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CHAPTER 1 CHAPTER 3
Introduction Introduction to
genetic testing
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A brief introduction to genetics

and what youll learn in this book. What does genetic testing involve?
What are some of the general
issues to think about while deciding
if genetic testing is right for you?
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CHAPTER 3
Introduction to genetic testing

In this chapter, well cover:
The idea that biology is about probability rather than a given outcome;
How genetic testing works;
Why and how genetic testing might be helpful or unhelpful;
Guidelines for genetic testing; and
Questions you can ask yourself when considering genetic testing.
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Biology is probability.
Probability is prediction and potential, not perfection.
Biology rarely gives us a definitive, simple answer to questions like:
What is the best diet?
or
What is the best exercise routine?
or
When exactly will I die, and how?
So any genetic testing service (along with any book, website, or coaching
service) that promises to give you a perfect nutrition plan or workout regime,
or exactly predict your health risks, is being misleading.
(And scientifically dodgy.)
There will almost never be a perfect solution

for anything related to biology.
As we like to say around Precision Nutrition:
Progress, not perfection.
Its almost impossible to control all the factors involved in a complex system.
Plus, knowledge and development are incremental. We learn bit by bit. Change
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bit by bit. Grow bit by bit.
Genetic information can tell us how we might change (if we wanted to), and
what the payoff from that change might be.
Lets imagine that based on your genetic tests, you knew exactly how likely
it was that you would get a particular disease, and exactly how that disease
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might progress.
(Just to be clear, were definitely not there yet. Its imagination time only.)
For instance, lets say that you know from genetic testing that you have a 70%
probability of dying from Alzheimers disease by age 70.
Now lets say that there is also a medication available. This medication will bring
your risk from 70% down to 30%. And it works in 90% of people.
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Would you take it?
Lets think about that.
No medication: 70% chance of dying at 70 from a known disease.
Medication: 30% chance of dying at 70 but you may be in the 10% for
whom it doesnt work.
Many people would probably figure OK, I am probably more likely to be in

the 90% of medication responders, and I like that 30% is much less of a
chance than 70%, so lets do it.
What if the medication only brought your risk down to 60%?
Or if it only worked in 30% of people?
What then?
Heres another example.
We know that many breast and ovarian cancers are related to mutations in the
BRCA1 and/or BRCA2 genes. Data suggest that in healthy 30-year old carriers
of these mutations, removing ovaries may add 0.2 to 1.8 years in life expectancy,
and a mastectomy may add 0.6 to 2.1 years.
Is that enough certainty to book surgery if you know you carry those mutations?
Of course, theres no right answer.

Some people might grab for any chance, and take the medication, or have
surgery. Other people might say Eh, not good enough odds for me, and not
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take those chances.
The point is:
Unless a mutation has taken you out of the game right off the bat, theres
almost never 100 100 100. |
As in: We know with 100% certainty that in 100% of cases, this genetic risk will
100% lead to this outcome.
Sometimes we dont even know with 50% certainty or 10% certainty or at all.
At best, we can only make informed guesses.

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Proceed with caution and critical
thought.
Now that you know from Chapter 2 the basics of how genes work, remember a
few key ideas:
Genetic interactions are vast and complex, and we dont have most
of them mapped.
Genetics isnt the whole story. Many physiological interactions

arent genetic.
This domain of research is still very new.

Mutations and alterations to our genetic code happen all the time.
Sometimes they matter. Sometimes not.
We still cant make strong predictions or recommendations about

most things.
Keep these concepts in mind, and wear your skeptical scientist hat.
Genetic testing is easier than ever.

What does that mean?
In the last few decades, technologies that measure DNA and RNA have
developed rapidly, becoming cheaper, faster, and more accessible.
In 2001, sequencing a full human genome (all the DNA in a human cell
nucleus) cost about $100 million US.
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In 2011, it cost about $10,000 US.
In 2016, two members of our PN team got their full genome sequenced for
$1,000 US each.
Still too much money?

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For only $200 US, you can buy a 23andMe kit and get hundreds of thousands
of your genetic variations tested without ever leaving your house. Just spit in a
tube and mail it away for analysis no fancy lab coat required.
The graphic below compares when various genetic sequencing technologies

were introduced to how much analytic power those technologies have.
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The graphic below compares when various genetic sequencing technologies
were introduced to how much analytic power those technologies have.
When more material can pass through the process, accuracy goes up and costs
go down. Researchers can now do high-fidelity sequencing on the entire human
genome at a cost that even projects that survive on grants can afford.
Note that the Y axis increases logarithmically (10, 100, 1,000, 10,000, etc.). What
looks like a small step on this graphs Y axis is actually a huge step forward:
The Illumina HighSeq X Ten sequencer has 10,000 times the throughput as the
Sequence Analyzer Illumina created just ten years before.
Figure 3.1: Improvements in gene sequencing with decreases in cost
We can look at the genetic code with more precision and accuracy than
ever before.
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This means we also need to consider how to deal with all the data we generate,
which has to be compiled, converted, and stored. We must then analyze the
results and balance any clinical advice or interpretation that we give.
This means that each stage of the genetic testing process is significant,
such as:
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collecting, transporting and storing a sample properly;

reading a sample correctly;
analyzing the sample;
storing the data; and
interpreting the data deciding what it all means, and what to do next.
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Generating so much data means that we have to think about where to put it,
how to understand it, and what to eventually do with it.
We can think about it in terms of bioinformatics combining technical domains

like computer science, statistics, mathematics, and engineering to analyze and
interpret the data weve collected.
We can also think of it in terms of behavior change and genetic counseling what
we might do with any data or insight we gain.
We have to be careful about making too many

assumptions about this process.
There is a lot that we dont yet know. A lot of things can go wrong with this
complex process. This affects the quality of the data we get, and the conclusions
that we can draw.
For example:
Many diseases or health conditions with a strong genetic basis are

rare or less common. Testing for these genetic variants may not apply
to most people.
Many diseases and health conditions are complex. There may be a genetic
contribution, but it may be from several interacting genes, or even regulatory
pathways that dont involve genes. And environmental or lifestyle choices
may affect the outcome more anyway.
Other outcomes, such as athletic performance, are also complex. For

instance, is there a sprinter gene? (Spoiler: No.) What if you have a certain
set of genes that give you muscularity and power, but not the set of genes
that give you the motivation to show up in the morning for a workout?
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Data are limited. There may not be a lot of research about a particular gene,
or its relationship to health and function.
We dont always know what to do about test results. In fact, research

suggests that just knowing whats in our DNA rarely changes our behavior.
The technologies for testing, analyzing, and interpreting genetic materials

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continue to evolve and change quickly.
Genetic testing services perhaps driven by commercial interests, or

patient advocacy groups are not always completely honest about what
their tests can and cannot do. They may market their products as more
useful or revealing than they really are.
To understand this better, lets look more closely at the process of genetic testing.
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What does clinical genetic testing
involve?
In general, clinical genetic tests:
analyze DNA for specific genetic variants (SNPs), that code for gene
products such as enzymes or other proteins;
look for variations that are related to disease or health (and, increasingly,
athletic capacity);
focus on a particular population (such as an ethnic group with a higher risk

of a specific hereditary disease); and
are aimed at producing information that patients can somehow use for
instance, to lower their risk of a disease, to choose the right medication, or
adjust their nutritional regime.
Some genetic tests (such as 23andMe) also include ancestry and ethnic
heritage. Well look at the importance of ancestry in Chapter 5.
An assay is a method for determining the presence or quantity of a particular

component, or a method to analyze or quantify a particular substance in a
sample.
A genetic test is a laboratory assay specifically for clinical testing. It identifies

specific genotype(s) to diagnose a specific disease in a specific group of people
for a specific purpose. Genetic testing is very targeted compared to a genetic
assay, which may be scanned, or may be targeted.
An open-ended assay looks for anything of interest, like scanning a landscape

to see what pops out.
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A closed assay identifies beforehand what its seeking, such as a particular
mutation or another variant.
Genetic tests might be used for:
disease diagnosis;
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health risk predictions;

carrier testing (in other words, if you carry a gene variant that isnt active in
you, but that you may pass along to your offspring);
prenatal testing, to identify particular conditions in fetuses;

newborn screening, done soon after birth to look for potential diseases;
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pharmacogenomic testing, to explore how you might respond to a particular
medication; or
research either for a specific purpose, or for general investigation.

Increasingly, some people are also exploring genetic testing for nutritional needs
and athletic performance.
For instance, genetic tests can currently help us explore such traits as:
how quickly you process caffeine;

how your body processes vitamin D;
how much inflammation youre likely to have (for instance, by testing for
C-reactive protein, a marker of inflammation);
how well you may recover from exercise; or

what your body weight range is more likely to be (for instance, whether you
are more likely to have a higher BMI).
Yet few of these are definitive or clear.
Test types
You might think that a genetic test would look at the entire genome, but this
is rarely the case. (Well talk more in upcoming chapters about studying entire
genomes, and why most commercially-available tests dont do it.)
Molecular genetic tests look at the smallest chunks of DNA perhaps a

single gene or short pieces of DNA usually looking for a specific variation
or mutation. An example of this might be testing for the cystic fibrosis variant
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or the BRCA1/2 mutations that are linked to breast and ovarian cancers.
Chromosomal genetic tests look at longer pieces of DNA, such as whole

chromosomes, to look for larger-scale genetic changes (such as an extra
chromosome copy). An example of this might be testing for Down syndrome.
Biochemical tests look at how much of a certain protein we have, or how

active that protein is. Here, the test doesnt look at the DNA, but rather the
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protein that it might be coding for. By looking at differences in the proteins,

testers can speculate about genetic variations. An example of this might be a
c-reactive protein (CRP) immunoassay; CRP is a protein marker of inflammation.
Genetic sequencing involves reading a strand of DNA by looking at its

nucleotides, one by one. The first sequencing of a full genetic code was
done on a simple virus (known as Phi X 174) in 1977; the human genome
sequence (or at least, 90% of it) was published in 2001. A test that reads the
entire genome is known as whole-genome sequencing.
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Again, commercial tests dont usually sequence entire genomes.
In fact, usually the opposite is true: Most commercially available genetic tests
examine single-nucleotide polymorphisms (SNPs), a variation in a single
nucleotide (e.g., having a cytosine, or C, where theres normally an adenine, or
A). Youll remember from Chapter 2 that small substitutions like this are one way
that we can get genetic variation.
SNPs and noncoding DNA

The testing service 23andMes genotyping test covers about 600,000 SNPs
of the potentially 3 billion SNPs that each person has or just 0.02% of the
genome. Even the most comprehensive genotyping services covers less than
0.15% of the genome.
Of those SNPs, 98.6% are in noncoding DNA, which means they are stretches
of DNA that arent transcribed into mRNA to make proteins. (This is what people
used to call junk DNA until they realized that it wasnt junk. Sure, some of it
includes leftover odds and ends from our evolutionary history, but a lot of it has
a purpose.)
Noncoding DNA includes a lot of different things. Much like after family get-
togethers when you end up with lots of leftovers and macaroni-salad-encrusted
Tupperware, our genome contains lots of leftover bits from millions of years of
our evolutionary process.
For instance, we have:
Pseudogenes: genes that used to be active but arent any more.

Proviruses: There is a class of viruses, known as retroviruses, that transcribe
their genome and insert it into the genome of the cells they infect. This
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genetic material is known as a provirus. HIV is probably the best-known
example of a retrovirus, but there are many others. Because the process by
which this happens (known as reverse transcription) is relatively unstable
and prone to error, many of these retroviral sequences are inactive.
Inactivated retroviral sequences make up a surprisingly large proportion of
our genome about 10%.
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Regulatory sequences: parts of DNA that act like a volume knob on gene
expression: They can turn it up (increase the genetic expression of a

certain protein), turn it down (decrease expression), or even turn it off
completely (prevent expression).
So, genetic testing services may test for functional SNPs, or they may test for
SNPs found in noncoding regions.
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On one hand, we can get a lot of useful information from SNPs, such as
predictions about our ancestry, or well-known associations with certain heritable
traits or diseases.
On the other hand, using SNPs depends on having known associations, or

identifying regions and points of common variation. We must already have
identified and interpreted these SNPs where they are, how common they are,
and sometimes what they do, to what degree, and in which population. This is
much like only getting information from books youve already read.
We also cant see copy number variation (again, how many copies of a particular
DNA sequence you have) nor translocation mutations (where a gene moves
from one chromosome to another, or from one part of a chromosome to another).
Both of these can affect our phenotype, but simply knowing SNP markers wont
tell us anything about their effects.
Thus, there are tradeoffs.
Genome-wide association studies (GWAS)

While commercial tests rarely look at whole genomes, laboratory research that is
looking for the relationship between particular gene variants and outcomes such
as health problems or biological processes might do genome-wide association
studies (GWAS).
With most GWAS, participants are usually picked based on some characteristic
that they share, such as having high blood pressure or osteoporosis. They are
then compared to a control group without that characteristic to see if the test
group shares any genetic variants, or somehow differs from the control group.
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Figure 3.2: Sample genome-wide association study model

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A GWAS is usually a broad scan.
Sometimes researchers are looking to confirm that Gene Variant X is,

indeed, significant.
Or maybe theyre looking to find novel loci in other words, new SNPs or
other variants such as haplotypes (which well look at in Chapter 5) that are
associated with the characteristic.
Theyre also looking to see whether the SNPs have predictive value: In
other words, does having this SNP make it significantly more or less likely
that you will have a certain trait or other outcome? Or is the relationship
between the SNP and the outcome just kinda random?
Often, the data that commercial genetic testing services use to look for certain
SNPs come from laboratory GWAS that have already identified those SNPs
as significant.
Commercial direct-to-consumer testing vs.

experimental lab testing
While we can now access many of the same scientific methods and tools that
researchers might use in high-end experimental labs, there are a few key
differences between them.
Partial vs. full-genome testing
At the time of writing this book, no one currently offers a commercial full-
genome testing service. (However, we did get our co-author Alainas genome
sequenced in a private lab. More on that later.)
Right now, whole-genome sequencing is expensive. However, as the price drops
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and researchers make discoveries about the intricacies of the human genome,
whole-genome sequencing will probably become more and more common.
Eventually your whole-genome sequence will just be a normal part of your
medical records.
It may seem like a commercial test is only offering you a half-assed version of a
real full-genome test, but when you know what parts of the genome you need
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to look at, theres no reason to sequence the entire genome.

Its faster, cheaper, and easier to look at only the regions of interest, so you
arent looking for a needle in a haystack. Instead, you already know where the
needle is; you just need to know how long it is.
The only challenge is that research hasnt uncovered all the different
relationships between our genes and our genetic expression. The scientific
community has only scratched the surface.
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So:
Commercially available testing services can tell us things about ourselves

based on what research knows today. Thats great if were looking for a
specific, well-researched genetic factor and belong to a population thats
been extensively studied.
These services are really only telling us a small fraction of all there is to
know about ourselves. Thats challenging if were looking for the best way
to eat, or exercise, or live to 120.
What is the process of genetic

testing?
Although there are various types of genetic tests, heres a general overview of
how most of them work.
Step 1: Collect a sample.

First, the test requires some type of sample material to analyze. In theory, this
can be any type of biological material, but is most often:
blood (though red blood cells would have to be removed);

buccal cells (aka a swab of skin cells from the inside of the cheek);
amniotic fluid (the fluid that surrounds a fetus in the womb); or
hair (specifically, the cells from the follicle).
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Criminal investigations using DNA as evidence may also use discarded DNA,
such as material left behind on coffee cups, straws, or cigarette butts.
Step 2: Prepare the sample.

Once the sample is collected and sent to the lab for analysis, we have to
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somehow get the DNA out of its container, the cell, and read it.
Step 2A: Get stuff out of cells.

This means that first, the cells have to be ruptured, a process known as lysing
(from the ancient Greek lusis, or loosening).
Because cell walls are lipid-based, we have to use some kind of surfactant or
detergent, much like dunking the cells in dish soap.
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Some processes may also use a base such as sodium hydroxide (NaOH) along
with the surfactant sodium dodecyl (lauryl) sulfate (SDS). (The combination of
a base like NaOH and a surfactant is known as alkaline lysis, and it was first
described in 1979 as a way to get DNA out of bacteria.)
Once the DNA is out of the cell, testers break up proteins using proteases
(protein-degrading enzymes) and break up RNA by using RNases (same idea).
Without this step, the sample can degrade rapidly and cause sampling errors.
Luckily, DNA is remarkably stable outside of the cell, much more than RNA or
protein. This is why we can do DNA matching days or even years after a sample
has been left. In fact, ancient DNA can be extracted and analyzed from samples
thousands of years old.
Step 2B: Separate the solution to get what

you want.
Now that youve got a solution of cell crud, add a concentrated salt solution to
make all the bits and chunks clump together.
You need to pick apart the crud from the DNA, so the next step is centrifuging,
which spins the mix in a wheel to separate things out (much like that spinning
wheel ride at the county fair that separates you from your stomach contents).
Solid chunks are flung to the bottom of the test sample tube, and the DNA is left
behind, dissolved in the solution.
Next, you want to tidy and purify the DNA from all the stuff you used to get it out
of the cell. Do one of the following:
Use ethanol (the same alcohol as in your martini) or isopropanol (aka rubbing
alcohol, definitely not in your martini) to come out of the solution (precipitate
it). DNA wont dissolve in this, so it clumps when you centrifuge it. If this
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clump is clear its pure DNA. If theres still some non-DNA, the clump is
white.
Use phenol-chloroform: Denature proteins with phenol; whisk nucleic acids

away with chloroform. This works sort of like making a salad dressing with oil
and vinegar.
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Use something solid, like silica, to which nucleic acids will bind. This works
sort of like dumping sawdust on spilt liquid. Most labs that have money use
silica bound to a membrane. This is faster and it gives us clean DNA.
Use a protease to break up and cleave off cellular and histone proteins
bound to the DNA.
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Step 2C: Amplify the DNA.
Lets say youre trying to listen to music, but youre somewhere with lots of
background noise. So what do you do? You turn up your music in other words,
you amplify it.
The same thing happens in DNA analysis you often have to amplify it and
make a lot more copies of the strand of DNA in order to make sure you get
a good signal to test. This is most often done using the polymerase chain
reaction process, or PCR.
The upside of this process is that after several rounds of amplification, you have
a nice big sample more DNA than you know what to do with. The downside is
that if theres contamination, thats amplified too.
In tightly-controlled experimental studies, researchers control for contamination.

The same may not be true of commercial tests.
Fun factoid!
Legend has it that the inventor of PCR, the Nobel Prize-winning American biochemist
Karey Mullis, got the idea for PCR while on an acid trip in 1983.
Also, he believes he was visited by an extraterrestrial bioluminescent raccoon and

denies anthropogenic climate change.
Goes to show that winning a Nobel Prize and transforming molecular biology doesnt
mean you arent also a crackpot.
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Step 3: Analysis
Once you have a nice big pile of DNA, you can start to read (i.e., sequence)
and analyze it.
Reading DNA isnt as simple as reading a book from start to finish. Its more
like this:
Take a book.
Open the book to a randomly-chosen page.
Start reading at a randomly-chosen word.
Read a few letters, or a word, or a phrase. Maybe a sentence.
Close the book.
Open the book to another randomly-chosen page.
Read a few more randomly-chosen bits.
And so on.
Do that about a zillion times until you understand what the book says.
In real-life terms, that means that sequencing creates a bunch of data that need
to be put together into an order that makes sense. We do this with complex
computing methods and algorithms, using bioinformatics techniques to identify,
understand, and analyze the raw data.
Step 4: Interpretation
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Finally, once you have your data, and its been read and analyzed, you can
decide what your findings mean. For example, did your sample have the variant
youre looking for?
What do you need to know about

this process?
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Obviously, you could write a Ph.D. thesis on a single aspect of genetic testing
alone.
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But here are a few key points:
There are several types of tests, depending on what you want to find.
Different tests use and look for different amounts of genetic material.
There are several methods for testing.
There are several steps in the process, each with the potential for variation
or mistakes.
Its complicated.
How do you know if genetic testing

is useful or valuable?
Why test?
Defining useful, beneficial, or valuable depends a lot on what we are
seeking from a genetic test.
For instance:
A researcher may be interested in the test methods themselves, and how

they advance basic science.
A computational biologist may be interested in new forms of data analysis.

A clinician may want to explore associations between particular genetic
variants and disease risk.
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A family doctor may want to know how to advise their patients about
medications, family planning, or lifestyle choices.
A genealogist may be curious about ancestry.

An evolutionary anthropologist may want to know about interesting
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features of specific populations, their origins, or how a trait spread across a

population.
A sports scientist may want to know how to select or train athletes for
optimal performance.
A family lawyer settling a patrimony case (or a sleazy TV talk show host
doing an OMG! Whos Your Baby Daddy?! episode) may want to know
which kids are the genetic offspring of a particular parent.
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For many people, genetic testing is a way to explore their risk of disease
or health conditions. Yet there is much we still dont know about genetic
contributions to disease, and how we might use information about our DNA to
either treat specific diseases, or improve our odds of staying healthy and fit.
In general, one definition of a genetic test is

that it has a purpose.
Researchers are trying to find something, even if they arent always exactly sure
what. And there is some reason for them to look, such as advising people about
reproduction or disease risk.
A cautionary tale about the science of testing

In 2006, some scientists published their findings about a method for how to use
gene expression profiles to personalize chemotherapy and other cancer drug
regimes.
When a second group of scientists tried to replicate these findings, they found
that, as they said, poor documentation hid many simple errors that undermined
the approach. This is a polite sciencey way of saying that the first team might
have fibbed a bit.
However, these problematic profiles were used anyway to direct patient therapy
in clinical trials at Duke University in 2007. When the second group of scientists
protested the poor science, trials were suspended in 2009, then re-started, and
then finally ended in 2010.
The original 2006 study was retracted.
The initial exploration held exciting promise: What if cancer patients could have
their treatment individualized, based on their genetic profile?
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Yet the scientific reality did not hold up under scrutiny.
That isnt to say that this couldnt happen one day. It very likely could.
The point is that the science is young, and all results must be reproduced
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reliably before we can have confidence in them, or use them to guide our
decisions.
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Establishing guidelines for genetic
testing
The researchers who protested the Duke study suggested that all genetic tests
share the following:
the raw data, such as the reads produced by a sequencer; the called
genotyping data in the file you can download from 23andMe; or the images
taken of gels;
Figure 3.3: A sample gel that Alaina ran in her lab
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the code used to derive the results from the raw data (in other words, how
software and algorithms computed and analyzed the findings);
evidence of the origin of the raw data so that labels could be checked;
written descriptions of all the steps in the analysis; and
how the researchers planned to run the analysis.
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Originally, these were meant as guidelines for researchers who wanted to

publish their work in scientific journals, but the scientists also suggested that
anyone starting a clinical trial that used genetic data to guide treatment should
meet these requirements.
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In 2004, the Centers for Disease Control and Prevention in the United States
established the Evaluation of Genomic Applications in Practice and Prevention
(EGAPP) initiative to establish and test a systematic, evidence-based process
for evaluating genetic tests and other applications of genomic technology that
are in transition from research to clinical and public health practice.
The EGAPP wanted to have a broad perspective on genetic testing. The groups
founding members included experts in:
evidence-based review;
clinical practice;
developing clinical guidelines;
public health;
laboratory methods;
genomics;
epidemiology;
economics;
ethics;
policy; and
health technology assessment.
EGAPP aimed to help healthcare practitioners and their patients understand
some of the results of genetic tests.
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After reviewing many genetic tests, they concluded that:
Only a few had enough evidence to be considered clinically useful.

Many simply did not have enough evidence yet to help patients and their
doctors make decisions about health risks and treatment.
In 2010, the United States Institute of Medicines (IOM) Review of Omics-Based

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Tests for Predicting Patient Outcomes in Clinical Trials met to discuss the
challenges of genetic testing.
The group concluded, based on reviewing how genetic testing was being used,
that problems were more widespread and severe than we knew.
For instance, many tests could not be reproduced accurately; many clinical trials
based on genetic data were called into question. Along with more complex
problems like statistical analysis, researchers were making basic mistakes like
mislabelling data.
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Clearly, a better system for scientific rigor was
needed.
This reminds us to always be critical and careful of grandiose claims for
genetic testing.
Genetic testing holds exciting promise, and may help us make incredible
breakthroughs in human understanding.
This promise must be tempered by thoughtful and careful review.
How can you decide whether a

genetic test makes sense?
If youre not a scientist, it can be hard to figure out whether a particular genetic
test is helpful.
Here are two ways to think about the answer: a simple 4-question rubric from us,
and a more complex checklist from the ACCE.
Keeping it simple: 4 questions to ask about

genetic testing
Is this particular test:
1 | Descriptive: Does it tell me something about the person being tested?
2 | Diagnostic: Does it allow me (or a medical professional) to diagnose a

problem or characteristic?
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3 | Predictive: Does it allow me to predict some future challenge or
occurrence, such as a disease or health risk later in life?
4 | Prescriptive: Does it tell me what to do next, or in the future?
More complex: ACCE criteria for disease-related

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genetic testing
If you want to think more deeply about how good or useful a genetic test is, you
can use the framework proposed by the ACCE (established by the Centers for
Disease Control and Prevention in the United States).
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ACCE takes its name from the four criteria for judging the value of a given
genetic test:
Analytical validity:
How accurately does a given test detect a gene variant or mutation?
How reliable and repeatable is a given test?
Are test results lab significant or real world significant? In other
words, if we find anything, does it mean anything?
Clinical validity:
What evidence supports the relationship between particular gene
variants and risk of disease?
Which variants in particular are important?

How great are those risks?
How have those risks been estimated?
Clinical utility:
How useful are these findings for making informed judgments about
ones health and medical treatment?
What should healthcare practitioners and patients do about genetic

test results?
Ethical, social, and legal issues:

How might privacy, social wellbeing, or legal status be affected by the
results of a genetic test?
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Are patients informed of all their rights and obligations beforehand?
Would prenatal screening be considered appropriate?
Who has access to these tests?
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To help explore these questions, the ACCE has produced a checklist that
can help evaluate particular genetic tests, especially those aimed at finding
relationships between gene variants and disease risk.
The ACCE checklist

1 | Test purpose and context
a | What is the specific clinical disorder to be studied?
b | What are the clinical findings defining this disorder? (In other words, what
does the existing clinical evidence tell us about diagnosing this disorder,
and its specific features?)
c | What is the clinical setting in which the test is to be performed?
d | What DNA test(s) are associated with this disorder?
e | Does this test include preliminary screening questions? For instance,

does the test also ask about family history, or look at overall medical
and lifestyle factors?
f | Is it a stand-alone test or is it one of a series of tests?
g | If this test is part of a series, are all tests done at once, or are some tests
done based on the results of previous tests? (e.g., if Test A finds something,
then do Test B?)
2 | Analytic validity
a | Is the test qualitative or quantitative? For instance, is it based on something

self-reported or subjective, or on something numeric or objectively
measurable?
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b | How sensitive is the test analysis? How often is the test positive when a
specific mutation is present?
c | How specific is the test analysis? How often is the test negative when a
specific mutation is not present?
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d | Is the test method regularly monitored and evaluated for quality control by
an external body? In other words, who and what tests the test?
e | Have repeated measurements been made on specimens?
f | What is the within- and between-laboratory precision? In other words, if

the same lab were to run the tests twice, or different labs were to repeat
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the tests, how close would the test results be? (Well look at this more in an
upcoming section, when we look at what we found with sending samples to
different labs.)
g | If appropriate, how is confirmatory testing performed to resolve false

positive results in a timely manner?
h | What range of patient specimens have been tested?
i | How often does the test give a useable result? Or fail to do so?
j | How similar are results obtained in multiple laboratories using the same,
or different technology?
3 | Clinical validity
a | How sensitive is the test for clinical purposes? How often is the test positive
when a specific disorder is present?
b | How specific is the test for clinical purposes? How often is the test negative
when a specific disorder is not present?
c | Are there ways to resolve clinical false positives quickly?
d | How often is this disorder found using this method?
e | Has the test been adequately validated on all populations to which it may
be offered?
f | How many false positives or negatives does the test produce?
g | What are the genotype/phenotype relationships? In other words, does a

genetic variant actually do anything noticeable? Can we see or measure that
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impact? If theres a gene for a trait, does that trait show up a little, a lot, or not
at all?
h | What are the genetic, environmental or other modifiers? In other words,

how significant is the role of the genetic component compared to other
factors, such as lifestyle choices? |
4 | Clinical utility
a | How does the disease normally progress? Can we actually intervene in that
process?
b | How will the test results affect patient care?
c | Are there other diagnostic tests available to confirm the results?

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d | What can be done about these results, if anything? For instance, are there
medications, actions, or some other measurable benefit to knowing these
genetic test results?
e | If the patient can do something about the results, can they access that?
For instance, can they get the medication that may help them, or make any
applicable lifestyle changes?
f | Is the test being offered to a socially vulnerable population?
g | What quality assurance measures are in place?
h | What are the results of pilot trials for these specific conditions or diseases?
i | Are there known health risks that benefit from follow-up

testing / intervention?
j | Is testing affordable?
k | Are there service providers able to help people understand or take action
with the test results?
l | Are there evidence-based educational materials that can help patients

understand their results?
m | Are there informed consent requirements?
n | Are there methods for long term monitoring?
o | How well does this program work over the long term, and how do we
know?
5 | Ethical, social, and legal issues
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a | When it comes to this particular test, do we need to think about:
1 | social stigmatization;
2 | discrimination;
3 | privacy/confidentiality; and/or
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4 | personal/family social issues?
b | Are there legal issues regarding consent, ownership of data and/or

samples, patents, licensing, proprietary testing, obligation to disclose, or
reporting requirements?
c | What safeguards are in place to protect participants?

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Other questions to ask about
genetic testing
Genetic testing isnt just about the science or clinical use. There are other factors
to think about as well.
How strong or compelling are these results?

Can these results be replicated reliably? (Well look at this in an upcoming
chapter.)
Are these results a for sure, a maybe, or I dunno?
How high is the risk or probability of a particular outcome? Do you have a 0.5%
higher chance of something? 5%? 50%?
What happens if you find a gene variant, but dont know what it does? Or dont
have any evidence-based strategies for what to do next?
How do these results matter in context?

Are you just a hobbyist who is curious about whats in your DNA?
Are you someone whos looking to start a family, and wondering what you might
pass along to a child?
Are you someone with a family history of a particular disease, and looking to
explore your risk for that disease?
Are you curious about your ethnic ancestry?
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Speaking of that
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Do these results align with your genetic and
ethnic ancestry?
What group was the genetic research done on?
If youre ethnically Hmong from Vietnam, or Quechua from Peru, how applicable
are genetic studies done (for example) on British Europeans?
What environmental factors could affect these

results?
For instance, does a gene you carry only turn on if youre exposed to cigarette
smoke, or sunshine, or shift work?
What legal and regulatory factors are involved?

Each jurisdiction may have different rules about what can be tested and shared.
Who can access your genetic information, and for what purpose? For instance,
can insurance companies review your genetic test results before deciding to
insure you? What about employers, before hiring you?
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Where are you protected from genetic
discrimination?
Different regions have different legislation and regulation of genetic testing.
In March 2017, Canada passed Bill S-201, the Genetic Non-Discrimination Act.
The Act prevents people being pressured to undergo genetic testing in order to be
eligible for goods or services (such as insurance); or from having to disclose their
results.
It prohibits employers from discriminating against workers on the basis of any genetic
test results. It also amends the Canadian Human Rights Act to prohibit discrimination
based on genetic characteristics.
The Canadian Coalition for Genetic Fairness is made up of several advocacy groups,
such as the Parkinson Society of Canada or Muscular Dystrophy Canada. They also
promote genetic nondiscrimination.
In the United States, the Genetic Information Nondiscrimination Act of 2008 (GINA)
prohibits discrimination based on genetic information in health insurance and
employment. Health insurance companies are not allowed to deny coverage to
healthy people based solely on potential genetic risk, nor are employers allowed to
discriminate based on genetic data.
In the UK, the 2010 Equality Act prevents employers from discriminating based on
genetic data.
In the European Union countries, the 2010 Lisbon Treaty prohibits discrimination based
on genetic features.
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The United Nations Educational, Scientific and Cultural Organization (UNESCO)
adopted the Universal Declaration on the Human Genome and Human Rights in
2003 and International Declaration on Human Genetic Data in 2012, which includes
provisions for preventing genetic discrimination and any use of genetic information that
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What behavioral factors are involved?
Once you get your test results, what could you do? What should you do?
What are you willing to change, or not change?
Who can help you understand all the information?
What moral and ethical questions are involved?

Are you fully informed about the test, and what it involves, before you do it (a.k.a.
informed consent)?
Are you obligated to do anything once you know your results?
For instance, if youre young enough and considering having a family, should the
results of genetic testing change your choice to reproduce?
What if you discover some awkward truths about your genetic heritage or
parentage?
Can, and should, we patent genes?
Fun factoid!
In one key case (Association for Molecular Pathology v. Myriad Genetics, No.
12-398 [569 U.S.June 13, 2013]), Judge Robert Sweet found that the claims on DNA
molecules were invalid because DNA represents the physical embodiment of
biological information, distinct in its essential characteristics from any other chemical
found in nature.
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We wont always have the right answers to
any of these questions.
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But we should be asking them.

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Whats up next: Exploring specific
tests
In this chapter, weve given you a broad background to consider.
In the next chapter, well look at specific types of tests, and what we discovered
about them with our own testing practices.
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CHAPTER 2 CHAPTER 4
The basics of genetics Specific genetic
testing services
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An overview of how genetics works,

and an introduction to some of the What should you think about when
key ideas youll need to understand considering particular genetic
genetic testing and its implications. testing services? Which services
did we choose, and why?
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CHAPTER 4
Specific genetic testing services

What types of tests are available commercially?

How scientifically credible are they?
How well-replicated are they? (In other words, are they the same from lab
to lab?)
Why did we choose particular tests?

What does this mean for you as a consumer?
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But first:
Here are some things to keep in mind.

Some quick refreshers and reminders:
One gene can affect many outcomes and processes.

Its not usually a simple one-to-one ratio where Gene X completely controls
Process Y.
Many links between specific genes or SNPs are only associations,

not causes.
We cant say right now that having a certain genetic variation necessarily makes
something happen.
We can only say that in this particular population studied, we can see that there
is maybe something happening with a particular gene or SNP. Thats all.
Genes are not destiny.

Outside of some highly genetically determined diseases (such as Huntingtons
disease, cystic fibrosis or Down syndrome), we can, to some degree, affect the
outcome of our biological programming.
Even if one particular gene determines 70% of an outcome (which is a lot,

relatively speaking), we may be able to affect the other 30%. Many genes and
SNPs well look at have much less of a role.
Were usually talking about possibilities and probabilities.

Youll see words like maybe, could be, sometimes, risk, percentages, odds, likely.
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Rarely can we know for sure that something will happen or even what that
something is. This might be disconcerting and hard to understand, so celebrate
this feeling of ambiguity. It runs throughout biology.
The research is new, often un-reproduced, and unreplicated.

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We cant say for sure based on a single study of fifty people of Finnish, Fijian, or
Filipino descent whether that study has any relevance to you even if youre
Finnish, Fijian, or Filipino too.
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4 questions to ask about genetic
testing
We also suggest you review our 4 simple questions to ask about genetic testing:
Is a particular test:


Keep these points and questions in mind as you read through this chapter, and
the rest of the book.
Genetic testing services: Whats

available?
There are many genetic testing services available, which have different
purposes, such as:
specific disease risks (such as cancer);
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carrier status (in other words, whether youre carrying something that you
may not want to pass on to your offspring);
ancestry and migration patterns;

paternity and relatives (e.g., whether two people are related, or screening for
donor tissue matches);
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specific traits;
newborn health;
drug response; or
individualized health, nutrition, and fitness recommendations.
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A study of 246 direct-to-consumer genetic testing services found that while
nutrigenetic tests were popular, the pressing question of What should I eat?
was outweighed by Is my kid mine? Some genetic testing services even
offered a discreet surreptitious option, as in, Steal a few bits of someones
body and send it to us; well tell you whether youre about to have an awkward
family conversation.
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Figure 4.1: Specific reasons for testing as a percentage of all commercial services offered
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A health, nutrition, and fitness focus
Of course, were interested in general health, nutrition, and fitness or athletic
performance, so thats where we focused our attention.
We looked for services that tested genetic markers known to be related to

particular traits, such as:
Metabolism
Blood sugar and insulin

Blood lipids and lipoproteins (HDL, LDL, etc.)
Resting metabolism
Other factors (such as thyroid health) that can affect metabolism
Body weight, size, and fatness (or leanness)
Food and nutrition
Taste preferences and sensitivity

Food intolerances
Nutrient processing (e.g., vitamins, salt, caffeine)
Exercise and athletics
Sprint-type vs endurance-type muscle fibers

Muscle performance
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Response to exercise
Recovery from exercise
Well cover these in more detail in upcoming chapters.
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What else were we looking for?
Along with a focus on general health, nutrition, and fitness, we looked for
services that fulfilled a few other criteria:
Scientific credibility
What claims were the companies making?
Research on direct-to-consumer tests has shown that many companies are

making claims about their data that are not supported by scientific evidence.
For instance, they may claim to be able:
to exactly predict your athletic talent (or your childs);

to tell you exactly what you should eat;
to tell you exactly how you should exercise; or
to tell you exactly what choices you are likely to make (for instance, whether
youre likely to give in to sugar cravings).
Unfortunately, none of these claims are true. (Yet.)
A 2015 article in the British Medical Journal examined 39 direct-to-consumer

testing services, and found that:
Over half (21 of the 39) companies didnt actually identify the specific DNA
sequence variants they tested.
Of the 18 companies that did identify what genetic markers they used:
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16 of 18 tested the ACTN3 R577X polymorphism (which well look at in
Chapter 10).
11 of 18 tested for the angiotensin I converting enzyme 1 (ACE) I/D

polymorphism.
Though ACTN3 and ACE polymorphisms are promising areas of

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research, they havent yet been conclusively shown to make a major

difference in strength, muscularity, or athletic performance certainly
not compared to environmental influences like training.
The number of variants tested overall was small. Most companies tested
around 6. Some tested only 1, others up to 27.
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When we consider that we have 3 billion base pairs of DNA, you can imagine
that this is still a pretty small sample for drawing potentially big conclusions.
Another large-scale meta-analysis study reviewed research from nearly 1,200

studies on 38 genes tested by nutrigenomics companies.
They concluded that:
Most studies couldnt predict any useful relationship between particular

genes of interest.
When there seemed to be a link, the studies or sample sizes were too
small to make broad recommendations.
Finally, what about the data used by genetic testing itself?
What if, for instance, a particular study finds an association between SNP X and
Nutrient Intake Y but the study is based on something like peoples recall of
what they ate a method known to be often so inaccurate that its potentially
useless? If a genetic testing service bases their interpretation on this study,
theres a chance that they might not be making valid scientific claims.
This doesnt mean, obviously, that nutrigenomics or other related types of

genetic testing services are useless.
Even the skeptical meta-analysis authors called genetic testing a highly

promising tool for precision medicine.
We just need to understand what claims are substantiated, and which ones
arent. (Yet.)
So we looked for genetic testing services whose claims:
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were supported by the most current scientific evidence;
were reasonable, relatively conservative, and realistic; and
included a discussion of both limitations and advantages of their testing
methods and findings.
Quality control
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What processes did each lab follow?
To ensure that high-quality, standardized scientific practices are followed, most

countries somehow regulate laboratory testing.
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This includes ensuring:
technical personnel are competent and qualified;

experimental processes are recognized as legitimate and correct;
equipment is calibrated and accurate; and
laboratories are impartial and independent.
For instance:
In the United States, all labs that test human specimens for health
assessment or to diagnose, prevent, or treat disease must abide by federal
Clinical Laboratory Improvement Amendments (CLIA) regulations.
In Canada, the Standards Council of Canada gives accreditation to labs that

meet International Standards Organization (ISO) requirements for medical
labs and analysis.
The International Laboratory Accreditation Cooperation is an umbrella

organization that covers other international lab certifying bodies such as EA
in the European Union, APLAC in Asia-Pacific countries, IAAC in the Americas,
AFRAC in Africa, SADCA in Southern Africa, and ARAC in the Arab region.
So we looked for genetic testing services:
who had a legitimate scientific staff;

that use certified/accredited labs, or operate certified labs themselves; and
who were involved in or had produced peer-reviewed research.
Reliability
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If we sent the same sample to two different labs, would they come up with
similar results?
Professional laboratories produce extremely reliable results over 99.9%

accuracy. They are also heavily scrutinized and monitored by industry and
scientific agencies, whereas commercial labs are not.
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We wanted to do our own review of the commercial services we used. So we

checked:
Would the same samples sent to different commercial labs come back
with similar results?
If we sent two of the same sample to the same lab, would we get the
same results?
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The answers: Yes, and yes. The results we got were a match with over 99.9%
accuracy.
Our experience closely matches other studies that compared the largest direct-
to-consumer testing services (such as 23andMe, deCODE, and the now-defunct
Navigenics) to one another, and found that lab-to-lab correlation (in other words,
how closely each labs results matched the others) was 99.6 to 99.7%, though
accuracy did vary somewhat for specific SNPs or disease risks.
In particular, predictions were less reliable when labs used genetic markers with
only weak associations (such as, Well, in some people, some of the time, given
some environmental conditions, this SNP may be linked to a 0.1% higher chance
of X).
Predictions were more reliable with strong associations, like Yep, you have
OCTFN1, the gene that always gives people octopus fingers 100% of the time.
Fun factoid!
Octopus finger is not a thing. Do not be alarmed.
Also, do not hate on octopodes, who are simply differently digitized.
So we looked for genetic testing services:
whose results were reliable and repeatable; and

who distinguished between stronger and weaker genetic markers and
associations.
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Vested interests
Are the testing services selling something else?
In many cases, genetic testing services may offer extended services (such
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as an app, individualized meal planning or tracking of other indicators like

physiological performance) that actually have nothing to do with genetic data.
These other services may indeed be helpful, but that help didnt actually come
from knowing your genetic information.
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For instance, while tracking your sleep habits or food intake is very useful and
can help you make some important decisions, that useful data is not based
on your sleep DNA or menu DNA. Its just plain old daily-life observation
that anyone can do. (Back in the old days, we just called that kind of careful
observation and outcome-based decision making coaching. Harrumph.)
Other services may sell supplements once they have determined your genetic
requirement for extra vitamins, minerals, antioxidants, etc. At the time of writing,
there are very, very few known, evidence-based, genetic requirements for
specific supplements. (You may benefit from supplements for other reasons, but
likely not because of any particular SNP that you have.)
So we looked for genetic testing services that:
were primarily testing, analysis, and/or interpretation services; and

did not sell additional products, unless those products and services were
clearly relevant to the genetic data (such as genetic counseling).
Testing methods and technologies

How were the samples tested and analyzed?
There are several technologies and methods that can be used for
genetic testing.
SNP genotyping arrays are fast and cheap. They look at a series of
predetermined locations on the genome (usually hundreds of thousands to
millions) to look for SNP variations. SNP genotyping works well if you know
which SNPs you are looking for, or want to search for novel associations
among well-known regions. Its less useful when the variations are not
SNPs, or when you are looking for variations that arent well characterized
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or understood.
Sequencing is building a list of actual nucleotides, in order. While a

SNP array might be able to tell you if you have a nucleotide at a certain
position, sequencing can tell you the actual genetic code around that
position. SNPs can tell you whether its A or T; sequencing can tell
you that its AACCTAATTAGA or TACCTAATTAGA, or even that its
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AACCTACTACTAATTAGA. An intrepid researcher can still do sequencing

by hand, but it is a tedious and laborious process, sweated over by

graduate students and postdocs toiling in the basement. These days, most
sequencing is done by high-throughput machines that perform the chemical
processes of sequencing, automated signal processing to transform
chemical information to digital and computers to turn the vast amounts
of raw data into usable information.
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Exome sequencing provides the genetic code for the exome (every part
of the genome that codes for a part of a protein), which is about 1% of
the total human genome. If researchers are specifically interested in the
protein-coding regions of the genome, exome sequencing gives the most
accurate and cost-effective data. It doesnt include the DNA regions outside
of exomes, which have important regulatory features.
Whole-genome sequencing can give researchers a view of the entire

genome. The entire genome is sequenced, regardless of whether a given
DNA region codes for a gene, provides a regulatory function, or just
happens to be a retroviral genome that lodged itself in one of our ancestors
and got cozy.
If researchers need a detailed, accurate view of a specific set of targeted

stretches of DNA, they might use amplicon sequencing.
In this technique, technicians use the polymerase chain reaction (PCR) to

make billions and billions of copies of a previously-identified stretch of DNA,
and sequence these copies (known as amplicons). Sequencing PCR products
gives a very high-fidelity view of the genetic code, but is of very limited use if
researchers dont know what they are looking for.
There are other preparation techniques that allow researchers to target specific
functions or regions of DNA.
For example, chromatin immunoprecipitation (ChIP) targets DNA-binding

proteins so you are only sequencing regions of DNA that are bound
to chromatin.
All sequencing technologies will have some bias and error. Biology and
chemistry are inherently chaotic processes, so nothing is perfect.
But of course, we want to get as close as possible to that magical 100%
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accuracy.
explained their process and method, including what they tested and how;
and
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used testing methods (such as the Illumina chip) that are widely accepted as
industry standards.
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Analysis and interpretation
How valid is the analysis, and how useful is the interpretation of the results?
An analysis that says, Here is a specific SNP that you have, heres what we
know about it, and heres what it might say about you if youre from X Population,
but were not totally sure just yet so check back in 10 years is probably accurate.
An analysis that says, BEHOLD YOUR GENES!! BROCCOLI IS DEAD TO YOU

NOW!! Hmm, maybe not so valid.
offered cautious, careful, conservative analyses and presentation of findings;

and
supported those findings with specific citations of peer-reviewed studies.
Risks and probabilities in context

How well does the test explain absolute and relative risk?
As we learned in the last chapter, biology is probability.
Probability is almost never perfection. Risks are possibilities, not destinies.
Thus, we want genetic testing services that give us our test results in context.
If we have, for example, a 1.5 higher lifetime risk of Disease X, what does that
really mean?
We have to know:
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what lifetime risk means: Will we likely get this disease at age 20? 50? 99?
how prevalent this disease is in our population: Is it a serious health threat,
or a rare condition?
what other factors besides this genetic variant are involved: Can we escape
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Disease X by doing Behavior Y? For instance, if we have a higher genetic

risk of lung cancer, can we avoid that cancer by not smoking?
Lets say theres a disease known as Crepitus Umbilicus.
Its terrible, really; peoples bellybuttons spontaneously explode and shoot

through their spine. Its an awful way to go out it happened to your dad while
he was peacefully watching a hockey game on TV one day.
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So youre worried: Will your bellybutton explode too?
You get genetic testing to see if you carry the deadly CRUMB gene variant.
Now lets say that Crepitus Umbilicus affects, for example, 50% of the
population. Thats the absolute risk in other words, everyones risk all lumped
together. That means 1 in 2 people will likely, at some point, die by exploding
bellybutton.
Lets say you have a 1.5 higher chance of getting that disease. Thats your
relative risk in other words, how your particular probability stacks up against
everyone else.
You might also want to know your odds ratio, which is the relationship between
an exposure and an outcome. An odds ratio (OR) tells you how likely it is that
Outcome X will happen if youre exposed to Condition Y for instance, how
likely it is that youll get this disease given your genetic makeup.
With an absolute risk of 50%, a 1.5 higher chance of getting it is a strong

possibility for you, and you should probably consider taking steps to change
your odds, such as surgically removing your bellybutton before it blows up.
(Dont worry, there are many very realistic bellybutton prostheses these days.)
But if Crepitus Umbilicus affects only 0.00000005% of the population (in other
words, 1 in 2,000,000 people rather than 1 in 2), a 1.5 higher chance of getting
it eh, probably dont worry too much. Just pack a little flame retardant foam in
your navel before you go to sleep each night, and youll likely be just fine.
gave us probabilities based on known epidemiological data;

were clear about the limitations of these data and risk predictions; and
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put results in context as much as possible by telling us the absolute risk as
well as the relative risk.
Support for next steps

Does this genetic testing service help me understand what to do next?
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If so, how? And how appropriate are the recommendations?
Again, research suggests that simply knowing about your DNA while very
cool may not change your behavior. In some cases, people may feel as
though they have less control over their choices once they know their genetic
test results.
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It might not be within the testing services scope of practice to make specific
recommendations about what to do next, but were they able to help us identify
where else we might look for guidance?
offered relatively impartial interpretations and support that might help

people take realistic, productive next steps.
Choosing testing services

For general health, nutrition, and fitness information, there are many services
available.
For instance:
23andMe was one of the first on the commercial testing scene, and offers
a wide array of genetic data ranging from ancestry, to health risks, to traits.
You can spend days deep-diving into all the scientific research and analysis
that theyve collected. https://www.23andme.com/
DNAFit tests about two dozen genes that are related to metabolic health,
nutrition, and athletic performance, and then offers comprehensive
recommendations for what to do with the test results.
https://www.dnafit.com/
Orig3n has a variety of kits available that test sets of variants for fitness and
performance. https://orig3n.com/
Habit offers genetic testing, personalized nutrition prescriptions, and even

meal delivery based on your individualized nutrition plan.
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https://habit.com/
LifeGenetics is heavily focused on weight loss, offering menu planning

based on test results. http://lifegenetics.net/
Nutrigenomix, based out of the University of Toronto, uses a panel of 45

genetic markers to explore factors related to weight management and body
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composition, nutrient metabolism, eating habits, cardiometabolic health,

food intolerances, and physical activity. https://www.nutrigenomix.com/

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Other services will analyze existing data (for instance, from 23andMe) in ways
that the original labs might not. For instance:
Genetic Genie explores genetic markers linked to detoxification and

methylation. Its also free. http://geneticgenie.org/
Athletigen doesnt do their own testing (they send it to a lab), but they
offer analysis and interpretation of particular genetic indicators of athletic
performance. https://athletigen.com/
What we chose and why

Wed love to say that were actually shills for Big Genome and that they gave us a
bunch of cool swag like personal polymerase shaker cups, Happy the Haplotype
stuffed toys, or a protruding-eyebrow-ridge piercing for our co-author Krista,
who scores big with the highest percentage of Neanderthal DNA.
But no.
In most cases, we dont know the testing services, and they dont know us.
(Well, they know us, kinda since DNA is us. But they dont usually know us, like
Hey whats up how are the kids and your sports team? know us.)
We chose three services to explore in particular for this book: 23AndMe,

GeneByGene, and Nutrigenomix.
Heres why.
Theyre relatively cheap. Hey, we aint made of money. At time of writing, for
instance, 23andMe cost $200 US.
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Theyre easily available. Spit in a tube, mail it off. A few weeks later, you
get your data. (Co-authors Helen and Alaina also took and prepped blood
samples for GeneByGene, who offered us the ability to test with both blood
samples and DNA we prepped ourselves in PNs lab.)
Theyre relatively accessible. Anyone who can afford it can do it.

You dont need to be a healthcare professional or a researcher to get access
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to your genetic data. The basic Nutrigenomix kits are used in undergraduate
courses.
They can connect to other services and analysis. Once you have your
23andMe data file, for instance, you can link it to other services (such as
Athletigen or Genetic Genie) who will run different analyses on it.
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Theyre relatively accurate. For instance, 23andMe uses the Illumina
HumanOmniExpress-24 format chip (considered an industry standard) in a
CLIA-certified, CAP-accredited laboratory in the United States. Nutrigenomix
uses a similar process in a top university laboratory in Canada, and clinically-
focused GeneByGene has an excellent facility in Texas.
23andMe and Nutrigenomix analyze and interpret the data for you.
(GeneByGene provided us only raw data that we had to analyze, which
makes sense in a clinical setting.)
They focus on what were interested in as a health, fitness, and nutrition

company. We want to know about stuff like which factors will affect key
physiological processes, our movement, our health risks, and how our
bodies process nutrients. If youre reading this, you likely have the same
interests for yourself (or perhaps for your clients). Other services, such as
National Geographics Genographic Project and Ancestry.coms DNA
service are also cool, but focus more on ancestry and migration patterns.

Be a critical consumer.
Research shows that the average person expects genetic testing results to be
much more helpful or directive than they really are.
Research also shows that people are better at correctly interpreting their results
when they are numerate that is, if they understand things like percentages,
odds and risks, and how to understand number-based data like This SNP
increases your odds of Health Condition X by 1.16 or This SNP is associated
with Health Condition Y (p <0.1).
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So, if this area interests you, you may want to brush up on your math skills.
Consider your reasons for genetic testing.

A survey that asked people why they tested their DNA found that most people
wanted to improve their health or learn more about their ancestry. But they were
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also curious, thought it would be fun, and/or simply wanted to help advance the
cause of science.
Your goals and reasons for testing will probably affect what test types you
choose, and how you view the test results.
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Consider independent genetic counseling or
coaching.
Genetic test results can be confusing or complex. And, studies suggest that
even if genetic testing results are easy to understand, people often misinterpret
them.
An independent genetic counselor who isnt affiliated with the testing

organization is your best bet for making sense of your test results.
Research also suggests that:
People tend not to change their behavior just because they know their
genetic test results.
But: They do tend to change their behavior if they share their data with
their doctor, another healthcare professional, or a coach.
If youre looking to make some improvements to your health, nutrition, and/or

fitness choices, make sure to supplement any genetic testing with independent,
individualized guidance from a qualified professional.
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Whats up next: What we found
In the next few chapters, well focus on some specific topics and explore what
we found in our own genetic tests.
Well cover:
Heredity and ancestry, and how these might affect your genetic test results;
Metabolism;
Nutrition and food preferences; and
Exercise and athletic performance.
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CHAPTER 3 CHAPTER 5
Introduction to What we found: Heredity
genetic testing
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How does heredity work? Why

What does genetic testing involve? dont we all share the same
What are some of the general genetic variations? How might our
issues to think about while deciding ethnic background and ancestry
if genetic testing is right for you? affect our overall health?
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CHAPTER 5
What we found: Heredity
How heredity works;

Some factors that make people diverse, such as biological sex, gender
identity, and genetic ancestry / ethnicity; and
Why our history matters, and why we have to consider ancestry when
understanding and interpreting genetic data.
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As you read this chapter, remember our usual caution:
It all begins with sex.

Humans reproduce sexually, which means one cells genetic information has to
hook up with another cells genetic information to make a new human.
In this process, genetic traits are passed on from parents to child. You might
inherit your fathers nose, or your mothers curly hair.
But this doesnt mean we are exact clones of our parents. Gametes (the
chromosome-containing cells we get from our mom, an egg/ovum and dad, a
sperm) combine in ways that we cant completely predict.
Gametes are haploid, which means they each have only one copy of the 23
chromosomes that make up the human genome. (The word haploid comes to
us from the ancient Greek haploos, or single, simple, once.)
When the haploid egg and sperm cells unite, they eventually create a person
with diploid cells twice the amount, or 46 chromosomes. (The prefix di refers
to two.) So, aside from our own sperm or egg cells, the rest of the cells in our
bodies have 46 chromosomes.
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How does heredity work?
Heredity is complex. Given all the DNA in our genetic code, and given that we
get stuff from mom and dad, there are almost infinite possible combinations of
traits. |
Some traits are dominant, meaning they are more likely to be expressed. Some
traits are recessive, meaning that they are less likely to be expressed. We might
need to inherit two copies of a recessive gene in order to express it, whereas we
might need only need one copy of a dominant gene.
If we have two copies of a particular gene type, thats called homozygous.

If we have one copy of one type, and a different copy of another type, thats
called heterozygous.
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Figure 5.1: Homozygous and heterozygous inheritance
Interestingly, many traits that are supposedly one-gene, or monogenic,

traits (like eye color or the curvature of your thumb) are not. Instead, they are
polygenic, controlled by multiple genes.
In our PN population sample, we included some multi-generational data:

grandparents, parents and children. And since the parents surveyed had more
than one child, we were also able to see how particular traits appeared in
different offspring.
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For example:
There is a gene that makes people more or less likely to think that fresh cilantro
(aka coriander, a herb often used in Latin American and Asian cuisines) tastes
yucky (which well look at in Chapter 8, on food preferences). |
Part of this gene can come in 3 nucleotide combinations:

AA (adenine-adenine): More likely to dislike cilantro

AG (adenine-guanine): So-so
GG (guanine-guanine): Less likely to dislike cilantro
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In our sample, we found different types of inheritance.
Parent-child group 1:
AG mom + AG dad = 2 GG children
AA dad + GG mom = AG child
AG dad + AG mom = 2 AG kids
And, as youll see in Chapter 8, just knowing a persons genetic makeup (i.e.,
their genotype) doesnt necessarily tell us what traits they express (i.e., their
phenotype). As it turns out, the cilantro-hatin gene didnt predict which of our
PN sample actually hated cilantro.
What this means for you

Genetic testing can tell you about what traits you may have inherited.
However, you may not necessarily express those traits.
Biological sex is complex.

Ova have only an X chromosome, while sperm can have either an X or a Y. Most
of the time, males have an XY chromosome combination, while females have an
XX combination.
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This combination of chromosomes is what gives us our biological sex our
collection of physiological characteristics that we might call male or female.
Biology is rarely so completely neat and tidy, though. Sexual dimorphism

(i.e. being able to divide a species into two sexes by their physiological
characteristics) does not mean that male and female bodies are opposites.
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Rather, its a bit more like biological sex is on a continuum. Its quite possible,
though less common, to have other combinations of chromosomes.

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For example:
A body can have XY (i.e. biologically male) chromosomes, but for other
genetic reasons (such as variations on other related genes), develop a
female body. Testes dont descend while XY fetuses are in the womb, so
when they are born, they might look like any other baby girl. Often this has
to do with insensitivity to the masculinizing hormones, known as androgens.
Many XY women do not discover they are unusual until they hit puberty and
dont menstruate.
Similarly, a body can have XX (i.e. biologically female) chromosomes

but look male during development. Typically this happens when haploid
chromosomes are created, and a Y-chromosome SRY gene (which
contributes to masculinized development) sneaks in from dad and ends up
on another chromosome.
Many bodies can also inherit additional chromosome copies, such as XXY,
XXX, XYY, and so on.
In general, these types of phenomena, where bodies are chromosomally or

developmentally sexually ambiguous (or both), are often known as intersex. Its
estimated that about 1 in 1,500-2,000 people are intersex in some way.
All you need to remember is:
Biology is complicated.
As is identity. Well look at ethnicity in a moment, but first, a quick detour.
Is transsexualism genetic?
One of our co-authors, Alaina, has an interesting feature: Shes transsexual. (We
also had one more trans woman in our genetic sample.)
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Nobody knows exactly how common it is to have some type of mismatch
between ones biological sex configuration (i.e., chromosomes and other
physiological characteristics), and ones gender identity (i.e., ones sense of self
as having a particular gender, or not).
But both gender variation and intersex are common enough that we now ask
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about it on our PN Coaching client intake form:

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Which sex/gender do you most identify with:
oo Man
oo Woman
oo Other
If other, please specify: _______________
Biological sexual characteristics (such as hormones) can affect peoples

metabolism, nutrition, and response to exercise. Gender identity affects who
they are in the world. We consider these important things to know about our
clients, so that we can take the best possible care of them.
Given the ways that chromosomal inheritance can work, intersex is a fairly clear-
cut phenomenon. Its simply a normal (though relatively infrequent) variation of
sexual development with a clear mechanism of action.
But what about gender identity? In other words, who we feel we are, at a deep
level? Could genetics play a role here too? Possibly.
For instance, some evidence suggests that genes involved in the production and
function of sex hormones may be important, such as:
androgen receptor genes (AR or NR3C4);

estrogen receptor genes (ESR2 or NR3A2); and
aromatase (CYP19) genes (genes involved in aromatization, or conversion of
sex hormones, such as from testosterone to estrogen).
Two studies, for example, found that female-to-male transsexuals were more
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likely to have variations in the CYP17 gene (which encodes 17-hydroxylase, an
enzyme involved in conversion of sex hormones.) Other research found no such
association.
Another study, yet to be reproduced, looked at the gene (AR, or NR3C4) that
codes for the human androgen receptor.
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Androgens are a group of sex steroid hormones that are considered to be

biologically masculinizing hormones, though they appear in all human bodies
to some degree. Testosterone is the best-known example, but there are others,
such as dihydrotestosterone (DHT) and androstenedion
Androgens and other hormones bind to receptors on cells to do their job.

This means that if receptors vary genetically (for instance, if they are shaped
differently, or more or less active), this can affect hormonal function.
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The AR gene has several variants where a stretch of 3-nucleotide codons
with the makeup of cytosine + adenine + guanine (giving it the acronym CAG)
is repeated different numbers of times. This is known as a variable number
tandem repeat (or VNTR).
For example, you might see this on some peoples AR gene:
Figure 5.2: One version of CAG repeats on the AR gene
You might see this on other peoples AR gene:
Figure 5.3: Another version of CAG repeats on the AR gene
The study looked at how often each variant, or allele, appeared in a study
population of both transsexual women (male-to-female) and non-transsexual
men, and found that there might be a link between certain alleles of AR and
being transsexual. Male-to-female transsexuals were more likely to have a
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particular number of tandem repeats in the AR gene.
As it turns out, Alaina does, indeed, have this variation. (We didnt test the other
womans full genome, so we dont know if she does.)
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A possible genetic correlation with gender identity is interesting in its
own right, and perhaps validating for many trans people. If these kinds
of results could be replicated and more solidly established scientifically,
it might help demonstrate (at least, for some people) that their deeply felt
sense of being a particular gender has at least some biological roots.
More broadly speaking, variations in genes and structures that affect sex
hormones might also:
offer possible drug therapies. For instance, changing the function of an

androgen receptor could also offer treatment for prostate cancer.
affect body composition. For instance, men who more easily convert
(aromatize) testosterone to estrogen may have trouble losing body fat.
affect athletic performance and, potentially, drug test results. For

instance, women with naturally higher-than-average androgen levels
may build muscle more easily. In extreme cases, elevated androgen
levels in some women who are intersex (such as the famous cases of
female sprinters Caster Semenya and Dutee Chand) may cause them to
fail drug tests. Well look more at other genes that may affect exercise,
muscular performance, and body composition later in the book.
Though you can do a chromosome test to determine biological sex, most

commercial genetic tests do not (yet) test for variants related to gender
identity. Our data came from a full-genome sequence.
Nor, by the way, can you currently test for sexual orientation. 23andMe
also looked for variants that might be related to sexual orientation in
other words, whom we prefer as sex partners. Using a survey of nearly
24,000 people, they eventually concluded that there were no clear links
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between any SNPs and sexual orientation. Genetic data in this area, while
intriguing, are still inconclusive and dont yet represent the full range of
human behavior.
Our history is complex.

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Along with our physiological sex, part of what makes us us in biological terms
is our ancestry, ethnicity, and heritage.
Where do you come from? Where are your roots? Who were your ancestors?
Of course, the first answer is that all of us descend from a relatively small
population of hominins (or early humans) who began their journey in Africa.
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Once they could stand upright, those adventurous, ancestral primates started
walking. And walking. And walking. Eventually they spread around the globe,
mutating and evolving and turning into a vast rainbow of humanity.
And now those curious little walking primates are us.
The second answer explains more recent history: Where have your ancestors
been for the last several thousand years? Where have they traveled? Who did
they meet, and marry, and trade with? (Did someone else trade them?)
How might someone recognize you (or not?) as being from somewhere,
perhaps a particular place on Earth, or a particular group of people? What traits
do you have that might be a dead giveaway or a mystery?
Almost all of us writing this book, and from the PN team who consented to let us
use their data, are from European backgrounds.
For instance:
Johns family is originally from Italy.

Helens family is originally from Greece.
Alainas ancestors are originally from England, Ireland, Scotland, and
Germany. Most of her family came to the United States between 1635 and
1650. Her Scottish ancestors landed in 1879.
Kristas family is a mix: part Northern European; part Eastern European; and
part Southern European (particularly the Balkan region).
The one exception:
Our PN team member Tims ancestry is about half European and half South
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Asian, with a bit of Sub-Saharan African (mostly West African) thrown in.
Our history can tell us about ourselves.

When clients start our PN Coaching program, we ask them about their ethnicity.
People can tick as many boxes as they like.
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Heres the list we use:
oo White/European
oo Black/African American
oo Hispanic
oo East Asian
oo South Asian
oo Pacific Islander
oo Arabic/Middle Eastern
oo North American Aboriginal/First Nations/Native American/Inuit
oo Aboriginal Australian
oo Other (please specify)
Many clients wonder:
Why do we ask about this?

The simple answer is that aside from social and cultural traditions, our ancestry
and ethnic origin are really just a way of saying genetically-related groups.
Genetically-related groups tend to inherit particular traits.
The traits we inherit may in turn affect things such as:
our food choices;
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our response to diet and exercise;
our food intolerances and sensitivities; and
our health risks or advantages. |
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But in reality, there is no simple answer.
Heredity is complex. (After all, you get stuff from mom, and stuff from dad,
and these days you might get stuff from a third person because why the
heck not!? Science! See below for more.)
Ancestry is complex.
Ethnicity is complex.
How all of these affect your nutrition, exercise, and health is complex.
(Remember, other biological, social, and environmental factors are still in the
mix too.)
And thats what well look at in this chapter.
How can a child have 3 parents?

The 3-parent artificial reproduction technique was first done successfully in 2016,
and is used to lower the risk of genetic diseases in mitochondrial DNA if there is a
known concern.
There are a few ways to do this.
One method, known as pronuclear transfer, uses two fertilized eggs, both fertilized
with the fathers sperm: one egg from the mother, and one egg from a donor.
Once eggs are fertilized, but before they start dividing, their nuclei are removed. The
nucleus from the donors fertilized egg is replaced with the nucleus from the mothers
egg.
A second method, known as spindle nuclear transfer, is similar, but the swap occurs
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before fertilization.
In this case, doctors purposely created and used a male embryo, so that the resulting
child wouldnt pass on any inherited mitochondrial DNA. (Thus, the genetic disorder
would end.)
Well read more about mitochondrial DNA later in this chapter.

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Genetic data tell us there is no such
thing as race.
At least, not in the way most people think about it, which is a few very simple
categories. Instead, genetically speaking, there are only ethnic subgroups or
common groups of genetic variations that can be loosely distinguished.
History tells us that humans have always been nomadic people. Were social
we like to meet n greet (even if sometimes that greet is with a whackin club to
drive off the other tribe).
We humans like to travel and trade. Some folks wandered up and out of Africa.
Some folks wandered all the way across Alaska to South America. Some of us
even got gutsy enough to take a raft across the ocean, resulting in relatively
historically isolated and genetically distinct populations such as indigenous
Aboriginals in Australia, Torres Strait Islanders, Maori, and Indonesians.
Once we figured out walking, riding, and sailing, we got busy swapping and
selling stuff like spices and silks and appallingly, shamefully, and horribly
sometimes, other humans too. (There is evidence that enslavement, sale, and
other forced migrations of humans happened all over the world, and goes back
at least to around 3,000 BC. Tims great-grandparents were brought to Trinidad
as part of human trafficking routes from India and Africa.)
This means that unless you and your ancestors have lived for tens of thousands
of years undisturbed in some pocket of the Amazon, an isolated mountain pass,
or a desert island that has yet to be turned into an all-inclusive resort, youve
probably got a buffet of mixed-up human DNA inside you.
For instance:
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Although Johns DNA is about 97% Southern European, hes got about
3% from North Africa, reflecting patterns of migration and the influence of
Arabic trading with the Mediterranean. Hes also got maternal and paternal
lineage of a type most common in the Middle East.
Krista has a smidge of East Asian, possibly from the dominant Mongol
Empire that swept through the Asian and eastern European continent in the
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13th and 14th centuries. In fact, genetic testing estimates that 1 in 200 men in
the world carries this lineage.
Tims DNA is about 1/4 Ashkenazi Jewish, a population of European

Jews who tend to be closely related as a relatively historically insulated
community. Even more interesting: Tims mother (of European descent)
hadnt known.
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We are all connected. We are family.
Europeans, East Asians, and Neanderthals
Evolution is rarely nice and tidy. There are lots of branches, dead ends, and false
starts.
Genetic data can tell us about our complex journey to modern humanity, as well
as about our closest relatives both living and extinct.
Though we might imagine we evolved in a clear, straight line from primate to

Homo sapiens (i.e., you), it didnt actually happen that way. In fact, we co-habited
with many types of hominins as recently as 100,000 years ago. Our ancestors
(like the ancestors of most other species) branched into many now-extinct
subspecies, such as Homo naledi and Homo florensis (aka the hobbit).
Though Neanderthals are a distinct evolutionary branch of the human family,

and disappeared around 40,000 years ago, they got in a few good romantic
moments with our Homo sapiens ancestors before they disappeared.
This means that many people of European ancestry carry at least a little bit
of Neanderthal DNA between 1-3% of their total. However, one study on
a sample from a modern human who lived in what is now Romania between
37,000 and 42,000 years ago contained about 6-9% percent Neanderthal
genetic material, more than any other modern human genome that has
yet been sequenced.
This isnt the whole story, though. Research also suggests that the ancestors
of present-day East Asians split from Europeans, then interacted later with
Neanderthals.
In other words, it wasnt a simple process of a single meeting there were many
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complex patterns of genetic mixing with different populations over the course of
early human history.
Krista scores 96th percentile for this genetic material; John 67th; and Alaina
38th. If youve got European or East Asian ancestry, you likely have at least a
little Neanderthal in you.
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Ethnic variation within a region
The 1992 film White Men Cant Jump, starring Woody Harrelson and Wesley
Snipes, played on the idea that white athletes would be lousy basketball players.
Indeed, black and white are easy, simple categories, often used to divide
and explain the world, whether in terms of ethnicity, ability, perspective, or other
physical and cultural differences.
In reality, these terms are not at all simple.
Theyre complex, laden with historical baggage, and change in subtle but
important meanings from place to place (for instance, Black historically meant
somewhat different groups of people in North America, South Africa, or the UK).
And they dont tell us much about many important features of people.
For now, lets set aside social and political issues of ethnicity, and look at the
physiology.
On one hand, we are all human.

We are more alike than we are different.
And we are more alike than other species for instance, there is more genetic
variation among fruit flies than among humans.
On the other hand, many distinct traits or

genetic variations can be reproduced within
populations.
This is especially true if those populations have traditionally tended not to travel
much, or marry outsiders.
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We can safely expect, for instance, that an Indigenous person from Australia
whose ancestors arrived on the island about 50,000 years ago will likely
be measurably different than an Indigenous person from an isolated mountain
village in Chile whose ancestors may have crossed the now-vanished Siberian
land bridge across the Bering Strait (between Russia and Alaska) approximately
30,000 years ago.
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Some traits (such as facial features or body shape) may be easy to see. Others,
such as immune system variations, may not be.
On the other other hand, some regions

have significant genetic variation and
ethnic subgroups.
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Somewhere around 1.5 to 2 million years ago, a group of early hominins
from Africa walked north and gave rise to most of modern humans. But other
hominins, of course, stayed.
Thanks to this ancient lineage, the massive continent of Africa is one of the most
genetically diverse regions in the world.
For instance, one study found that the average nucleotide diversity was twice
as high among Africans as among Europeans and Asians. North Africans are
genetically distinct from sub-Saharan Africans, since the Sahara Desert would
have been a barrier that few crossed before modern means of transport. The
further from East Africa early human populations traveled, the less genetically
variable they tended to become.
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Figure 5.4: Global migration patterns and genetic diversity

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However, areas with lots of trade (such as the Mediterranean or the Malaysian
peninsula) were perfect environments for population and genetic material
exchange. Not surprisingly, there is more genetic diversity in southern than in
northern Europe, which is further away from the busy shipping routes between
the Middle East, Asia and Africa.
Yet even some small regions such as northern Europe have at least a bit of
diversity evidence suggests that multiple waves of early humans ebbed and
flowed into the northern regions of Europe as Ice Ages came and went. And
Melanesia (the area northeast of Australia that contains Papua New Guinea, Fiji
and other small Pacific islands) has significant genetic diversity.
So being white, European, black, African, or any other ethnic category,

is not a simple thing at all.
Well see this when we look more closely at specific responses to nutrition and
exercise in the upcoming chapters.

By virtue of being human, you contain complexity. Genetics is not
simplistic, nor are physiological categories like sex or ethnicity.
Genetic testing can tell you about your history, which may be more
diverse than you anticipated. After all, your ancestors had lots of time to
mix things up.
Youre not destined to be anything in particular just because of

biological sex or genetic ancestry. Genetics can only tell us about
probabilities and relative frequency of particular instructions for
making proteins.
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How can you trace your lineage?
The words haplotype and haplogroup come to us from the same ancient
Greek root as haploid. |
We can think of haplotypes as something like a cluster or constellation of genes

(in other words, a small chunk of genetic material) inherited together from a
single parent, and a haplogroup as a group of closely linked haplotypes that
tend to be inherited together.
Generally, haplogroups can be traced back to a single line of descent from a

common ancestor.
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Moms lineage: Mitochondrial DNA
Mitochondria are organelles (cell components) that convert energy from food
into a usable form (in humans, thats adenosine triphosphate, or ATP).
Mitochondria have their own DNA (aka mtDNA) that is distinct and independent
from the 46-chromosome DNA of a cells nucleus. There isnt a lot in there only
16,569 base pairs of mitochondrial DNA that code for only 37 genes but this
relatively small snippet of DNA can tell us a lot about ourselves.
Figure 5.5: Mitochondrial DNA
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Many people have wondered why we have mtDNA, and why the mitochondrial
chromosome is circular, like a bacterial chromosome.
MtDNA does seem to be related to certain species of modern bacteria. Many

of the former-bacterias genes encode for the stuff specifically related to the
function of the mitochondria. Some even seem to have been transferred to the
host organisms genome.
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Mitochondria were likely originally bacteria that invaded the ancestor(s) of

eukaryotic cells (i.e., cells with a nucleus and organelles) and developed a
symbiotic relationship. The resulting friendship was a common ancestor for an
entire domain of life: the taxon Eukarya, which includes plants, animals, fungi,
algae, and many single-celled organisms, such as amoebas.
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In humans, while sperm cells have mitochondria, they seem to get destroyed by
the egg after it is fertilized. We usually inherit mitochondrial DNA only from our
mothers, not our fathers.
So by categorizing mtDNA and looking at where its spread in the world, we can
retrace the footsteps of our female ancestors.
Fun factoid!
Mitochondrial DNA inheritance is rare but does happen in some species, such as
bivalve molluscs. And, to date, it has been discovered in a human male.
These clusters of mtDNA which generally share a single mutation that

happened to a particular ancestor at a particular place and time are known as
maternal haplogroups.
We can trace our maternal ancestry back to a woman known as mitochondrial

Eve, a woman who lived around 190,000 years ago in East Africa. (Tanzania has
both high genetic diversity and ancient mtDNA haplogroups, many of which are
either uncommon or not found in other parts of Africa.)
Mitochondrial Eve gave rise to the L haplogroups, which formed the basis for all
others, and which eventually branched into other haplogroups spread all over
the world. Later, nomadic humans returned to Africa, bringing fresh haplogroups
(such as H, U6, X1 and potentially M1) back to the homeland.
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Figure 5.6: Distribution and migration of L maternal haplogroups from Africa
Dads lineage: The Y chromosome

Of course, youre wondering what great-great-great-grandpappy was up to.
Paternal haplogroups are families of Y chromosomes that, like maternal

haplotypes, can be traced back to one mutation that happened at a particular
place and time, and, likewise, help us see the pathways our male ancestors took.
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Figure 5.7: Paternal haplogroups and migration routes.

Image credit: Chakazul. World Map of Y-Chromosome Haplogroups Dominant Haplogroups in
Pre-Colonial Populations with Possible Migrations Routes. Available via Wikimedia Commons.
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However, well only see paternal haplotypes in folks with a Y chromosome
(i.e., most males).
The Y chromosome is the shortest chromosome.
Though it has few genes including the crucial SRY gene (aka testis-
determining factor or TDF) these genes are important. They code for
things that masculinize bodies, such as developing testicles and producing
sperm. The Y chromosome also carries many duplications and noncoding
genes or transcripts.
Figure 5.8: XX and XY chromosomes
Male infertility is a complex phenomenon (and also depends on factors such
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as health, medication use, nutritional status, body fat, and so forth). It can also
have a strong genetic component that may include mutations to Y chromosome
material.
What we found in our sample |
As expected, most of our samples haplogroups were European. But, as weve

seen with ancestry, things can get complicated. Maternal ancestors migrated;
branches of haplogroups spontaneously emerged.
So, as with being African, to be European is not a simple thing, genetically

speaking.
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Here are just a few examples.
Haplotype I
For instance, Tims maternal ancestor haplogroup, I, was known to migrate into
southwestern Asia as well as into northern Europe (some speculate that it was
carried by the Vikings).
His specific haplogroup, I2, is relatively young, perhaps a few thousand years
old. I2 traveled with a woman out of Iran and the Middle East through Anatolia
and into Europe, where its now predominantly a European haplotype.
Conversely, his paternal ancestor haplogroup, H-M69, is an ancient one, around

50,000 years old, originating in South Asia.
Haplotype H
Kristas maternal haplogroup is H, originally a Southwestern Asian group about
20-25,000 years old.
Antecedents of this group (haplogroups HV and R0) have been found

throughout the Middle East and northern Africa, including in samples from
ancient Mesopotamian civilizations as well as Egyptian mummies.
R0 has also been found in over half of bone remains from a large pre-Bronze
Age settlement from around 4300-4000 BC, known as Trypillia, which today is in
central Ukraine more or less where Kristas maternal grandfather was from.
John has a later version of the H group, known as H5a1, which may have
emerged around 5,000 to 8,000 years ago in the western Caucasus or Near
East (for example, Syria or Lebanon).
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Haplotype U5a1a
Meanwhile, Alaina carries another relatively young haplogroup: U5a1a, which is
between 8-16,000 years old, and commonly found in far northern Europeans,
particularly Scandinavians. |
Although U5 is mainly a European haplogroup, it has been found in the

mitochondrial DNA of a 6th-century AD Chinese chieftain.

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Youve inherited some stuff from your mother, and some stuff from your
father. We can trace your mothers ancestry through mitochondrial DNA. If
you have a Y chromosome, then we can also trace your fathers ancestry.
Genes tend to travel in groups. If you share some known traits with your
populations of ethnic origin and ancestry, youre more likely to share others.
But this isnt for sure; its just a probability.
If you are male and concerned about infertility, genetic testing may be
able to tell you if particular genes on the Y chromosome are involved.
However, there are many other factors that go into determining fertility for
both men and women (such as nutritional status, stress, etc.).
This is pretty cool, right? Knowing our origins and our roots can give us a
sense of wonder and pride about who we are, and how we got here. Many
people from ethnic groups who have been socially marginalized find that
learning about their ancestry and heritage gives them a stronger sense of
identity and purpose. We can also link ourselves to the larger human family.
How does ancestry affect health?

Another reason that we ask our clients about their ethnicity is that many
chronic health concerns and diseases, such as cardiovascular diseases,
neurodegenerative diseases, or Type 2 diabetes, are not equal-opportunity
employers. Instead, they seem to appear at different rates in different ethnic
groups, populations, and regions.
For example:
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People of South Asian descent (i.e., originating from the Indian subcontinent)
tend to have higher rates of visceral adiposity (fat around the middle) and
higher rates of Type 2 diabetes.
Indigenous people (e.g. Inuit, First Nations, Native Americans, Maya,

Australian Aboriginal, etc.) from many regions have higher rates of chronic
metabolic diseases, such as obesity, CVD, and Type 2 diabetes, especially
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when they eat modern Western diets that are heavy in processed foods.
People of Ashkenazi Jewish descent, a particular European population

that has tended to be insular and inter-marry, often carry a higher risk of
recessive-linked diseases as well as genetic markers for diseases such as
Crohns and breast cancer.
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This relationship is not straightforward.
For instance, black men in the US have higher rates of cancer than other ethnic
groups, but the same is not true for women. However, both black men and
women in the US are more likely to die of cancer.
What does this reflect?
Sex differences? Differences by genetic ancestry? Lifestyle differences? Other

factors, like access to health care and cancer screening? Socioeconomic and
political factors, like being marginalized or confronting daily discrimination?
The answer is probably all of the above, and more.
Heres just one example.
Heredity and the (failed) hypertension

hypothesis
One of the more contentious topics in the field of heredity and ancestry was
a hypothesis about why people of West African descent now living in North
America and the Caribbean are more likely to have high blood pressure (aka
hypertension).
As early as the 1960s, epidemiologists began to observe that on average,

black people in North America and the Caribbean had nearly twice the level of
clinically defined hypertension as many white populations of European descent
living in the same areas. Yet black people from various populations in Africa (in
other words, people who were relatively genetically related) did not seem to
have the same high blood pressure.
Why the disparity?
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And did this difference truly represent a racial divide?
In the late 1980s and early 1990s, some researchers proposed what came to be
known as the slavery hypothesis. This theory suggested that Africans taken
from their homeland and transported to the slave-based economies of the early
Americas and the Caribbean became a genetically distinct group those who
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survived a long and dangerous trip across the ocean, imprisoned in slave ships,
often without adequate food or water.
The idea was that people with bodies that retained salt better might be more
likely to survive dehydration, starvation, and illnesses such as diarrhea, vomiting,
and fevers. Those few people who survived may then eventually have passed
along those genes once they arrived at the destination.
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In one sense, this is a scientifically attractive hypothesis it seems logical, it
points to a large-scale social phenomenon that may have created biological
changes in a distinct population, and it may help explain underlying factors for
chronic disease. A body that processes electrolytes (such as sodium) in certain
ways may indeed be more predisposed to high blood pressure, which is (in part)
related to the physiology of fluid and electrolyte balance.
However, the hypothesis was roundly criticized by other researchers, who

pointed out things like:
Some groups of white Europeans (such as Finns) also had higher-than-

average blood pressure.
Within Africa as a geographic region, there is tremendous genetic diversity

(as weve seen).
People of African descent, particularly in North America, have higher rates of

other chronic diseases as well, such as cardiovascular disease or diabetes.
As these diseases are polygenic in other words, many genes contribute in
complex and interacting ways this cant be explained by a single gene or
even a small cluster of genes.
Blood pressure is a complex physiological state that depends on many

factors, of which sodium processing is only one.
Most importantly, when researchers looked for genetic markers of

hypertension in African American populations, they found none. Instead, the
main factors that correlated with high blood pressure were age, body size,
and birthplace.
Scientifically, this hypothesis, while convenient, is invalid. Nor is it supported

by evidence.
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Instead, social factors seem to account much more for high blood pressure
and other chronic diseases, particularly in the United States.
These factors include:
Residential segregation (i.e., different groups in different neighborhoods),

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which may expose black people to more environmental toxins.

On average, compared to whites in the US, black people in the US have

less access to quality health care, and higher levels of poverty. They may be
more likely to smoke and drink, have poorer diets, and less access to fresh,
healthy foods.
Most importantly, social factors such as racism and stress are strongly linked
to chronic diseases.
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So, being of African descent and living in North America may indeed be linked to
high blood pressure or other chronic metabolic diseases but not necessarily
for genetic reasons.
Why is this story important?
It reminds us that simplistic ideas about race are incorrect.
It helps us understand how ancestry, genes, and disease risk work.
There is no ethnicity gene. There are no genes found only in one broad ethnic
group, although there may be small, localized genetic variations.
It also reminds us that there is no disease gene for most diseases.
Most chronic diseases and physiological processes are polygenic. To date,

genetic factors appear to explain only about 2-3% of high blood pressure cases.
Lifestyle factors and body composition (i.e., body size and amount of body fat
/ lean mass) are much more important, as are broader social, economic, and
political determinants of health (such as where people live, what resources they
can access, or the discrimination they may face).
Even if there were a clear genetic basis for certain diseases, such a genetic
basis might require a particular environment (such as one with pollution or easy
access to high-sodium, high-sugar processed fast foods) to be expressed.
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Regardless of your biological sex or genetic ancestry, monitor your blood
pressure and other risk factors, especially as you get older. High blood
pressure is a risk factor for many other diseases, such as cardiovascular
diseases. But it doesnt act alone. It works with other lifestyle factors.
Ethnicity is one factor that may change your risk of chronic diseases,
whether because of inherited genetic or social factors. Get regular
checkups where possible.
Control the factors that you can control. You cant control your genetic
ancestry. But there are many ways to reduce your risk of high blood
pressure, such as:
eating fewer processed foods, which tend to be high in sodium;

drinking less alcohol;
getting regular exercise; and
maintaining a healthy body weight.
Recognize that other factors may contribute to high blood pressure. Stress
is one of the biggest. If you belong to a group that has traditionally been
marginalized in society, recognize that you may feel extra stress thanks to
daily-life discrimination and prejudices. (Unfortunately, you probably already
know this, though.)
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Whats up next: Metabolism
Now that youre thinking about blood pressure, you might also be wondering
about other metabolic factors. Perfect timing!
In the next chapter, well give you an overview of metabolism, and look at some
of the processes that can be affected by genetic factors.
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CHAPTER 4 CHAPTER 6
Specific genetic What we found: Metabolism
testing services
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In this chapter, we explore

What should you think about when some of the basic metabolic
considering particular genetic processes, such as how we
testing services? Which services regulate our blood sugar or thyroid
did we choose, and why? output, and how they might be
affected by genetic factors.
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CHAPTER 6
What we found: Metabolism
What metabolism is, and what helps regulate it;

How vitamin D plays a role, and how genetic variations might affect
vitamin D metabolism;
Thyroid function and the shared genetic roots of autoimmune diseases;

The role that genes may play in regulating glucose / insulin, blood lipids,
and metabolic syndrome;
Whether genes can predict risks for Alzheimers disease; and
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What you can learn about all of this through genetic testing.
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Two important points to keep in mind:
While science is cool, and we have some interesting genetic findings and
areas for further exploration, we still know comparatively very little.
Just because a genetic test can tell you what factors might affect your
metabolic health, it doesnt mean that it can tell you the perfect diet,
exercise, or supplement plan for you.
What is metabolism?
Life is constant change.
The term metabolism comes to us from the ancient Greek metabol, or

change, and it refers to all the coordinated, dynamic processes that must take
place for us to stay alive. These processes include absorbing, transporting and
using nutrients or synthesizing substances we need.
By way of the proteins they code for, genes affect all metabolic processes, such
as:
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growth, tissue recovery and repair;
processing nutrients and transporting them into cells;
synthesizing hormones and other cell signaling molecules;
establishing basal metabolic rate (aka our idling speed); and
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how well we digest, absorb, use, and/or store any nutrients we eat.
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Genes are involved in many ways.
For instance:
Genes may directly act on these metabolic processes for example, by

coding for a cellular protein that controls how nutrients get transported into
that cell.
Genes may affect the activity of other genes.

Genes may have a strong effect, a weak effect, or no effect at all unless
other factors are present. Sometimes seemingly unrelated genes must be
co-transcribed to have a physiological impact.
We could write an entire textbook (or ten) about metabolism, and how genes
may affect it.
For this chapter, well focus on a few key indicators that may affect your
metabolic health, fitness, and function.
In the next chapter, well look at what affects your body weight and composition.
What regulates metabolism?

Mission Control: the hypothalamus
Deep in your brain is an almond-sized nugget known as the hypothalamus. This
gland is tiny but powerful: It regulates many of your bodys metabolic functions.
The hypothalamus bridges the endocrine (organ-to-organ signaling) system and
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the nervous system: It interprets chemical messages and information from both
inner physiological processes and the outside world into what to do next.
In particular, the hypothalamus helps maintain homeostasis by interpreting

the bodys actions and reactions and initiating responses to keep things in
equilibrium.
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For instance, the hypothalamus helps to regulate:
blood pressure and heart rate;

body temperature;
fluid-salt (aka electrolyte) balance;
appetite / hunger and thirst;
basal metabolic rate (BMR), the bodys idling speed;
body weight and energy storage;
digestion and gastric motility; and
sleep and wakefulness.
The hypothalamus monitors and responds to signals from inside the body as
well as the outside world, such as:
how much energy we have available or stored (e.g., in the form of body fat or
circulating glucose);
inputs from our autonomic nervous system (ANS), which is the nervous
system that controls internal organs such as our heart, lungs, or digestive
tract;
light and dark (which help cue sleep cycles);

temperature outside and inside our bodies;
scents and other volatile chemicals; or
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pathogens such as bacteria or viruses.
As the hypothalamus gathers environmental information from external and

internal cues, it sends chemical messages downstream to other endocrine
glands, such as the pituitary.
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Peripheral regulation: sensors and storage
Along with central regulation of our metabolism, we are always gathering
information from physiological processes that are happening peripherally in
other parts of the body besides the brain, such as our:
sensory organs (e.g., eyes, skin, taste buds, etc.);

vestibular (balance-sensing) and proprioceptive (position- and movement-
sensing) systems;
other endocrine organs (e.g. thyroid, adrenals, gonads, etc.);

digestive organs;
innate and adaptive immune systems; and
energy storage depots (such as our stored body fat or stored liver glycogen).
Feedback loops and signaling pathways

We regulate our metabolism via a series of complex feedback loops, a cycle
where the output of a process is used as input for the next step.
For instance, if our hypothalamus senses we are getting low on stored energy
(perhaps because blood glucose drops, or our body fat stores are getting low), it
triggers our appetite centers, pushing us to eat.
Conversely, if the hypothalamus senses we have excess energy available, it

might store that energy, use it to drive metabolic functions, or burn it off as heat.
You can think of genetic expression as part of these feedback loops: When stuff
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happens, it triggers other stuff to happen (or stop happening).
Gene expression and epigenetic regulation control what gets turned on or off;
what gets enabled or inhibited. The proteins that genes produce respond to one
another, or what substances are circulating nearby, or environmental factors.
Cells secrete and receive molecules, which help them communicate with
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signaling pathways. These are a series of interactions that trigger each other in
a step-by-step process.
Imagine a courier delivering a package to the front desk of an office. The

receptionist receives the package, then calls someone else to let them know the
package has been delivered.
The same idea works here.

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Most often, a substance (known as a first messenger) will bind to a receptor on
a cell membrane. This binding sends signals known as second messengers
elsewhere in the cell to do a specific task. This whole process is known as
signal transduction.
Figure 6.1: Signal transduction
Many of the genes that well talk about code for mRNAs that make messenger
proteins in other words, essential parts of metabolic processes. Variations
in the expression of genes that code for these proteins can affect, for example,
whether the signal even makes it to the cell, whether the cell accepts the signal,
whether the first messenger is able to communicate with the second one, and
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so forth.
You cant change your genes.
But you can affect these signaling pathways with your lifestyle choices and
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The genetics of metabolism

When you consider all the moving parts of metabolism, its easy to imagine how
genetic factors might play significant and complex roles.
In this chapter, well look at a few biological markers and processes to see how
your genes may play a role, and what you might learn via genetic testing.
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Vitamin D
Looking at vitamin D helps us understand some of the mechanisms by which
genetic expression and regulation can affect our metabolism, which can, in turn,
affect how we respond to stimuli like food and exercise.
Vitamin D is the name we give to a group of fat-soluble secosteroids. Steroid

molecules have a variety of functions in our bodies (for instance, our sex
hormones are also steroids). Well look more at steroid molecules below when
we look at cholesterol.
We can get vitamin D from food. Vitamin D3 (cholecalciferol) is found in animal

foods like oily fish, egg yolk, liver and milk. Vitamin D2 (ergocalciferol) is found
in some plants and mushrooms. Many indigenous Arctic peoples traditionally
ate marine animal livers and lichen a symbiotic algae-bacteria organism
for their vitamin D. And of course, we get vitamin D (also in the form of
cholecalciferol) from sunshine.
Regardless of the source, our bodies need to convert vitamin D into a bioactive
form a form that they can use.
This takes three steps.
1 | First, in the GI tract, cholesterol is converted to pro-vitamin D3

(7-dehydrocholesterol), which is then transported to the skin, where UVB
radiation converts it to vitamin D3 (cholecalciferol).
2 | Our liver hydroxylates (adds an oxygen-hydrogen pair to) D2 or D3, so that

they become 25(OH)D (calcidiol or calcifediol). This is the form of vitamin D
that we can store in our tissues such as muscle or body fat (adipose tissue).
3 | Then, our kidneys convert 25(OH)D to its active form: 1,25(OH)2D (calcitriol
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or calciferol). (Other cells can do this as well, such as cells of our immune
system.)
To do steps 2 and 3, our liver and kidneys use the enzymes 25-hydroxylase and
1--hydroxylase, respectively.
Once vitamin D is made into 1,25(OH)2D, it can affect the activity of over 900
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genes. 1,25(OH)2D that is circulating in our bloodstream can pass through the
plasma membrane of cells, and bind to the vitamin D receptor (VDR) in the
cytoplasm. The VDR is a nuclear receptor, which means its then transported
into the nucleus, where it binds to DNA to affect the expression of genes.
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What vitamin D does
1,25(OH)2D has lots of jobs. For instance:
It can affect the metabolism of skeletal muscle and protein synthesis,

influencing how well we build muscle and recover from our workouts.
It affects how calcium and phosphate move across the sarcolemma, the
sheath of our muscle fibers, influencing muscular contraction and fueling.
It upregulates insulin-like growth factor (IGF-1), which plays a role in

anabolism and recovery. (Well look more at IGF-1 in Chapter 11, when we
look at exercise and muscle performance.)
It can regulate our immune system, helping us fight off pathogens such as
viruses or bacteria.
It can affect programmed cell death (apoptosis). This is a normal part of a

cells life cycle that kills dysfunctional cells.
Its involved in the transport and absorption of minerals like calcium,

magnesium, iron, phosphate and zinc, all of which can affect cell signaling,
tissue repair, and bone health.
It can strengthen tight junctions, the seals between cells such as our skin
cells or intestinal lining cells (much like mortar between bricks), which also
prevent pathogens from getting in.
It helps to regulate genes involved in glucose and lipid (fat) metabolism. Low
vitamin D is correlated with metabolic problems such as insulin resistance or
hypertension.
Its involved in the health of our reproductive system. Low vitamin D is linked
to diseases such as polycystic ovarian syndrome (PCOS), ovarian and breast
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cancer, and endometriosis. In men, vitamin D levels are correlated with
testosterone levels.
Thus, how our bodies process and use vitamin D significantly affects our health
and fitness.
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People whose vitamin D is low might not recover, build muscle, or fight off
infections as well as those with more vitamin D. People with low vitamin D
may also feel more pain and have more inflammation. (By the way, this doesnt
necessarily mean that low vitamin D is the cause of all of these things. It may be
a correlation or a secondary effect.)
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Genetic variations in using vitamin D
If you understand the basics of how vitamin D works, you can probably imagine
that genetic variation could affect many components of vitamin D metabolism, as
well as vitamin Ds ability to influence genetic expression.
Here are some examples of how this might work.
Cholesterol synthesis polymorphisms

Well learn more about cholesterol below, but since vitamin D is part of the family
of ster molecules that are related to cholesterol, variations in genes involved in
cholesterol metabolism can also affect vitamin D metabolism.
The gene DHCR7 codes for the 7-dehydrocholesterol reductase enzyme, which
converts 7-dehydrocholesterol (7-DHC) to cholesterol. Since both cholesterol
and vitamin D can be synthesized from 7-dehydrocholesterol, a loss of function
mutation in DHCR7 can interrupt vitamin D synthesis.
Hydroxylase polymorphisms
We might differ genetically in how well our bodies are able to make hydroxlases
the family of enzymes that (among other jobs) convert vitamin D2 and D3 to
the form of vitamin D that we can store and use.
Variations in genes coding for cytochrome p450 (CYP) enzymes (such as

CYP3A4, CYP2R1, CYP24A1, or CYP27) can affect how much vitamin D we
naturally have. People with mutations in these genes may not make enough
vitamin D even if they eat well and get enough sunshine.
Vitamin D receptor (VDR) polymorphisms
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Once bioavailable vitamin D enters the cell, it binds to the VDR. There are
several VDR polymorphisms that affect gene expression, and are linked to
many metabolic diseases (such as cancer, diabetes or heart disease), infectious
diseases (such as tuberculosis), autoimmune diseases (such as multiple sclerosis
or asthma), and chronic inflammation.
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For instance, the FokI variation (rs10735810) can change the length of the VDR
protein, which can then change how it works. Other VDR polymorphisms such
as the ApaI variation (rs7975232), the TaqI variation (rs731236) and the BsmI
variation (rs1544410) are linked to a higher risk of bone and connective tissue
disorders (such as spinal disc degeneration, low bone density, and fractures) as
well as other chronic diseases.
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One handy thing about many of these VDR variations: Unlike many genetic
variations, theyve been studied in non-European populations (such as people of
Iranian, Chinese Kazakh, Gujarati, Indonesian, and Kenyan descent). This gives
us some useful data about what these variants effects might be in different
groups of people.
Vitamin D binding protein polymorphisms

To have effects on tissues throughout the body, vitamin D has to get to them.
The GC gene codes for the vitamin D binding protein (DBP), otherwise known as
Gc-globulin. This protein binds to and transports vitamin D.
Gc-globulin is part of our bodys response to injury. It can activate macrophages

(a type of immune system cell thats part of our cleanup crew) and bind to
actin released by dying cells, preventing it from coagulating and gumming up
the works. Well learn more about actin in Chapter 11 on exercise and muscle
performance.
There are 3 common variants of GC (Gc1F, Gc1S and Gc2), along with over 120
rarer variants. (Because these variants are relatively infrequent, they can help
us explore heredity and links between global populations.) People of European
descent tend to have Gc2, which is rare in people of African descent, who
typically have Gc1f instead.
Variations in GC (and hence DBP / Gc-globulin) have been linked to risk of (or
resistance to) many types of diseases, such as osteoporosis, thyroid disease,
diabetes, cardiovascular disease, multiple sclerosis, and more.

Blood levels of vitamin D are strongly linked to health and disease, as
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well as athletic performance and fitness. Typically, vitamin D deficiency is
correlated with poorer health and recovery.
Given the complexity of vitamin D metabolism, its entirely likely that you
might have a genetic polymorphism that affects your vitamin D levels. The
effect of having this genetic variant may range from significant to minor.
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Genetic testing may give you useful information about your potential
vitamin D levels and/or risk of deficiency.
23andMe tests for several dozen VDR SNPs, though it doesnt include
any predictions about vitamin D levels in its trait or health condition lists.
The Nutrigenomix test kit analyzes CYP2R1 (rs10741657) and GC

(rs2282679) variations to assess risk for vitamin D insufficiency.
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It may be simpler and more straightforward to simply do a vitamin D lab
test to assess your current blood levels.
Based on your lab test, you can then work with a nutrition professional to
decide whether vitamin D supplementation (or getting out in the sunshine) is
appropriate.
Thyroid function
Our thyroid, which hugs our windpipe, is an endocrine gland that helps regulate
many important physiological processes.
Our hypothalamus secretes thyrotropin-releasing hormone (TRH), which then

stimulates the pituitary to release thyrotropin (aka thyroid-stimulating hormone,
or TSH).
In turn, this stimulates the production and synthesis of hormones like calcitonin,
triiodothyronine (T3) and thyroxine (T4), which act elsewhere in the body to help
regulate:
basal metabolic rate (BMR);

gut motility;
digestion, absorption, and use of nutrients;
cardiovascular and respiratory function;
energy use and storage;
development;
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sexual and reproductive functions;
sleep;
moods; and
calcium metabolism (which includes bone health and density).
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Importantly, T3 also acts on mitochondrial and nuclear DNA to regulate gene

expression through binding to THR and activating transcription.
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Hypothyroidism and autoimmunity
Many of our Precision Nutrition clients, particularly women, come to us frustrated
because they cant seem to lose fat. Or their digestion is sluggish. Or they dont
seem to have the energy they used to have.
In many cases, part of the problem is hypothyroidism their thyroid

has slowed down, and thus their metabolism has too. (The opposite is
hyperthyroidism, an over-active thyroid that speeds things up.)
Environmental factors (such as chronic dieting) can play a role in thyroid

problems, but so can genetic factors, for example, genetic variants that increase
a persons risk of autoimmune thyroid diseases (AITD) such as Graves disease
or Hashimotos thyroiditis.
In AITD, as with other autoimmune diseases, the bodys immune system attacks
and slowly destroys healthy tissue in this case, the thyroid gland. Over time,
the thyroid is unable to produce the hormones it needs to support a healthy
metabolism.
Some estimates suggest that AITD affects about 5% of the American population,
and perhaps as many as 10-20% of all women in their lifetime.
While AITD can be inherited, studies using twins and family members show that
environmental factors and stressors also play a role.
Genes related to AITD risk fall into three general groups:
The human leukocyte antigen (HLA) gene complex that codes for major
histocompatibility complex (MHC) proteins in humans. These cell surface
proteins regulate our immune system by helping our cells recognize
foreign molecules. (Well look at HLA genes more when we look at food
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sensitivities.)
Non-HLA immune-related genes such as CD40, CTLA-4, PTPN-22, FOXP3,

and CD25, which code for other proteins of our immune system.
Thyroid-specific genes, such as:

TG, which codes for thyroglobulin proteins.
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TSHR, which codes for a receptor that binds to thyroid stimulating

hormone (TSH). Second to HLA-related genes, TSHR is the gene most
closely linked to the risk of Graves disease.
TPO, which codes for thyroid peroxidase, an enzyme that helps produce
the thyroid hormones T3 and T4.
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Some evidence also suggests that other factors, such as variants in genes
coding for our vitamin D receptors (there they are again!), may play a role.
Lets look at a few SNPs that 23andMe tests for.
PTPN22
The PTPN22 gene codes for the protein tyrosine phosphatase, non-receptor
type 22, a protein expressed mostly in lymphoid, or immune system, tissues.
Variations in this gene are associated with autoimmune disorders such as
rheumatoid arthritis, multiple sclerosis, Type 1 diabetes, and/or Crohns disease.
23andMe tests for a SNP on this gene known as rs2476601.
Research on European subjects found that each copy of an adenine (A) at this
SNP increases a persons odds of hypothyroidism by 1.36 times, and increases
their odds of developing Hashimotos thyroiditis by 1.7 times.
Other research testing PTPN22 variations in a Korean population didnt find the
same results, but another SNP (rs12730735) and a particular haplotype were
both associated with the risk of autoimmune thyroiditis. Similar results were
found in a Chinese population. In a Japanese population, PTPN22 doesnt seem
to have any connection at all to AITD, though having a particular haplotype
seems to offer some protection against the disease.
In a Jordanian population, researchers did not find that rs2476601 played a role,
perhaps because the SNP doesnt often appear in this group. However, it was
found in an Egyptian population, and did increase the risk of AITD.
Thus, the contribution of rs2476601 may vary by ethnicity.
FOXE1
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Forkhead box (FOX) proteins are typically involved in regulating cell growth,
development, differentiation, and survival. FOXE1 codes for forkhead box protein
E1, a protein that helps develop the physical structure of the thyroid.
Mutations in this gene cause BamforthLazarus syndrome (a rare disease in

which thyroid tissue is underdeveloped or missing entirely) and congenital
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hypothyroidism. FOXE1 has been associated with TSH levels, hypothyroidism,

and thyroid cancer.
Research in a European population found that people with the guanine-guanine

(GG) genotype at rs7850258 in the FOXE1 gene were 1.35 times more likely to
have primary hypothyroidism compared to those with the adenine-guanine (AG)
genotype, whereas people with the adenine-adenine (AA) genotype have a
slightly lower risk.
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Another SNP near the FOXE1 gene (rs755109) was found to be associated with
TSH levels in an isolated Pacific Island population.
SH2B3
The SH2B3 gene codes for the Src homology 2-B 3 (SH2B3) protein, which is
part of the SH2B family of proteins. These proteins are found in many types of
tissues and cells.
In particular, SH2B3 regulates signaling related to hematopoiesis (the formation

of blood cells), inflammation, and cell migration (the programmed movement of
cells to specific locations).
As with PTPN22, mutations of SH2B3 are related to autoimmune diseases

such as celiac disease and Type 1 diabetes (T1D). Thyroid disease may involve
autoantibodies against thyroid peroxidase (TPO). In both PTPN22 and SH2B3,
variants associated with an increased risk of Type 1 diabetes were also linked to
having TPO antibodies.
23andMe tests for a SNP called rs3184504. In people of European descent,

having the thymine-thymine (TT) genotype slightly increased the risk of having
hypothyroidism, while having the cytosine-cytosine (CC) genotype lowered the
risk slightly.
Another study, also in Europeans, showed a link between the rs653178 SNP and
Graves disease.
VAV3
VAV3 codes for a protein (guanine nucleotide exchange factor VAV3) that
regulates the Rho family of proteins, which regulate a wide range of cellular
activities, such as signal transduction. You can think of Rho proteins as cogs in a
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communication system that allows your cells to respond properly to external and
internal changes.
VAV3, like other genes related to AITD, is involved in immune function.
According to 23andMe studies, in populations of European descent:

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Each copy of a C at rs4915077 in the VAV3 gene was associated with 1.3
times the odds of hypothyroidism.
People with the GG genotype at rs2517532 had 1.16 times higher odds of
hypothyroidism compared to those with the AG genotype. Those with the
AA genotype had 1.16 times lower odds of hypothyroidism.
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What we found in our sample
We asked people whether theyd been diagnosed as hypothyroid.
Four people had. So we looked at their genetic data to see how they stacked up.
We also looked at the people who should (by the genetic prediction) have been
at a higher risk.
Our sample is small, so its hard to draw conclusions. But we did find that these
particular SNPs didnt generally have strong predictive value.
Many people who should have hypothyroid symptoms didnt. Conversely,

people who had diagnosed hypothyroid disease didnt have any known genetic
variants that might have increased their risk.
PTPN22 rs2476601
Each copy of an adenine (A) in a European population should theoretically
increase a persons risk of hypothyroidism 1.36 times, and their odds of
developing Hashimotos thyroiditis by 1.7 times.
Yet we had only 1 adenine-guanine (AG) among our diagnosed hypothyroid

group; the rest were guanine-guanine (GGs) in other words, low-risk.
In this sample, we had no highest-risk AAs, but we did have 5 other AGs who
seemed perfectly healthy.
FOXE1 rs7850258
People with the GG (guanine-guanine) genotype at this SNP in the FOXE1 gene
were 1.35 times more likely to have primary hypothyroidism compared to those
with the AG (adenine-guanine) genotype.
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In our sample, 2 people with GG had hypothyroidism, while 2 had the AG.
But again, 12 other people had GG without hypothyroid symptoms.
SH2B3 rs3184504
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Having the TT (thymine-thymine) variant of this SNP slightly increased the risk
of having hypothyroidism, while having the CC (cytosine-cytosine) genotype
lowered the risk slightly.
In our hypothyroid sample, we had 2 CCs and 2 CTs, plus two other healthy TTs.
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VAV3 rs2517532 and rs4915077
Each copy of a C at rs4915077 in the VAV3 gene was associated with 1.3 times
the odds of hypothyroidism.
In our sample, no person with hypothyroidism had a C. All were TT.
People with the GG genotype at rs2517532 had 1.16 times higher odds of
hypothyroidism compared to those with the AG genotype, and those with the AA
genotype had 1.16 times lower odds of hypothyroidism.
In our sample, 2 had AG (moderate risk) and two had GG (highest risk). 9 other
healthy people also had the higher-risk GG.
Thyroid disease doesnt just affect our thyroid. It can also affect what is
downstream, such as other metabolic processes.
There is a strong genetic risk component to thyroid disease. Further,

genetic risk factors for thyroid disease are genetic risk factors for other
(autoimmune) conditions. If thyroid disease or other autoimmune conditions
run in your family, consider genetic testing to alert you to any potential risk.
Your specific genetic risk may vary by ethnicity. This might mean a different
gene variant is more significant than another, or that thyroid disease may
emerge from related but distinct pathways.
Even if you have genetic risk factors, it doesnt necessarily mean you will
get a given disease.
Consider the big picture of other contributing factors. For instance, the
prevalence of AITD varies significantly by geography, from 448 cases per
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100,000 in Scotland to 273/100,000 in Western Australia, to 27/100,000 in
Spain. Since these countries all have a large population of white European
descent, there are clearly other environmental components at work.
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Glucose, insulin and metabolic
syndrome
Glucose, a simple sugar or monosaccharide, is the raw material for building ATP,
our cells energy.
Normally, our bodies maintain glucose homeostasis. In other words, we balance

our blood sugar within a relatively narrow range.
If we eat carbohydrates (say, bread or rice), they break down into glucose when
we digest them. Our pancreas then releases insulin to transport the glucose into
our cells, to be eventually made into ATP or stored as glycogen or fat for later
use.
This process is tightly regulated. Our bodies sense the presence of glucose;
insulin is released as needed; and glucose is stored in cells. When glucose drops
too low, we release stored fuel and our brain sends us the signal to eat.
Both insulin production (i.e., how well we can make insulin) and insulin
resistance (i.e., whether our cells respond appropriately to insulin) are heritable.
Insulin helps signal glucose transporters (GLUTs), particularly GLUT4, to move

glucose into cells. When insulin doesnt work properly, we may have both higher
circulating levels of blood sugar / glucose and insulin. This can eventually
damage tissues.
So we want insulin sensitivity to be high in other words, we want our cells to

be able to hear insulins signals, and respond.
Metabolic syndrome
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If our blood sugar is consistently higher than normal, this signals a metabolic
problem. We may be in the early stages of prediabetes, or even full-blown Type
2 diabetes (T2D).
This situation, and other phenomena that go with it (such as high blood pressure,
altered blood lipids, fatty deposits in and around internal organs such as liver
or kidneys) are collectively known as metabolic syndrome. (Well look at
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cholesterol and triglycerides more below.)
Metabolic syndrome is a disease of affluence, and currently one of the biggest

health problems worldwide. Populations that may have avoided it a few decades
ago (such as in mainland China or many parts of sub-Saharan Africa) are now
confronting its health effects.
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Metabolic syndrome is a complex health problem that involves many processes
and tissues. Over time, almost the entire body can be affected in some way.
For example:
Nerves may be damaged (aka neuropathy) along with blood vessels.

Fat may infiltrate our liver, kidney, muscles, heart, and other organs.
Our immune system may become over-active, and we may have chronic
inflammation.
Our gut motility and microbiota may change.

Our eyes may deteriorate.
Our skin and connective tissues may break down.
Like other complex health conditions, there is no single metabolic syndrome

gene.
Obesity susceptibility genes and dietary

carbohydrates
Typically, metabolic syndrome goes along with higher levels of body fat,
especially around the midsection or in the abdominal cavity (aka visceral fat).
Along with being a storage depot for excess energy, adipose (fat) tissue is part
of our endocrine system: It secretes hormones (such as estrogen or leptin) along
with other cell signals and messengers.
Adipose tissue is closely linked to insulin sensitivity / resistance, and hence, our
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risk of T2D. Yet researchers have wondered:
How are some people metabolically healthier than others, even with the same
amount of body fat?
Our genetic makeup is one factor.

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For instance, through its effects on the AMPK signaling pathway, the fat-secreted
hormone adiponectin plays an important role in insulin sensitivity by helping
our muscles and liver oxidize fatty acids and take up glucose. (This is good.)
When we have a lot of adipose tissue, adiponectin tends to go down. (This is
not so good.)
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Yet people may have genetic variants in ADIPOQ, the adiponectin gene, that
change their risk of metabolic disease. For instance, in some populations (such
as East Asians), having the GT/TT version of the rs1501299 SNP (rather than
GG) is associated with a higher rate of metabolic disorders such as fatty liver or
insulin resistance.
So, our risk for metabolic disease may depend not just on the absolute amount
of adipose tissue we have (though past a certain point, even the luckiest
combination of genes cant protect us from the health effects of extremely low or
high amounts of body fat) but on our genetic makeup as well.
Well look more at body fat in the next chapter.
For now, here are the basic concepts:
Many genes linked to body weight and fatness are also involved in glucose
metabolism.
In general, gene variants associated with higher body weight or more body
fat are also linked to weight gain when people eat a high-carbohydrate diet.
Importantly, this doesnt mean that carbohydrates are bad.
Or that glucose makes us obese.
Or that insulin is a silent but deadly killer (as is often claimed by promoters of
low-carb fad diets).
Lets take another perspective:
Our genetic makeup may make us more likely to respond in certain ways to
certain nutrients.
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This is especially true with processed carbohydrates, since many processed
foods make a lot of sugar available in a form that is digested very quickly (which
means that a lot of sugar hits our system all at once).
Some research suggests that genes that may make us more susceptible
to obesity also affect how our bodies respond to dietary carbohydrates.
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Importantly, this response often isnt just about carbohydrates, but also about
how our bodies manage and mobilize fats. (More on this below.)
Also bear in mind: Research here is often somewhat contradictory. Its not as
simple as saying More sugar is bad.
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PLIN and ADRB2 genes
For instance, there is a complex relationship between carbohydrate intake, body
fatness, and the family of PLIN genes, which code for perilipin (PLIN).
In our fat cells (adipocytes), we have a lipid droplet essentially an oily bubble
of stored fat.
Perilipin surrounds these lipid droplets, and helps control the metabolism of
adipocytes by regulating how fat-mobilizing enzymes (lipases) interact with the
stored fat.
Since the job of lipases is to break down fats so they can be used for energy,
perilipin surrounds the lipid droplet like a protective wall, and ensures that it
doesnt get randomly digested.
Our -adrenergic receptors respond to catecholamine hormones like

epinephrine (adrenaline), and activate processes to help us free up stored
energy, get our muscles moving, and do other autonomic nervous system jobs.
Three genes code for -adrenoreceptors: ADRB1, ADRB2 and ADRB3.
These genes and their variants vary by ethnicity, which can (along with many
other genetic factors, of course) affect how lean or fat you may naturally be.
When certain -adrenergic receptors are activated (for example, during

exercise), they also tell our bodies to start making stored fat available so that we
can use it. Once -adrenergic receptors get the word that its go time, they tell
perilipin to change shape to roll back the gate protecting the lipid droplet, and
expose the stored fat to lipases that can start breaking it down for fuel.
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Figure 6.2: Activation of -adrenoreceptors and effects on perilipin
In general, we usually want our stored fat to be easily available. However, with
some variations of the PLIN genes, which code for perilipin, the perilipin may
be less responsive to the signal to open the gate. Fat stays locked behind the
protective wall.
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Conversely, rare genetic mutations of PLIN genes may result in lipodystrophy,

disorders of fat metabolism that result in wasting of fat stores, or fat deposits in
unusual places (such as on the hands).
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In a study of Hispanic people of Caribbean origin, researchers found that
when participants with a particular variant of the PLIN gene (PLIN 11482 G > A)
ate more complex, higher-fiber carbs, they were leaner; when they ate fewer
complex carbs, they were more likely to be obese. Interestingly, at least in this
study, simple sugars or total carbohydrates didnt seem to have any relationship
to body fatness, nor did other PLIN variants.
Other studies have confirmed that PLIN variants predict both metabolic
syndrome and weight loss.
Similar results with some PLIN variants and insulin resistance were found in a
Singaporean population made up of Chinese, Malay, and South Asians. These
variants of the PLIN genes may be old ones, present before human populations
diverged.
The association between specific PLIN gene variants and fatness also seemed
related to fat intake, particularly saturated fats when people with two
copies of a PLIN variant consumed carbohydrates and saturated fats, they
were significantly more likely to have insulin resistance, a precursor to Type 2
diabetes.
Other genes related to obesity susceptibility, such as FAIM2, FLJ35779, FTO,

LRRN6C, RBJ, and SEC16B also seem to interact with dietary carbohydrates to
increase BMI.

Studies on human diets are generally self-reported (rather than carefully
controlled, like in lab animals). Ways of measuring dietary responses also vary.
So we have to be careful about how we interpret results from any single study.
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Nevertheless, the findings suggest:
Not all bodies respond the same way to the same diet. Your friend may
thrive on a low-carb, high-fat diet (or a high-carb, low-fat diet), whereas you
may find yourself feeling and performing worse when you try the same
thing. |
Theres no one-size-fits-all diet plan that will work for everyone, all the
time. Its important to test, observe, and assess (based on evidence) what
nutrition protocols work best for your unique body.
Genetic testing can give us some clues, but not a detailed prescription,
for your best diet. We still dont completely understand the complex
relationship between genetic variants and metabolic health. Genetic testing
may suggest particular dietary strategies that might help you make wise
dietary choices for your physiological needs.
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Understanding the impact of genetics on metabolism helps you make
informed decisions about your diet. At the very least, genetic testing
may help explain why a particular diet may affect your health or physical
performance. At best, you may find a diet that matches your metabolic
strengths (i.e., what your body prefers).
Processed sugars seem to cause the most metabolic problems, regardless

of specific genetic variations.
Fasting glucose predictions

What predicts our risk of Type 2 diabetes (T2D)?
We know that T2D is correlated with many physiological and lifestyle factors,
such as:
having more body fat (and less lean mass);

being sedentary; and
eating a diet with lots of processed foods.
We also know that adipose (fat) tissue is a hormonally active tissue.
Early studies on Type 2 diabetes (T2D) often used people with more body
fat, who were more likely to develop T2D. It wasnt always clear whether the
progression of T2D was due to environmental effects (for instance, a high-
sugar diet), having a certain amount of body fat, or an underlying genetic
predisposition (in other words, what someone was born with).
Later studies looked at relatively leaner people to account for the environmental
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component of T2D, or for the role that adipose tissue gained in later life might
play.
One way to test for insulin resistance and prediabetes is with fasting glucose:
measuring blood sugar levels after a person hasnt eaten for several hours.
Alhough research suggests that genetic variants linked to higher fasting glucose
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dont always correlate neatly with T2D risk, theres a lot of overlap and fasting
glucose is still a pretty good predictor.

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G6PC2
23andMe looks at a SNP known as rs560887, which is associated with fasting

blood glucose levels in European populations.
This SNP appears in the G6PC2 gene, which codes for glucose-6-phosphatase
catalytic subunit-related protein (also known as IGRP), a protein that is expressed
in islet cells of the pancreas.
This SNP is associated with the function of pancreatic beta cells, which store and
release insulin, as well as C-peptide and amylin (which helps control how quickly
glucose is released into the bloodstream).
In the study used by 23andMe, each T at rs560887 lowered subjects fasting

plasma glucose level by 0.06 mmol/L (1 mg/dl).
Allele Average fasting glucose levels
CC 5.18 mmol/L (about 93 mg/dl)
CT 5.12 mmol/L (92 mg/dl)
TT 5.06 mmol/L (91 mg/dl)
For reference, a fasting blood glucose level lower than 5.6 mmol/L is considered
normal, while anything over that is considered prediabetic.
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We had some blood tests lying around, so we looked for correlations.
One person from of our PN sample had just been diagnosed with prediabetes.
Yet according to the G6PC2 SNP, with a CC profile, they should have had lower
than average blood sugar.
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We also had 2 TTs, who were predicted to have higher than average blood sugar
but whom, to date, seem healthy.
Not surprisingly in our health-and-fitness-oriented population, many CT people

had normal or lower than average fasting blood glucose. This suggests that
lifestyle choices play a bigger part than a single SNP.
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Blood glucose is an important health indicator. Dont rely only on a

genetic test. At best, a genetic test can only predict possible risk. It cant
tell you what your blood glucose actually looks like. While blood glucose
normally rises and falls as we eat and fast between meals, chronically
elevated blood sugar can tell you that there is an underlying health problem.
Get regular bloodwork done. Generally, by the time fasting glucose is

affected, people may be well on their way to metabolic syndrome. So having
your fasting glucose tested, along with your blood lipids (see below) as
part of your regular medical checkup (for instance, annually) is a good idea,
especially as you age.
If you are a do-it-yourself kind of person, you can buy a home glucose
monitor and test your glucose throughout the day, including after meals.
Postprandial after meals blood sugar levels will give you a better idea,
sooner, of what your blood glucose is up to, compared to fasting glucose.
If youd like to improve your overall wellness, see our strategies for
healthy metabolism in Chapter 12.
Blood lipids and lipoproteins

Once we eat and digest foods containing dietary fats, these fats (aka lipids) are
packaged into various formats (such as triglycerides) to be transported around
the body and used.
Much like blood glucose, levels of these blood triglycerides and lipoproteins
(proteins that transport lipids) are important indicators of metabolic health. (Well
look more closely at lipids, triglycerides, and lipoproteins below.)
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As with glucose, its normal to have some circulating lipids and lipoproteins, but
we dont want too many, too often.
Lipid and lipoprotein levels are strongly influenced by how much body fat we
have along with our environment and our choices, such as our nutrition, our
activity, smoking or drinking, or other medications. They can also be influenced
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by genetic factors.
Everyone has that proverbial great-aunt who lived to be 103 and swore by her
daily whiskey and buttered bacon sandwich. And as we witness this fiercely
unrepentant and apparently immortal boozing, buttering, and bacon-ing, we ask
ourselves, Why am I eating all this damn healthy food anyway?
On one level, thats a good question.

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Some people seem able to consume unhealthy food, drink like a fish, smoke a
pack of cigarettes a day, and make it to triple digits completely unfazed.
Other people seem to do everything right and get taken out by a heart attack
or some other metabolic disease far too early.
Frankly, it seems deeply unfair sometimes.
And, indeed, it may be unfair, in the sense that some people may be naturally
better at managing their blood lipids than others. This relative advantage may, in
part, be due to genetic factors.
The genetics of lipids

To date, we know of about 160 genetic variants associated with lipid levels.
Of course, not all are equally important or strongly linked. Some operate mainly
in particular processes (such as regulating the expression of other genes) or
particular tissues (such as the liver).
We still dont fully know how all genetic variants interact with blood lipids and
other relevant biomarkers.
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Figure 6.3: Genes involved in lipids and lipoproteins.

Diagram adapted from Willer CJ, Schmidt EM, Sengupta S, et al. Discovery and Refinement of
Loci Associated with Lipid Levels. Nature Genetics. 2013;45(11):1274-1283. doi:10.1038/ng.2797.
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Lipoproteins and the basic blood lipid panel
If you go to your doctor and get a cholesterol test done, its helpful to
understand what this really means.
Cholesterol is a waxy lipid (imagine something like lard). We make cholesterol

in our liver, but its also in our food. We use cholesterol to make many important
molecules that our bodies use, including our sex hormones.
Triglycerides are molecules of fat made of three fatty acids hooked to a glycerol
backbone. When we digest fat, our bodies package fatty acids into this format,
and transport them through the bloodstream to be stored in adipose cells.
Lipoproteins are proteins that transport lipids. Oil and water dont mix, and
neither do lipids and blood. Fats have to hitch a ride on lipoproteins, like a bunch
of passengers on a little inner tube floating down a river. Lipoproteins come in
different sizes, amounts, and densities. Density refers to the fat-to-protein ratio:
When theres more fat and less protein, the particles are considered less dense,
and they become more buoyant.
Apolipoproteins are protein-based components of lipoproteins. Theyre

encoded by genes that start with the letters APO (such as APOB or APOE). Well
look at apolipoproteins a little later.
We can divide lipoproteins into a few general categories based on density:
HDL-C is high-density lipoprotein, aka the good cholesterol. This brings

cholesterol back to the liver for recycling.
LDL-C is low-density lipoprotein, aka the bad cholesterol. This transports

cholesterol away from the liver to elsewhere in the body, and can be part of
the process of inflammation that underlies cardiovascular disease risk.
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IDLs, or intermediate-density lipoproteins, somewhere between LDL and
VLDL particles.
VLDL is very low-density lipoprotein, also a kind of bad cholesterol. We

also want this to be lower.
Chylomicrons, also known as ultra-low-density lipoproteins (ULDLs).

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When we get a basic blood lipid panel done at our doctors appointment, it will
most commonly measure:
Blood triglycerides: how much total triglyceride is in all the lipoprotein

particles combined.
Total cholesterol: how much cholesterol is in all the lipoprotein particles

combined.
HDL-C: how much HDL-C we have.

LDL-C: how much LDL-C we have.
Generally, we want most of these to be lower, except for HDL, which we want to
be relatively higher.
Having too many triglycerides circulating in our blood is known as

hypertriglyceridemia. Very high cholesterol levels are known as
hypercholesterolemia. The combination of these, which creates a poor blood
lipid profile, is known as dyslipidemia.
All of these are risk factors associated with metabolic syndrome and its
associated diseases, although they dont necessarily mean that someone will
always develop health problems.
All of these risk factors can be affected by diet and exercise, along with other
lifestyle choices and environmental factors but can also be partially shaped by
genetics.
For instance, research has found ethnic differences in the LPL and LIPC
genes, which code for lipases (enzymes that help us break down fats) and are
expressed in liver, heart, muscle and fat tissues.
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Compared to people of European ancestry, people of African descent (including
West African, Afro-Caribbean and African-American) were more likely to have
particular lipase variants that protected them from coronary atherosclerosis (aka
hardening of the arteries).
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Blood lipids are important health indicators. If youd like to know what they
are, measure them directly with a blood test.
Dont rely only on a genetic test. At best, a genetic test can only predict
possible risk. It cant tell you what your blood lipids actually look like.
Get regular bloodwork done. Having your blood lipids tested along with
your blood glucose (see above) as part of your regular medical checkup
(perhaps annually) is a good idea.
If you are diagnosed with dyslipidemia or other metabolic health

concerns, discuss this with your health care professional. If you have
heritable dyslipidemia, you should still be doing all the things that promote
healthy metabolism (you know, the whole Dont smoke, keep a healthy
body fat level, get some exercise thing), but you may need additional
medical support.
Review our strategies for healthy metabolism in upcoming chapters.
Hypertriglyceridemia and zinc fingers

Normally, we want triglycerides to be stored safely in our fat cells, waiting
to be used for energy. We dont want too many of them roaming around our
bloodstream for too long.
Some people are genetically more likely to have higher blood triglycerides, aka
hypertriglyceridemia.
ZNF259 and rs964184
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23andMe tests for a SNP known as rs964184 on the ZNF259 gene (which is also
sometimes known as ZPR1).
The ZNF in this gene name stands for zinc finger.
While Zinc Finger would be a terrific band name (and, indeed, someone has
already created a song that uses the primary structure of another ZNF
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protein), it actually refers to a zinc-based part of a protein that gives a protein a

particular shape. (Youll remember from Chapter 2 that the physical shape and
structure of a protein affects how it works.)
Most proteins with zinc fingers are interaction molecules that are designed to
bind to DNA, RNA, or other protein molecules. So their shape crucially affects
how they are able to do this job.
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The protein coded by ZNF259 binds proteins that are involved in insulin
sensitivity, glucose and fat metabolism, and fat storage, such as peroxisome
proliferator-activated receptor gamma (PPAR-) or hepatocyte nuclear factor 4
(HNF4A).
ZNF259 is also located close to another gene complex that is strongly linked
to blood lipids: APOA5A4-C3-A1. Variants in APOA5 affect metabolism of
chylomicrons, VLDL-C, and HDL-C. (Well look at the APO gene family below.)
In one study of people of European descent who had hypertriglyceridemia,

each copy of a G at the rs964184 SNP on ZNF259 increased peoples risk of
hypertriglyceridemia by about 3.3 times.
Other research in Japanese and South Asian populations has found a similar
relationship between ZNF259 and the overall risk of metabolic syndrome.
In this case, having the G form of the rs964184 SNP was linked to having
higher blood triglycerides along with higher fasting plasma glucose and lower
HDL cholesterol.
This suggests, again, that many features of metabolic syndrome are related.
Hypercholesterolemia
Like hypertriglyceridemia, hypercholesterolemia (excessively high blood
cholesterol) can be inherited, a condition known as familial hypercholesterolemia
(FH). FH is a risk factor for metabolic syndrome and related health problems like
cardiovascular disease.
FH happens when genetic variations affect our bodys ability to clear LDL
effectively from the blood. Over time, LDL and its cholesterol passengers can
build up in tissues such as our blood vessels or connective tissues.
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The most common genetic cause of FH is variations in the LDLR gene. LDLR
codes for the low-density lipoprotein receptor that determines whether LDL-C
can bind to a cell, and then be transported into it for safe storage. About 80-90%
of people with FH who are genetically tested show variations in this gene.
The second most common cause of FH (only about 5% of cases) is variations in

the APOB gene. Youll remember that APO genes code for apolipoproteins in
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this case apolipoprotein B.

23andMe looks at two variations in the APOB gene that are linked to FH:
R3500Q, found mainly in people with European ancestry.

R3500W, found mainly in people of Asian ancestry.
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Several PN team members sampled reported having had a total cholesterol test
that was higher than average.
Yet none of these people had the genetic variants of APOB that suggested they
should have this profile.
Interestingly, all of these people were fit, often leaner than average. This tells us
that other factors are probably at work in these higher-than-average blood tests.
Blood lipids are important health indicators. If youd like to know what they
are, have them measured directly with a blood test.
Dont rely only on a genetic test. At best, a genetic test can only predict
possible risk. It cant tell you what your blood lipids actually look like.
Get regular bloodwork done. Having your blood lipids tested along with
your blood glucose (see above) as part of your regular medical checkup
(perhaps annually) is a good idea.
If you discover hypertriglyceridemia, hypercholesterolemia, or other

metabolic health concerns, discuss this with your health care professional.
If you have a heritable condition, you should still be doing all the things
that promote healthy metabolism (you know, the whole Dont smoke,
keep a healthy body fat level, get some exercise thing), but you may need
additional medical support.
Alzheimers disease
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Alzheimers disease is a neurodegenerative disease in which brain cells and
their connections slowly break down, while wastes, plaques, and other bits of
crud (such as neurofibrillary tangles, which are sort of like the hairballs that clog
up drains) build up.
(Heres more reading on Alzheimers from our PN blog.)

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Alzheimers is now sometimes called diabetes of the brain, since some

researchers suggest that it may be related to the same types of dysregulated
glucose and insulin mechanisms as we find in Type 2 diabetes.
Alzheimers is a frightening prospect, and this fear may affect our choice to have
our DNA tested.
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Many of us at PN researching genetic data asked our parents to take part. Some
parents were game. Some parents were not.
The most common reason given?
I dont want to find out Ill get Alzheimers or something.
We fear neurodegeneration. Losing our mind and physical function in an

irreversible, inexorable march is a scary prospect.
Our co-author Krista watched her once mentally-agile, fiercely self-reliant

grandfather become confused, frail, and terrified as Alzheimers punched holes
in his brain. Now she (and her mother) wonder: Whos next?
Currently, more than 5 million people in the US alone are diagnosed with
Alzheimers disease, and this number is expected to triple by 2050. 1 in 9 people
over 65 has some form of neurodegeneration attributed to Alzheimers; over 1 in
3 people over 85 does. Its one of the fastest-growing causes of death for
older people.
Alzheimers does, indeed, run in families. But, much like Type 2 diabetes and other
chronic diseases, while Alzheimers is a genetic risk, it is not a genetic destiny.
One of the known genetic risk factors in developing Alzheimers disease is our
friend the apolipoprotein in this case, a variant on the APOE gene, which
codes for the protein apolipoprotein E, a cholesterol carrier found in the brain
and elsewhere in the body.
The APOE protein comes in three forms: 2, 3, and 4. (The is the Greek
letter epsilon.)
The APO 4 variant is a major risk factor for Alzheimers in many populations,
and seems to span people of European, African, and East Asian descent. In fact,
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compared to the averages for both of those groups:
Among people of African descent, one copy of the 4 variant is associated

with 1.5 times higher odds of developing Alzheimers; two copies is
associated with about 4 times higher odds in people of African descent.
Among people of East Asian descent, one copy of the 4 variant is

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associated with 4 times higher odds; two copies is associated with 12 times
higher odds.
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While the APO 4 variant is associated with a higher risk of developing
Alzheimers, it doesnt act alone. For instance, risk increases when in addition
to the APO 4 variant people also have:
A particular variant of rs2373115, a SNP in the GAB2 gene, which codes for
the growth factor receptor-bound protein 2 (GRB2). This protein is involved
in signaling and communication within and between cells.
A particular form of rs1799724, a SNP near the tumor necrosis factor (TNF)
gene, associated with altered levels of beta-amyloid plaques (one of the
particular plaque types linked to Alzheimers) in cerebrospinal fluid (CSF).
Variants in genes that regulate polymerases, enzymes involved in DNA and

RNA assembly. For instance, having an I-G-T haplotype of 3 SNPs in the
POLD1 gene and the ApoE-4 variant almost doubles the risk of Alzheimers,
compared to just having the ApoE-4 variant alone. The POLD gene, which
codes for the protein polymerase delta 1, is also associated with colon
cancer, deafness, and lipodystrophy.
Maintain good overall health. Body health includes brain health.

If youre concerned about possible genetic risk, this is worth
getting tested for. We still dont have cures for Alzheimers and other
neurodegenerative diseases yet, but it does help to act preventively and
catch potential issues early.
Understand your data clearly. Be sure to discuss all results with your doctor
and/or genetic counsellor, to understand the findings and discover what you
can do to lower your risk.
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Whats up next
Now that we have a basic understanding of how metabolism works, and a few
genetic factors that may affect it, lets look at how genetics can also influence
our body size, shape, and fatness (or leanness).
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CHAPTER 5 CHAPTER 7
What we found: Heredity What we found: Body
weight and body comp
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How does heredity work? Why

dont we all share the same In this chapter, we look at

genetic variations? How might our some genetic factors related
ethnic background and ancestry to energy balance, what makes
affect our overall health? our bodies naturally bigger or
smaller, and how much lean or
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CHAPTER 7
What we found: Body weight and

body comp
In this chapter, well look at:
How body size, weight, and composition (i.e., our ratio of lean mass to
fat mass) are complex phenomena that are in part, shaped by genetic
mechanisms but not as much as we might assume;
The role of genes involved in energy balance and regulation, and

evolutions legacy of protecting us from scarcity; and
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The role of other environmental factors, such as food availability, food
reward, eating behaviors, and so on.
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Just because a genetic test can tell you what body weight or composition
you might have, it doesnt mean that it can tell you the perfect diet,
supplement, or exercise plan for you.
The complexity of body weight and

body fat
When it comes to weight and body fat, many people will say things like:
I must have a slow metabolism.

I think Im genetically programmed to be fat / skinny / muscular / whatever.
That person is in good shape because they have good genetics.
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But is it really that simple?
(Spoiler alert: Ha ha! Its biology! You already know by now that it aint.)
The key points in this chapter are: |
Body weight, body composition (i.e., our ratio of lean to fat mass) and
body fat levels are influenced by our genes.
But they are also affected by our environment and lifestyle choices.
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Energy balance, nutrient processing, and eating
behavior
Why do you eat? (Or not eat?)
Why are you the body size that you are?
The answer is complex.
Its not just about willpower or your workout program.
There are many processes that affect body weight and composition:
Energy balance: The balance between food energy consumed, and energy
being expended to support our metabolism and activity. If more energy
comes in than goes out, we will gain mass. If less energy comes in than goes
out, we will lose mass. Thus, our energy balance determines body mass.
Energy sensing: Our bodies ability to know how much energy we have
available (for instance, in the form of stored fat).
Nutrient partitioning: Will the nutrients you eat be stored (e.g., as fat or
muscle glycogen) used (e.g., to build muscles, to repair damaged tissues, to
fuel cellular activities), or burned off as heat?
Appetite and food reward: Do we want to eat? Does eating seem fun and
interesting?
Eating behavior: What foods do we choose? How do we know when to stop

eating?
Of course, all of these are influenced by the interactions between our genes and
our environment.
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As you can imagine, there are many genes involved in regulating metabolism,
body weight or fatness, and eating habits.
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Here are just a handful. As you read about what each one does, try to imagine
how mutations in these genes might have a physiological consequence:
There are 21 APO family genes that code for apolipoproteins, a large family
of molecules involved in lipid transport and processing. We looked at the
role of some APO proteins in the previous chapter.
TCF7L2, which codes for transcription factor 7 and is linked to balancing

blood sugar; variants of this gene are associated with a higher risk of Type 2
diabetes.
PPARG, which codes for one of the peroxisome proliferator-activated

receptor (PPAR) subfamily of nuclear receptors (youll remember we learned
about nuclear receptors in Chapter 6 with the vitamin D receptor). PPARs
are involved in regulating the expression of metabolic genes. Depending
on the tissue and PPAR, they can promote fatty acid storage or breakdown,
glucose metabolism, antioxidant responses, and so on. Because of this, they
are likely involved in metabolic diseases such as cardiovascular disease or
diabetes.
LEPR, which codes for the leptin receptor. Leptin is a hormone involved in
sensing how much energy we have available, whether stored in the form of
body fat, or how much weve recently eaten.
MC4R, which codes for the melanocortin receptor. The encoded protein
interacts with adrenal and pituitary hormones. Defects in this gene can
cause autosomal dominant obesity, meaning that you only need one copy
of a gene variant to see effects.
FTO, which codes for fat mass and obesity-associated protein, is related to
glucose and energy metabolism, as well as the regulation of body fatness
and size. FTO is also an RNA editor and is involved in regulation of muscle.
Well look at FTO more below.
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LRP5, which codes for bone mass. LRP5 gene mutations are associated with
lower bone density and a higher risk of osteoporotic fractures.
There are also genes involved in regulating eating behavior and energy balance
(the balance between energy in from food, and energy out from metabolism and
activity).
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These include:
UCP codes for mitochondrial uncoupling proteins (UCPs), which separate

oxidative phosphorylation from ATP synthesis and dissipate energy as heat.
People who naturally maintain a lower body weight may be more likely to
convert excess energy from food to heat, rather than storing it as body fat.
Related to this process is the gene ADRB3, which codes for a protein in the
beta adrenergic receptor family. Beta adrenergic receptors are found mostly
in fat tissue, and help regulate lipolysis (fat breakdown) and thermogenesis
(heat production).
AGRP codes for agouti-related peptide (or agouti-related protein). Along

with other substances such as neuropeptide Y, this protein works in the
hypothalamus, aka the bodys metabolic Mission Control, to regulate
appetite and eating behavior.
GHRL codes for two proteins: ghrelin and obestatin. Ghrelin goes up when
we are hungry, stimulating hunger. The function of obestatin isnt completely
clear yet, but it may oppose the action of ghrelin.
Measuring body size and

composition
Body mass
Many studies that explore the relationship between genes and body size or
fatness use body mass index, or BMI.
BMI is simply a measure of the relationship between someones height and
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weight. The higher BMI is, the heavier someone is for their height.
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The World Health Organization divides BMI into the following categories.
BMI Category
Below 18.5 Underweight
18.524.9 Normal weight
25.029.9 Overweight
30.034.9 Obesity class I
35.039.9 Obesity class II
Above 40 Obesity class III
To put this in real terms, lets say we have a person who is 56 (1.68 m) tall.
How might various BMIs look for them?
BMI Category Sample weight
Below 18.5 Underweight Less than 114 lb (~52 kg)
18.524.9 Normal weight 115 to 154 lb (~52-70 kg)
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25.029.9 Overweight 155 to 185 lb (~70-84 kg)
30.034.9 Obesity class I 186 to 216 lb (~84 kg-98 kg)
35.039.9 Obesity class II 217 to 247 lb (~98 kg-112 kg)
Above 40 Obesity class III Over 247 lb (~112 kg)

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What can BMI tell us?
In general, we know that at the population level (in other words, in a big group of
people), if you have a higher BMI (past a certain point), you are more likely to:
develop chronic diseases such as cardiovascular diseases, Type 2 diabetes,

and cancer;
have more body fat; and/or

have certain kinds of metabolic problems.
At the population level, BMI is a proxy for body fatness.
If we took a randomly-selected group of 100,000 people, peoples BMI would be

closely related to their body fat levels. Having a much higher-than-average BMI
would likely mean higher-than-average body fat.
At the individual level (i.e., you), BMI is often too broad to be helpful.
The relationship between BMI and body composition is just an average. It

doesnt necessarily tell us about you specifically.
BMI tells us only how much body mass someone has, not what that mass is
made of.
So a fit and lean but heavy rugby or American football player may have the
same BMI as a sedentary person with much more body fat and much less dense
muscle and bone. Similarly, an extremely lean ultramarathoner with naturally
lighter bones may be designated as underweight though they are still also very
fit and strong.
In our PN sample, not surprisingly, many people were overweight or even
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obese despite being fit and athletic, perhaps even leaner than average.
So when we look at how BMI is correlated with genetic data, we want to be

careful about how we draw conclusions from that correlation.
Body composition
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Thus, along with height and weight, we also look at body composition: the
relative proportion of fat and lean mass (which, again, includes muscle, bone,
and connective tissues).
Some genetic studies use waist circumference (WC) as a measure of body

composition. Fewer genetic studies have used more accurate methods (such
as caliper skinfolds, BodPod or hydrostatic immersion) to look for precise
relationships between genes and how much fat or lean mass a person has.
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Well look at data from some genome-wide association studies (GWAS) that
uses the extremely precise computed tomography (CT) method, below.
As with BMI, we need to carefully interpret studies that correlate body

composition with genetic data.
How measurements of BMI and body composition are taken and used can
affect our conclusions.
Variations in BMI
Though many risk factors (such as FTO gene variants, which well look at below)
seem to be common across most groups, various populations differ in their risk.
For instance, although people of East Asian and South Asian origin tend to be
among the worlds lightest and smallest (both traits shaped by heredity), they
have a higher risk of metabolic disease at a lower BMI than people of European
ancestry.
This means that knowing BMI alone, or potential links between genes and BMI,
may not fully predict health or disease for people from certain groups.
As with many biological factors, both heredity and environment matter.
Height is strongly shaped by genetics, but weve been getting taller and taller
over the last several decades. Were also getting heavier.
Population-wide genetic changes are typically slower than this, while

environmental conditions can change much more quickly (for instance, imagine
how moving from a poor, rural region to an affluent, industrialized urban region
might change many factors in a persons body).
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Figure 7.1: Changes in average height, 1810-1980

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In 1996, about 52% of Bangladeshi women were considered underweight (BMI
lower than 18.5). Today, its only about 30%.
Conversely, in 1996, only about 3% of Bangladeshi women were considered

overweight (BMI 25); thats now quadrupled to about 12%.
Lightest countries in the world: Percentage of women with BMI lower

than 18.5
% with BMI <18.5 Average height (cm) Average height (ft/in)
Eritrea 37.30 NA NA
India 35.60 151.9 cm 50
Bangladesh 29.70 150.6 cm 411
Vietnam 28.30 152.2 cm 50
Ethiopia 26.50 157.6 cm 52
Nepal 24.40 150.8 cm 411
Cambodia 20.30 152.4 cm 50
Philippines 14.20 151.7 cm 411
Data from WHO Global Database on Body Mass Index (BMI). Data for height / weight are most
recent data available.
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Although the United States, on average, has some of the worlds tallest and
heaviest people, there are differences by ethnic group. (See table below.)
This is not 100% genetic, though.
(As weve seen, theres significant variation within broader groups. For
instance, labels like Asian American or Latin American, as are used in the
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US Census, are pretty loose categories that cover a wide range of groups
and geographic origin.)
People from a given ethnic group not born in the US are more likely to have a
lower BMI than their American-born genetic relatives.
(In other words, if you were born and raised in Somalia or Thailand, and your
genetically similar sibling was born and raised in the US, theyd probably be
heavier than you even if you later moved to the US to join them.)
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Heaviest countries in the world: Percentage of women with BMI higher
than 30
% BMI >30 Average height (cm)) Average height (ft/in)
American Samoa
37.30 NA NA
USA 35.60 151.9 cm 50
African American 56.6 163.6 cm 54
Latin American 44.4 158.9 cm 52
Asian American 11.4 158.4 cm 52
European American
32.8 165.0 cm 55
Australia 24 163.8 cm 54
United Kingdom 23 164.5 cm 55
Croatia 22.7 166.49 cm 55
Malta 19.3 163.8 cm 5 4
United Arab Emirates

16 156.4 cm 54
Greece 13.5 166 cm 55
Data from Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of childhood and adult obesity in
the United States, 2011-2012. JAMA. 2014;311(8):806-814. doi:10.1001/jama.2014.73
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BMIs here and elsewhere in the world are going up, often quickly.
This suggests that other factors besides genes are probably contributing.
How might environment play a role?

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If, as weve seen, body size and mass depend on factors like energy balance or
sensing, as well as eating and activity patterns, then changing environments can
often disrupt our natural regulatory systems as well.
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This can include, for instance:
changes to physical environments e.g., increasing industrialization of

previously rural areas, or living out of sync with normal light-dark cycles in a
24/7 society.
changes to social environments e.g., changing social norms of eating and

activity.
changes in microbial environments e.g., introducing new pathogens or

having less diversity in our own personal microbiome.
changes in physical activity e.g., being able to commute long distances

by car instead of walking.
changes in food availability and production e.g., a shift from working in

the field growing staple crops to buying processed foods in supermarkets.
changes in food palatability and reward e.g., traditionally boiled hand-

dug potatoes may become delicious, crave-able potato chips.
changes in economic conditions and living standards e.g., having an

emerging middle class that does less physical labor and can buy more and
better food.
changes in crucial developmental conditions e.g., childhood vaccinations

that prevent diseases, or better maternal and infant nutrition, both of which
can affect adult BMI.
changes in chronic stressors e.g., well everything that were all freaking
out about right now.
So even if we have light / small genes or heavy / big genes (were there
such things), our environment would still strongly affect our BMI and body
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composition.
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Understand how genetic research measures body size, composition, and

weight, and what that means (or doesnt). Genetic testing may look for
genes related to BMI, or amount of body fat, or both.
Understand that populations are different than individuals. Your

experience and body size, shape, or fitness is unique to you. Two people
with the same body weight but different ancestry or environment will have
a different probability of metabolic disease, and that metabolic disease may
emerge through slightly different signaling pathways. Even if your genetic
test results suggest, for example, you have a given risk of BMI-related
metabolic disease based on a sample of 100,000 people that risk may not
apply to you.
Understand that human variation is normal. Theres about 11 of height

difference between the average woman in Bosnia-Herzegovina (57) and
the average woman in Bolivia (48). There is a wide range of BMI that can
be normal and healthy, and a wide range of people that can be healthy at a
given BMI. So even if your BMI is genetically predicted to be higher or lower
than average you may be perfectly fine.
Look at the interaction between genes and environment. Well mention

this often through this chapter.
The genetics of body weight and fat

Evolutions legacy
The medical and fitness communities have debated whether people who have
excess body fat, or who have trouble managing their weight and/or their eating
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habits have a disease or addiction.
In fact, most of us who struggle to maintain a healthy body fat level or

say no to that second donut are perfectly normal in genetic and
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For example:
Most humans evolved to store body fat. Humans who couldnt do this well
would risk starvation during times of scarcity. In particular, women need to
have enough body fat to support the potential long-term energy demands of
pregnancy and breastfeeding.
Most humans evolved to prefer things that taste good, and to want to
eat lots of food when its available. For most of our history, food was hard
to get, and sweetness signaled things that were energy-dense and good
to eat. This legacy affects our appetite, hunger, and fullness signals and
regulation, especially in the 21st century when delicious, energy-rich foods
are everywhere.
Most humans evolved to conserve energy. In other words, we are naturally

less inclined to move around if theres no reason to do it. Why waste
valuable energy when you dont have to?
Most humans evolved to seek rewards. What gets us off our butts and out
of the safety of the burrow? The promise of something good. Our brains
have complex circuits that inspire us to explore, be curious, and chase
things that reward us (such as food, fun, and mates). Many types of energy-
dense foods give us a chemical hit, helping us synthesize feel-good
neurotransmitters.
So having some squish on your body, or loving ice cream, or preferring to lie on
the couch rather than go to the gym, doesnt mean your body is broken.
It probably means your genes are doing their job of finding and conserving
precious energy.
Traits that were evolutionary advantages for most of our history when food
was scarce, daily energy demands were high, and rewards were hard to come
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by are simply a mismatch now. Especially if we want to be lean or stay away
from the chocolate-covered pretzels.
For genetic expression, environment matters.
Epigenetics and environments

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In Chapter 2, we introduced you to the concept of epigenetics the ways in

which our genetic expression is regulated.
Lets say we have two genetically identical people in other words, identical
twins.
One twin is leaner. The other is heavier and/or fatter.

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Why the difference?
Good question.
One of the most useful ways to explore the contribution of genes and
environment, particularly when it comes to body size and metabolism, is to look
at twin studies.
Identical twins, of course, share the same genetic blueprint, and often the same
early-life experiences. Yet they end up looking different as adults if they do
different things, or live in different environments.
If we examine our two different-looking twins perhaps one twin is leaner and
lighter, while the other is significantly overweight or obese what might we
find?
Well, differences may have started in utero.
For instance, if one twin hogs all the nutrients while both twins are in the womb,
this also affects genes such as IGF1R, which codes for insulin-like growth factor
1. IGF1 is an important protein involved in anabolism (growth) and development,
and thus affects body size and mass.
Fun factoid!
The gene that codes for another insulin-like growth factor, IGF2, is only expressed
from paternal inheritance in other words, the genetic material you got from dad.
This epigenetic phenomenon is known as imprinting: the silencing of genetic

material from one parent or another.
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As adults, compared to their leaner twins:
Obese twins tend to have more fat in the areas wed expect: under the
skin (subcutaneous fat), around the internal organs (visceral fat), marbled in
muscle tissue (intramuscular fat) and laced into the liver and kidneys.
Obese twins tend to be less sensitive to insulin (which is related to how

much fat they have in their liver).
Obese twins express some gene pathways more strongly, particularly

genes involved in inflammation, as well as genes involved in organizing cell
structures, cell growth, and transport between cells.
Obese twins immune systems are more highly activated (aka upregulated),
as if preparing to fight off pathogens. One study found that the most
overexpressed gene in obese twins is SPP1, which codes for osteopontin,
a cytokine (cell signaling molecule) that helps recruit immune cells such as
macrophages and T cells during inflammatory processes.
Obese twins have other gene pathways that are less expressed (i.e.,
downregulated), such as pathways involved in energy metabolism and/or
breaking down fatty acids and amino acids.
Obese twins have fewer copies of mitochondrial DNA in their fat tissue
sometimes nearly half as much as their leaner twins. This might partly
explain the metabolic problems we see. Defects in mitochondrial energy
metabolism in subcutaneous adipose tissue may encourage the body to
store fat elsewhere, particularly in tissues that are especially sensitive to
insulin (such as the liver, skeletal muscle, and pancreas), resulting in severe
insulin resistance.
Obese twins often prefer fatty or sugary foods more than their leaner
siblings.
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Given, again, that each pair of monozygotic (identical) twins are essentially
genetic clones, these differences tell us:
Body size, fatness, and metabolic health are not just about the genetic code
we are given.
Rather, epigenetic expression of these genes is also crucially important.

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The good news, though, is that many of these up- or down-regulations can
change if:
body weight / fat changes;

people change what they eat; and/or
they change their physical activity.
Well look at this more in the final chapter on what to do.
The polygenic basis of obesity

Regulating all of these functions above (such as energy balance and storage,
hunger and appetite, etc.) is pretty important for our survival.
To date, we know of about 185 genes that are implicated in obesity or more
accurately, in making it slightly more likely that a person may be heavier or fatter
than average.
These genes may be expressed differently in adults and children, and/or in

various populations, due to environmental factors or genetic variations.
More advanced GWAS using computed tomography (CT) let researchers look
at various types of body fat and differentiate visceral fat (around the internal
organs) from subcutaneous fat (under the skin).
Such studies have, to date, only confirmed links between fat and 8 SNPs near
the following genes:
ETV5, which codes for ERM proteins, an ancient protein family of

transcription factors.
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FLJ35779, which codes for POC5, a protein involved in regulating cell
mitosis and structure. POC5 is mostly expressed in the prostate. Other key
sites include thymus, mammary gland, and bone marrow.
FTO, which well look at more below.

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GIPR, which codes for receptors involved with signaling for gastric inhibitory
polypeptide (GIP), one of the incretin (insulin-stimulating) hormones released

by the gastrointestinal tract that enable our bodies to process glucose.
Variants in this gene may be related to developing Type 2 diabetes or
having more visceral fat. Some research also suggests that high levels of
GIP might be involved in adipose tissue inflammation, a characteristic of
obesity.
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LINGO2, which codes for a protein called leucine-rich repeat and
immunoglobulin domain (LINGO), involved in growth and regulation of axons
in the nervous system (for instance, its linked to Parkinsons disease). Its
also involved in cell signaling (aka signal transduction), the process by
which cells send chemical messages to each other. (Youll remember we
learned about signaling pathways in Chapter 6.) Its not clear exactly how
this protein contributes, though.
NEGR1, which codes for neuronal growth regulation factor 1 (NEGR1). This
protein, strongly expressed in the hypothalamus (which, youll remember
from Chapter 6, helps regulate body weight and appetite), seems to play a
role in brain function and structural integrity. Its also expressed in adipose
tissue, particularly subcutaneous fat. This gene showed up in a study of
patients with bulimia nervosa, and correlated with some of the cognitive
dimensions of disordered eating, such as having poor interoception (i.e.,
being able to correctly read signals from inside ones body).
SH2B1, which codes for sarcoma homology 2 B adaptor protein 1 (SH2B1).

This protein is part of a family of proteins involved in signaling for many
hormones, peptides, and cytokines (cell signaling molecules), such as
leptin, insulin, growth hormone (GH), IGF-I, nerve growth factor (NGF), and
brain-derived neurotrophic factor (BDNF), which well look at below. These
regulate energy balance, body weight, insulin and glucose, anabolism, and
other metabolic activities.
TMEM18, which is an evolutionarily conserved gene (in other words, its

been around a long time and appears in many species) that codes for a
transmembrane protein (a protein that runs through a cell membrane, usually
as a bridge between the inside and outside of the cell). We dont completely
know what this protein does. 23andMe tests for a SNP, rs6548238, that
seems to predict small variations in body weight (between about 1-3 lb of
difference). Each copy of a T rather than a C at rs6548238 near the TMEM18
gene was associated with 0.26 units lower BMI (equivalent to 1-3 pounds,
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depending on height).
Each of these genes can affect a different yet related physiological process: fat
or glucose metabolism, cell signaling and gene regulation pathways, membrane
transport, etc. |
While there are certainly some rare genetic conditions that can make a
few people more likely to be obese, its not as clear-cut as many people
might think.
Outside of environmental effects, simply having a single genetic variant (or

even a collection of variants) might only affect body weight by a pound or two
(0.5 to 1 kg).
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Even in extreme cases of apparently genetic obesity that dont respond to
nutrition and exercise, the most common mutations (in the melanocortin-4
receptor gene) only appear in 1-6% of people with obesity.
Allelic heterogeneity
Lets say on a few separate occasions, you eat:
suicide-spicy chicken wings

an extra helping of pie with whipped cream
an entire bag of gummy candy
a hot dog with fried onions, cheese curds, and sauerkraut
Each time, you are wracked with heartburn afterwards.
The foods that caused that heartburn were different, but all might fall loosely
under the heading of foods you might eat at a carnival.
Allelic heterogeneity works the same way: Related genetic variants, or alleles
(different types of junk food), in the same general location (our carnival) are
associated with the same trait or outcome (heartburn).
This means that if we look only at hot dogs, or only at pie-eating contests, we
might miss the fact that a wide variety of foods might lead to the same result.
We might even come up with inaccurate theories like Round-shaped foods

are bad, instead of looking at carnival food overall as a broader, more complex
phenomenon.
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Similarly, if we look only at one gene variant, we might not realize that many
related gene variants can affect the same biological process. In the case of
obesity, this is certainly true.
(And come to think of it, most carnival foods dont do our metabolism any favors.)
Probabilities and risk score

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Many studies on the relationship between body fatness / size and genetics look
at several genetic variants, and create a risk score.
This score simply adds up all the known possibilities from each combination of
variants, and decides how likely (or not) a certain outcome is.
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Lets say a study looks at 10 different genetic variants that are known to affect
body fatness / size. And lets say you have 4 of those variants. Now you have a
risk score of 4, which may explain 0.1% of your body fatness.
Most research has found that even with elaborate risk scores (for instance, with
a dozen or more genetic variants known to affect body fatness / size), specific
genetic combinations may only explain 1 or 2% of the differences in body weight.
So even if you have, say, 15 or 20 of the known genetic variations that make
you more likely to have more body fat than average, those variations may only
explain 2% of the reasons why youre bigger than your buddy.
For instance, a study done in people with Han Chinese ancestry explored 26
genetic variants that might affect BMI.
Of those, four variants (TMEM18, PCSK1, BDNF and MAP2K5) were statistically
significant for a BMI 0.13 higher per variant.
Thus, having all four statistically significant variants might give you a BMI thats
0.52 higher than average, assuming all your other environmental conditions are
the same as everyone else.
To put that in real terms:
Lets say youre from that population. Youre 56 (1.68 m) tall:
Your average buddy might be 150 lb (68 kg), with a BMI of 24.2, in the
healthy range.
You with your four genetic variants might be 153 lb (69.4 kg), with a BMI
of 24.7.
Hardly a shocking difference.
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Another study that looked at approximately 12,500 people of European descent
concluded that lifestyle factors, particularly exercise, explained about 6 times
more of the BMI variation than genetic factors.
Overall, researchers estimate that only about 50-60% of BMI is inherited.

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This means that even if you have quite a lot of genetic variations that make
you more likely to be heavier or fatter, those variations only play small roles.
What you eat, how you exercise, your daily routines, your stress level all of
these are far more important in shaping how your genetics are expressed.
Obviously, we cant look at all the genes that might affect your personal body
size and shape.
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But lets look at one that may play a major role: FTO.
FTO
The FTO gene codes for a protein known as fat mass and obesity-associated
protein. It regulates the expression of genes involved in metabolism by
demethylating nucleic acids.
Methylation is an important process in epigenetics that involves attaching a

methyl group (a carbon and 3 hydrogens, aka CH3), to a strand of DNA or RNA,
often to the cytosine molecule.
When DNA or RNA is methylated, certain genes are often switched off, which
can be a problem if you want those genes to be transcribed and protein made.
FTO can reverse this process with demethylation removing the methyl group,
and switching on certain genes by increasing gene transcription. Well look
more at methylation in Chapter 8.
The FTO gene is an ancient one, found in many vertebrates. It may have
appeared about 450 million years ago. It even appears in algae, though not
other invertebrates, which suggests that perhaps a horizontal gene transfer
occurred.
Originally, researchers discovered the FTO gene in mice with odd-looking feet,
leading to the original gene name of Ft fused toes.
FTO was one of the first genes to be identified in GWAS. Unlike many other
genes linked to particular traits, its effects in many populations have been fairly
well replicated.
FTO is expressed throughout the body (for instance, in fat, stomach, and skeletal
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muscle tissue) but most strongly in the brain, particularly in regions associated
with energy balance and reward-seeking. This suggests that FTO may also
be involved in particular behaviors, such as appetite regulation, self-control or
impulsivity.
Along with FTOs potential effects on things like growth or metabolism,

this implies that FTO genetic variants can have widespread effects on both
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physiological processes and behaviors that affect body size and fatness. Indeed,
FTO is upregulated during periods of food deprivation.
Many SNPs on the FTO gene have been explored, and potentially linked to
differences in body fatness.
Importantly, these SNPs may not cause changes in body fat; they may simply
predict it. Other factors may be involved.
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These SNPs include:
rs1121980, strongly linked to adult obesity (BMI > 40) with odds ratio of 1.55
in a population of French individuals of European ancestry.
rs1421085, found to be significant in a smaller study of about 600 women

of European ancestry who were currently obese (BMI > 40) and who had
gained weight quickly and dramatically as teenagers. Interestingly, this
study was also able to compare about 100 women with their sisters, who
had much lower BMIs (25), and show that the heavier sisters were, indeed,
genetically different in this SNP. The role of rs1421085 was also shown in a
population of Hispanic Americans.
rs17817449, which was found to have a strong predictive value in a small

group of about 200 people in Western Spain who not only gained weight
quickly as teenagers, but also had two or more close relatives with BMI
higher than 40.
rs8057044, found to be most predictive of higher body weight in a

population of about 500 African American girls compared to their
classmates of white European ancestry. rs3751812 was also found to be
significant in a similar African American population, as well as Hispanic
Americans.
rs9939609, which well look at more below.
FTO expression seems to be connected specifically to fat tissue, rather than

other types of tissue that could affect body weight, such as muscle and bone.
Thus, having particular FTO variations probably means that if you have more
body weight (i.e., a higher BMI), its from body fat rather than lean mass.
In populations with European and East Asian ancestry, there seems to be a
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larger cluster of FTO SNPs that may relate to BMI, whereas in populations
of African ancestry, there seem to be fewer BMI-related SNPs across a
smaller region.
That said, other more detailed studies in smaller populations (such as Old Order
Amish or Japanese) have also found other SNPs that seem significant to that
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specific population for instance, rs1861868 was found to be significant in

Old Order Amish, but hadnt been previously associated with obesity in other
studies.
To date, about 90 genetic variants within FTO have been associated with BMI.
23andMe tests for 124 SNPs on FTO.

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In particular, 23andMe highlights the SNP rs9939609. People with an AA
genotype for this SNP tend to have a higher BMI, while people with TT tend to
be lower. (ATs are typical odds.)
For some people of European ancestry, having the AA form of rs9939609

does seem to relate to being heavier. This seems to start younger, and persists
into adulthood.
The 16% of European adults who were AA weighed about 6-7 lbs (about 3 kg)
more than those who were AT or TT. Their chance of being obese was 1.67
times greater.
Other research in Europeans suggests that the AA form was linked to feeling
less satisfied after meals. Some AAs also seemed to have loss-of-control eating
episodes, especially with high-fat foods.
Researchers have found similar relationships between an AA variant of this

SNP and being heavier in Japanese populations, Korean populations, Pakistani
and North Indian populations, indigenous North American populations (such as
Ojibway-Cree or Inuit) and Mexican-mestizo populations (i.e., people who have
indigenous Central American ancestry).
Yet, this SNP did not always seem to have the same relationship for people of
Han Chinese descent, nor did it appear as often in general in that population.
Same goes for several Oceanic populations (Melanesians, Micronesians, and
Polynesians) and a Gambian population in Africa.
In addition, the rs9939609 SNP seemed to flip its function depending on age
before about age 3, having the AA version was associated with lower body
weight.
OK it sounds like FTO plays some important role, right?
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Well we still dont have the whole picture just yet.
Basically:
Some studies suggest that FTO can affect body size, fatness, and weight loss,
but its not clear to what extent.
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On top of this, lifestyle choices and environmental factors can strongly

change the outcome.
For instance, if youre more active, youre often leaner.
As with other genetic variants that may predispose people to more body fat,
physical activity often seems to override any potential FTO effect on body mass.
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One systematic review found that no matter what type of rs9939609 FTO variant
people had, they responded equally well to weight-loss interventions such as
improving their diet, getting more exercise, or taking weight-loss drugs.
In other words:
Regardless of your genetic makeup, the way to get and stay relatively lean, fit,
and healthy is the same for everyone.
Darn you biology!
Why must you be so complicated and fickle?!
Interestingly, this SNP was also linked to other traits, such as:
Alcohol use people of European descent with the AA variant tended to

drink less.
ADHD in preschool children

Age-related cognitive decline, such as Alzheimers or memory loss.
Particular FTO SNPs (such as rs9939609, rs8050136, rs3751812) may
interact with the Alzheimers apolipoprotein E (APOE) 4 risk allele,
increasing the risk for dementia and Alzheimers nearly three times. Youll
remember we looked at Alzheimers in the previous chapter.

In our PN sample of 32 people, we found some interesting things.
We looked at 8 SNPs with a suggested relationship to BMI.
Note that each SNP combination has a slightly different possible outcome. For
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instance, some predict a higher, typical, and lower BMI. Others might predict
only higher-than-typical and typical (rather than lower).
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Gene SNP Variants and trait associated with each
near MTCH2 rs10838738 GG higher AG typical AA lower

BMI BMI BMI
near MC4R rs10871777 GG higher AG slightly AA typical

BMI higher BMI BMI
near GNPDA2 rs13130484 TT higher CT typical CC lower

BMI BMI BMI
near SH2B1 rs4788102 AA higher AG typical GG lower

BMI BMI BMI
near TMEM18 rs6548238 CC typical CT lower TT much

BMI BMI lower BMI
near FAIM2 rs7138803 AA higher AG typical GG lower

BMI BMI BMI
near BDNF rs925946 TT higher GT typical GG lower

BMI BMI BMI
FTO rs9939609 AA higher AT typical TT lower

BMI BMI BMI
First, there seemed to be no strong or consistent correlation between

particular SNPs and BMI.
On average, the trend for the PN folks was to be heavier than predicted by a
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given SNP.
(This makes sense if we think about the PN population, which is likely to have
more lean body mass than average.)
Second, many people had the wrong SNPs for the predicted outcome.
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For instance, people whose SNP combos said they should be heavier were
actually lighter. People who should be lighter were actually heavier often
significantly.
Along with objective measurement of BMI, we also asked people to self-report

on whether they struggled with managing their weight or body fat.
Some peoples self-reports were objectively accurate.

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For instance, if they said theyd always been lean / normal, their histories and
BMI showed this. Or if they said theyd always struggled with their weight / fat,
their histories and BMI showed this as well.
In particular, some people who were heavier also said they didnt feel like they
had a shutoff switch with eating. They often found it hard to stop when theyd
had enough.
However, this trouble with satiety didnt necessarily correlate to alleles

associated with obesity. There are probably other factors at work (such as stress
or habit).
Nor did liking sugar correlate to body weight. Some of the biggest sugar fiends
in the group were normal weight, perhaps even on the low end of normal.
Other peoples self-reports were not objectively accurate.
In particular, many people reported struggling with their weight even if they had
maintained a consistently normal or even low BMI or body fat level for most of
their lives.
What does this tell us?
BMI (and body fat percentage) can be objectively measured, and potentially
connected to genetic variants, especially with a large population.
However, some SNP associations may not be strong enough to show a

consistent trend. They might not give us enough useful information to help
us make decisions.
Peoples subjective experience of feeling heavier / fatter (or smaller / skinnier)

may affect their perception of what their genetic makeup is, or should be.
This perception may affect their behaviors. If we think we are destined to
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be a certain way, might we make choices that reflect that? Might we self-
report as different than we really are, thus confounding the data?
Once we get our test results, which results will we believe? For instance,
you are technically obese but your genetic test tells you that you have
skinny genes, how might you respond? Will this result inspire you, puzzle
you, demotivate you, or somehow change your perspective about your body?
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Your genes are probably working just fine. Most humans have evolved to
store body fat, enjoy eating tasty things, and avoid unnecessary activity. If
you have more body fat than you (or current social norms) would prefer, like
eating tasty things, and dont always feel motivated to exercise, it doesnt
mean there is anything genetically wrong with you.
Unless you have a measurable genetic condition, you are probably

somewhere within the zone of genetically average for your age and
ancestry. While genetic tests seem to help predict risk, the evidence doesnt
support this yet.
In most cases, energy balance, lifestyle choices, and environment affect

our body weight and fatness much more than genetics. Though it may
sometimes feel like its harder or easier to gain or lose weight, this may be
more related to how your unique body is living in its environment, and less
related to a genetic blueprint.
Even if you carry a ton of genetic variants that may make it more likely
that youll be heavier or have more body fat than average, these will likely
only explain a small percentage of your body size and fat levels.
If you want to change your body weight and/or body fat levels, look at
your environment and behaviors. Nutrition and lifestyle habits (such as
smoking or drinking), plus regular physical activity are the most important
factors affecting body weight and body fat.
Again:
No matter what your genes are, the path to get and stay lean, healthy, and fit
is more or less the same for everyone.
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Well look specifically at what you can do in the last chapter of the book.
The polygenic base of underweight

and anorexia
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What about the opposite end of the spectrum of BMI being lighter, smaller, or
thinner than average?
Outside of childhood wasting diseases and clinical cases of anorexia nervosa,

this domain of genetic research has gotten less attention.
As with a genetic propensity to be heavier and/or fatter, a genetic propensity to

be lighter and/or thinner probably involves many factors such as natural body
structure, energy balance regulation, and/or eating behaviors.
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One group of researchers initially studying extreme cases of apparently genetic
obesity discovered that the opposite of a particular genetic configuration
that is, duplication of a short region on chromosome 16, rather than a deletion
resulted in the opposite body weight as well. Duplication was often associated
with being underweight, while deletion was associated with being obese.
As with the higher end of the BMI spectrum, being significantly thinner / smaller /
lighter than average often means that energy balance is out of sync with normal
physiological demands. Of course, this often happens when we are sick, injured,
or under extreme stress.
But when circumstances are otherwise normal, very low BMI usually means
that people are eating much less food than their body might need in order to
function properly.
The terminology of orexia

The ancient Greek word orexis, or appetite, gives us many words.
Orexins are hormones that regulate appetite. (Interestingly, no clear link has been
found between HCRT, the gene that codes for orexins, and weight.)
The term anorexia simply means without appetite.
Low appetite can happen for many reasons: illness, injury, stress, aging, medications,
and so forth.
Anorexia nervosa is a form of disordered eating and persistent food restriction thats
usually accompanied by an unusually low body weight, an intense fear of gaining
weight, and a distorted perception of body weight.
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People may be choosing to eat less (thus overriding their natural desire to eat).
Or they may be responding to strong signals from their appetite centers that tell
them to stop eating, even though the body is not necessarily getting the energy
or nutrients it requires. (This latter situation is common in older people for
various physiological reasons, and is known as the anorexia of aging.)
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Again, there are many factors involved in having a significantly lower body
weight or less body fat than average, including several possible genetic
contributors.
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BDNF
One of the most-studied genes is variations on the BDNF gene, which can affect
metabolism, eating behaviors, and activity.
BDNF codes for brain-derived neurotrophic factor (BDNF), which is part of a

family known as neurotrophins.
The suffix -troph comes from the ancient Greek trophe, meaning food
or nourishment, and generally refers to growth. Thus, neurotrophins are
chemicals involved in the growth, development, differentiation, and survival of
neurons, the cells of our nervous system.
BDNF is found throughout our nervous system, as well as in our blood and other
tissues such as the retinas of our eyes, the kidneys, skeletal muscle, and the
prostate.
Not surprisingly for something so widespread, BDNF has many jobs.
For instance:
It regulates the development of neurons as well as neuronal plasticity (i.e.,

changing neural pathways).
Its involved in learning and memory.

It can affect our perception of pain.
Its involved in behavior (such as aggression or addictions).
Its involved in many mood disorders (such as anxiety or depression),
personality disorders (such as schizophrenia or bipolar disorder), and
neurodegenerative diseases (such as Alzheimers).
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It helps regulate metabolism, body weight, and energy balance (food energy
in versus metabolic or movement energy out).
It seems to play a role in eating behavior and activity, including excessive

activity or disordered eating.
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Since BDNF is involved in so many metabolic, energy-regulating, eating, and

activity behaviors, variations in the BDNF gene can be related to both lower and
higher body mass. BDNF protein levels are often low in people who are obese
or have Type 2 diabetes.
Conversely, exercise can increase BDNF levels, suggesting that even if we have
a particular genetic variant of the BDNF gene, we can change how much BDNF
protein we actually have circulating.
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BDNF expression can also be affected by other epigenetic factors from the
environment, such as:
recreational drug use;

early life stress; and
intellectual stimulation and learning.
One particular BDNF allele known as Val66Met (SNP: rs6265) is so named
because the nucleotides adenine and guanine vary, which results in a variation
between valine and methionine at codon 66.
Some research has found that people with the methionine-methionine

combination (aka met66) tended to be thinner than those with other
combinations (i.e. valine-methionine or valine-valine).
Other research in participants of European descent has found that people with
the met66 variant of BDNF were more likely to have various types of disordered
eating behaviors, such as restricting food, binge eating, or purging.
These variants of BDNF didnt just affect eating behavior; they were also
involved in other behaviors like avoiding harm or taking risks.
Other genetic contributors

Researchers estimate that about 40-60% of our risk for disordered eating
behaviors may be inherited.
By the way, remember our FTO gene from above, particularly the rs9939609
SNP? Of course you do! Well, it too may be involved in disordered eating,
including restricting-type behaviors.
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This tells us that FTOs role is more complicated than simply being a fat gene.
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Other sets of genes that may be involved in disordered eating behaviors include:
genes such as MAOA (monoamine oxidase A), NET (NE transporter), and/or
SERT (serotonin transporter) related to synthesizing and transporting feel-
good neurotransmitters like oxytocin and serotonin;
genes such as CNR1 (endocannabinoid CB1 receptor) and FAAH (fatty acid
amide hydrolase) related to endocannabinoid pathways. These are involved
in various processes such as our stress response, maintaining homeostasis,
perceiving or dulling pain, and regulating food motivation and appetite
(which is why using cannabis often gives you the munchies and is used for
medical patients who have lost their appetite);
genes involved in monitoring energy balance, such as LEP, which codes for
leptin, a hormone that senses how much stored fat we have;
genes related to appetite peptides such as GHRL, which codes for ghrelin, a
potent stimulator of hunger; and
genes such as DRD2, which codes for dopamine, related to the

neurobiological reward and decision-making pathways (which are also
involved in addictions).
We asked our test population whether theyd consistently or often done any of
the following disordered eating-type behaviors:
Going on a strict diet or cutting back a lot on their eating;

Over-eating well past the point of satiety;
Eating foods they craved, even though they werent hungry;
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Compensated for their eating (for instance, by restricting their food the next
day, or by exercising a lot);
Worked out a lot (more than 7 hours a week of purposeful exercise);

Purged (e.g. vomiting, used laxatives, etc.); or
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Thought a lot about restricting food, going on a diet, specific food choices,
working out, etc.

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Heres what they said:
Figure 7.2: Percent of people reporting disrupted eating and exercise behaviors
OK, so does that mean that three-quarters of our sample has the genes for
disordered eating because theyve gone on strict diets?
Or that over two-thirds have a genetic inability to manage their appetite because
they over-ate, or ate foods they craved when they werent hungry?
Or does that mean that this is common behavior in 2017? Especially for health-
conscious, fitness-oriented people?
Our guess is that it probably means that average or normal genes (in other
words, a genetic makeup without any unusually strong predisposition to do
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these things) can interact with our 21st-century environment that is:
stressful and anxiety-provoking;

focused on healthiness, fitness, nutrition and food fads;
focused on bodies and body discipline;
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increasingly preoccupied with social comparison while also being socially

isolating; and
full of tasty, easily accessible, crave-able foods that are hard to stop eating.
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Genes affect our body shape, size, and leanness or fatness. You are at
least slightly predisposed to have a certain physical makeup. However, you
are not destined to have a certain physical makeup.
Genes also affect the processes that happen when our body shape is
smaller or bigger, leaner or fatter. For instance, if we gain or lose body fat,
we can up- or down-regulate genes involved in processes like inflammation
or blood sugar regulation.
Human body shape and size is normally variable and diverse. There are
many ways to have a healthy, fit, and functional body. Bodies come in
all shapes and sizes. Some of that is inherited and some it is acquired or
influenced by our environment. Even if you have many genetic variations
that might predispose you to be a certain body shape or size, you are
probably well within the range of average in most ways. Few genetic
disorders are so extreme that they put you outside of normal human
variation.
Your body size and shape does not necessarily tell us everything about
your genes or your behavior. For instance, we dont know for sure that:
a person with a specific body type is necessarily more or less likely to

have problems with their metabolism, or how they eat.
a person with a lower body weight is purposely eating less. They may
also be genetically more likely to burn off excess energy as heat, for
example, or have a stronger stop eating signal.
a person with a higher body weight is purposely eating more. They may
also be genetically inclined to store nutrients as fat, or have a stronger
appetite and reward system.
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Energy balance, metabolism, and eating behaviors are all complex
phenomena. A change in one can affect the others.
Our environment matters. Consider what is around you: the cues, foods
available, social norms, stressors, and so forth.
Many factors that affect body weight and fat are within our control.
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Despite our natural inclinations and makeup, we can choose to eat less or
more, to be more or less active, to eat particular foods, and so on. Well look
specifically at what you can do in Chapter 12.
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Whats up next
In the next chapter, well continue with the theme of food to look at food
preferences, and how these may be affected by our genetic makeup.
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CHAPTER 6 CHAPTER 8
What we found: Metabolism What we found: Food
preferences
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In this chapter, we explore

some of the basic metabolic Why we might dislike some

processes, such as how we foods, like others, and really like
regulate our blood sugar or thyroid others? In this chapter, we'll cover
output, and how they might be how genetics influence how we
affected by genetic factors. experience the taste of food.
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CHAPTER 8
What we found: Food preferences

some of the genetic and environmental factors that can affect food
choices and preferences, such as whether we like:
sweet tastes;
fatty tastes;
bitter tastes; or
cilantro (coriander); and
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what genetic testing can tell us (or not) about food preferences.
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Just because a genetic test can tell you what kinds of tastes you might
prefer doesnt mean that it can tell you the perfect diet or supplement
for you.
Why is there no single best diet or

exercise plan?
At PN, weve long been interested in the idea of a best diet debunking it,
that is.
Over the years, weve explored human variation and why the concept of a single,
one-size-fits-all perfect diet doesnt make sense.
You can read more about that here.
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Non-genetic factors can affect nutrition and
food choices.
There are many non-genetic factors to consider in developing an optimal
nutrition plan for each one of our clients.
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For instance, we might ask:
What do people know about nutrition?

What can people do? (For instance, can they cook?)
What can people do consistently? What habits can they stick to realistically
and reliably?
What else is happening in their lives? Are they busy? Working? Students?
Parents?
Whats around them? Do they have access to fresh food?

How fit and active are they?
If theyre active, in what sports or activities?
How old are they? Babies? Seniors? Teens?
What do they like and enjoy?
Whats their cultural and social environment?
What are their food traditions and values?
How healthy is their gastrointestinal tract right now? What about their dental
health?
How is their overall health right now? Are they injured or ill?
What emotional associations do they have with food?
Etc.
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Genetic factors can affect nutrition and food
choices too.
For example:
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Genetic factors may affect taste preferences.

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This may be because:
of the physical structures of tasting (such as how many taste buds we have,
or how densely packed they are);
of how we process those tastes at the molecular signaling level (for instance,
whether we can chemically sense some types of compounds); and
we are naturally predisposed to find some tastes good or compelling.
Genetic factors may affect what foods we can

tolerate.
Does food feel physically good or bad?
When you drink milk or eat ice cream, do your intestines regret it?
What about a few slices of bread, or some high-fructose fruit?
Along with other factors, such as the health of our gastrointestinal tract, our
genetic makeup can affect which foods we digest well, and which ones we dont.
Well look at food tolerance in Chapter 9.
Genetic factors may affect how we process

nutrients.
In Chapter 6, we saw how various forms (aka polymorphisms) of the cell receptor
for vitamin D, and genes coding for proteins involved in vitamin D metabolism
and transport, may affect our risk for chronic diseases or whether we need to
supplement additional vitamin D (if we arent getting enough from sunlight).
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Vitamin D isnt the only nutrient whose digestion, absorption, or use can be
affected by genetic variation.
Well look more at nutrient use in Chapter 10. |
In this chapter, well start with food preferences.

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Why do we prefer particular tastes?
Our taste preferences are strongly shaped by
the culture and social milieu that we grew up in.
If you grew up Anglo in North America, you probably have particular taste
preferences and food routines. For instance, breakfast for you might be toast or
cereal with orange juice. You probably like things to be sweet, and you might not
like too many things that are bitter or pungent.
Meanwhile, in Japan, you might be enjoying fish and miso soup for breakfast. In
Sweden, you might be tucking into a smoked herring and dark rye bread smorgs
(open-faced sandwich) with strong coffee. In Nigeria, you might be longing for your
grandmothers traditional akamu, or fermented sour corn porridge.
Tastes are malleable. They can change.
We can discover (and learn to love) new tastes and textures with travel
whether we literally go to new places, or simply explore the world of cuisine
around us.
Genetic data suggest that to some degree, our tastes are also shaped
by heredity.
If you have had a lifelong preference for sugar, or a lifelong hatred of cilantro
(coriander), or struggle to enjoy vegetables there may be a reason.
How does tasting work?

Taste receptors
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Taste receptors, like other receptors that weve learned about, are proteins that
bind to particular molecules.
Like all sensory input (such as sights, smells, and sounds), perceiving and
interpreting taste requires an interaction between one or more specialized
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receptors and our brains.

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A chemical must interact with a taste receptor, which sends a signal to our
brains. Our brains then decide whether the taste is good, bad, or something to
ignore completely.
TAS1R receptors detect sweetness.

TAS2R receptors detect bitterness.
TRPV1 receptors detect heat (e.g., from chili peppers).
CMR1 receptors detect cold (e.g., from mint).
Other tastes (salty and sour) are detected by ion channels, such as the
epithelial sodium channel (ENaC), or the acid-sensing ion channels (ASICs),
which can tell how much of a substance (such as salt) is in a solution.
Olfactory receptors in our nose add information from what we smell, which
also affects our brains perception of taste.
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Figure 8.1: How taste receptors work

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We can vary in:
How many taste receptor proteins we have, as well as the physical

structures of our taste buds.
How sensitive they are (or how much of a certain chemical signal they
require to get the message).
How our brains interpret the information they get from our receptors.
Where these receptors are in addition to those in our mouths, we actually
have taste receptors throughout our gastrointestinal tract, including in
our nasal epithelia, our tracheas, our stomachs, our bile ducts, and our
small intestines. These types of receptors even show up in the skin, thyroid,
bladder, testes, and bone.
Taste receptors arent just for tasting.
They may, for instance, be involved in:
immunity;
our response to prescription drugs;
appetite control (for instance, TAS2R receptors can communicate
with hormone-secreting cells in our GI tract like those that produce
cholecystokinin (CCK), one of our satiety hormones);
glucose homeostasis; or
whether we like to drink alcohol or smoke.
Again, many of these factors are shaped by our genes, which means that genes
(to some degree) can affect what foods we instinctively like, or avoid.
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Some examples:
Variants in the TAS2R16 gene can affect how we perceive the bitterness of
certain plant compounds and our preferences for alcohol.
A TAS2R19 variant may predict how well we taste and/or like grapefruit or
quinine (a bitter extract used in some soft drinks like Brio, or the tonic water
in your cocktail)
TAS2R31 polymorphisms seem to be related to our perception of artificial

sweeteners such as saccharin and acesulfame-K. TAS2R4 and TAS2R14
variations can affect whether we notice a yucky aftertaste to steviol
glycosides, some of the active compounds in stevia.
Speaking of sweeteners, humans can taste many artificial sweeteners, such

as aspartame, neotame, cyclamate, and neohesperidin dihydrochalcone.
We can also taste sweet-tasting proteins, such as brazzein, monellin, and
thaumatin, that other species like mice cant.
Gustin is a protein that promotes taste bud development. Variations in the

CA6 gene that codes for gustin can affect super-tasting, which well look
at below.
There are many genes that contribute to taste perception and food preferences.
And there can be many genetic variations within one person, and between
people, which means that we cant definitely say what a persons preferences or
taste experiences will be.
Do you like sweetness?

Most of us naturally prefer sweetness.
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This makes evolutionary sense. Sweetness usually meant something was good
to eat and energy-dense (like honey or fruit). Even newborn babies typically
prefer sucrose (sugar) solutions to water.
So what are a few genetic contributions to sweet taste preference?

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TAS1R2 and TAS1R3

Two genes TAS1R2 and TAS1R3 code for taste receptor proteins that react
to sweetness.
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In one study in a European population, researchers looked at two types of
sweetness preference:
how sweet something was (intensity); and

how much people liked it.
They found that genetic variance didnt explain peoples preference for intensity,
but did partly correlate (between 30-50%) to peoples liking for sweetness.
FGF21
FGF21 codes for fibroblast growth factor 21, a protein thats involved in many
metabolic processes, including glucose uptake and the adaptive response
to starvation.
According to crowd-sourced 23andMe data, about 120,000 people of European

descent with the AA (adenine-adenine) variation in the rs838133 SNP of FGF21
were a little more likely to prefer sweet tastes to savory or salty tastes, compared
to people with AG (adenine-guanine) or GG (guanine-guanine).
Interestingly, almost none of us surveyed at PN had the AA genotype for the

FGF21 variant. We were about half-and-half AG or GG.
Indeed, the folks who had GG are meh about sugar. One bite of it and theyre
bored.
However, John, whos an AG, says hes a dessert monster.
Fun factoid!
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Note from Krista: This is true. I have personally witnessed Johns passionate love for
cookies.
The FGF21 gene and its protein product dont just affect whether were more
likely to reach for the candy dish. They also play other roles in metabolism,
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and may have relationships with metabolic health. Well look more at FGF21 in
Chapter 10.
The short version, though, is that sweet taste preference is likely just one small
part of a much larger system of genetic and epigenetic metabolic regulation.
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SLC2A2 and GLUT2
As we saw in the chapter on metabolism, glucose transport in the body can
affect health. Research suggests that it can also affect taste preferences.
After we eat something sugary or starchy and break it down to glucose, we need
to move it somewhere to do a metabolic job (such as storing nutrients in cells).
This is done by a family of glucose transporter proteins known as GLUTs.
The SLCA2 gene codes for one of these GLUT transporters, GLUT2, which is
found in the pancreas, liver, small intestine, kidney, and brain. Because of these
locations, its probably involved in local glucose transport as well as sensing
overall glucose levels throughout our bodies.
The rs5400 SNP of SLC2A2 may be related to sweet taste preferences.
Two studies of prediabetics as well as young, healthy people in their 20s found
that in both populations, people with a CT (cytosine-thymine) or TT (thymine-
thymine) at rs5400 ate more sweet foods. These variants of SLCA2 rs5400 and
another SNP, rs5393, are also associated with a higher risk of Type 2 diabetes.
What did we find in our sample?

You may remember our friend, the FTO gene, from Chapter 7 about body
weight.
Along with the FGF21 SNP rs838133, the FTO SNP rs1421085 is associated with
sweet taste preference.
Heres what we found in our sample:
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FTO var rs1421085 FGF21 rs838133
CC higher odds of sweet 16% AA higher odds of sweet 3%

preference preference
CT typical odds 53% AG typical odds 50%

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TT lower odds of sweet 31% GG typical odds 47%

preference
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How do you feel about sugar?
I LOVE sweet stuff. I find it hard to stop eating sweets once I get started 30%
Sweet stuff is OK but Im not a sugar-holic. 39%
I dont really care much for sugar. 30%
First, youll notice that genetically, most people had typical odds of preferring
sweet foods.
And yet, about one-third of people said they loved sweet stuff and found it hard
to stop eating sugar once theyd started.
Many peoples preferences did not match their SNPs.
For instance, many people with a TT allele of the FTO SNP, who should have
liked sugar less, liked it more. Some people with an AA version of the FGF21
SNP, who should have liked sugar more, liked it less.
You might ask:
How does being a health- and fitness-conscious population affect sweet

taste preferences?
Is it more likely that the PN sample is less likely to prefer sugar, simply out of
healthy eating habits that have retrained their palates?
Do other genes contribute to our taste preferences?
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Right now, we cant know for sure.
But the potential effect of practicing several years of good nutrition, as well as
exercising regularly and having a lean and healthy body composition (which
typically means that glucose and insulin mechanics work as they should) are
important factors we cant ignore.
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Your genetic makeup may affect your preference for sweet foods. Genetic
testing may tell you more about your natural tendencies.
23andMe tests for FTO rs1421085 and FGF21 rs838133.

Nutrigenomix tests for the rs5400 variation on the GLUT2 gene.
Your environment will also affect your preference for sweet foods. If you
grew up eating Sugar Frosted Marshmallow Flakes for breakfast, theres a
good chance that these and other types of sweet processed foods shaped
your taste habits.
You probably dont need a genetic test to tell you if you like sweet foods.
Most people already know whether they do.
Finding sweetness rewarding doesnt mean youre a sugar addict or

doomed by your genes. It simply means that in an environment where
sugar and sweetness is abundant, youll have to be careful to make wise
choices, and might have to work a little harder to counteract your natural
tendencies.
Tastes can change. Though taste is shaped by our genes, its not
determined by it. Taste is one of the most malleable of our senses. We can
learn to like or dislike all kinds of foods, regardless of our genetic makeup.
You may also notice that your preference for sweet foods changes as you age.
Regardless of your genetic makeup, basic nutritional principles still apply.

If want to improve your food quality and choices because of health or other
reasons, well give you some more ideas in Chapter 12.
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Do you like fat?
You order salad in a restaurant. It comes with an oily dressing, plus avocado,
bacon, and blue cheese. Whats your response?
Euw, too rich!

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Or
Theres too much lettuce in this blue cheese!
If youre in the second camp, you might have a genetic predisposition for liking
fatty tastes and textures.
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Whether its butter, cheese, avocado, bacon, extra olive oil for dipping, or that
peanut butter thats like a black hole for your spoon, fat can make food delicious.
Yet not everyone likes rich, creamy, oily foods. Why not?
CD36
The CD36 gene codes for a glycoprotein, CD36, with many roles.
Glycoproteins are proteins with carbohydrates stuck to them (youll remember

we talked about lipoproteins, proteins that can bind to lipids, in the metabolism
chapter). Some of our hormones, such as follicle-stimulating hormone (FSH),
luteinizing hormone (LH), and thyroid hormone are glycoproteins.
Because glycoproteins can bind to all kinds of molecules, they can do lots of
jobs. Theyre often cellular receptors.
CD36 is a transmembrane protein (a protein that crosses a cell membrane,

bridging inside and outside) that binds to things like:
connective tissue proteins;

immune and vascular system proteins; and
lipoproteins, phospholipids, and long-chain fatty acids.
That last role is what interests us the most, because CD36 is expressed in our
mouths, our small intestines, and our hypothalamus, all sites of taste and energy
balance regulation.
CD36 bonds strongly with certain types of fatty acids. It seems that people with
variants of the CD36 gene (such as a GG or GA at the rs1761667 SNP, or a TT or
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CT at rs1527483) might perceive fattier tastes more acutely than others.
This may mean that less is more for these people, since fat packs more of a
taste punch, they may prefer to eat less fat, or find some foods too rich.
Conversely, people (such as the folks with an AA at rs1761667) who taste fat less
may like it more.
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And, indeed, research suggests that people who are more sensitive to fatty
tastes tend to eat less overall and less fat specifically; they also tend to weigh
less.
The association between having CD36 variations and body weight seems to be
consistent in many populations, including people of European, Latin American,
Middle Eastern, and African ancestry.
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Just a reminder that biology in general and metabolism in particular are complex
systems: CD36 variations are also associated with:
risk of hypertension and cardiovascular diseases;

risk of Alzheimers disease;
risk of cancer; and
fatty acid oxidation during exercise.
Well look more at exercise in Chapter 11.

Your genetic makeup may affect your preference for fatty foods. Genetic
testing may tell you more about your natural tendencies.
Nutrigenomix tests for the rs1761667 SNP of CD36.

Your environment will also affect your preference for fatty foods. As with
sweet foods, what we grow up with and habitually choose will shape our
taste habits.
You probably dont need a genetic test to tell you if you like fatty foods.
Most people already know whether they do.
Finding fatty tastes rewarding doesnt mean youre a fat addict or

doomed by your genes. It simply means that in an environment where
fatty foods are abundant, and often combined with sugars or starches (which
makes them doubly delicious) youll have to be careful to make wise choices,
and might have to work a little harder to counteract your natural tendencies.
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You may also notice that your preference for fatty foods changes as you age.
Regardless of your genetic makeup, basic nutritional principles still apply.

If want to improve your food quality and choices because of health or other
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reasons, well give you some more ideas in Chapter 12.

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Do you dislike bitterness?
While many of us learn to like bitter tastes as adults (think coffee or tea, lime,
radicchio (aka red chicory), hoppy beers, and dark chocolate), some of us will
have a lifelong aversion to bitterness.
In our evolutionary past, we tended to avoid bitterness, which can tell us that
certain foods might be bad for us. So it makes sense that genetically, some of us
might be more sensitive to bitter tastes than others.
Indeed, being extra-sensitive to bitter tastes is a highly heritable trait that is

strongly shaped by your genes, and less affected by environment or learning.
Because of their chemical composition, many vegetables have a bitter taste that
sensitive people can detect, and generally dont like.
Think of foods like:
cabbage;
Brussels sprouts;
kale;
dandelion greens;
rapini;
green peppers;
turnips and rutabaga; and
broccoli.
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Many of these foods contain compounds (such as sulfur compounds and/or
terpenes yes, related to turpentine) that make them taste bitter.
There are about 25 known genes that code for TAS2R bitter taste receptor
proteins in humans. Historically, bitterness usually meant poison, so it was handy
to have several mechanisms for detecting it.
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Heres just one example of how this might affect your preferences.
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TAS2R38
A gene known as TAS2R38 affects how well you can taste the presence of bitter
compounds such as 6-n-propylthiouracil (PROP), phenylthiocarbamide (PTC),
goitrin (found in cruciferous vegetables), and related molecules.
TAS2R38 is also associated with different preferences for alcohol.
23andMe tests for the SNP rs713598 on this gene. The G variant of the SNP
in TAS2R38 is dominant. This means well be able to taste bitter PROP-like
compounds even if we only have one copy, rather than two.
If you get one C and one G, you might also be able to taste another type of bitter
chemical along with the PROPs. This gives you a double evolutionary advantage,
something known as heterozygote advantage.

For this SNP at least, there were few surprises. Peoples preferences were pretty
consistent with their predicted genetic correlations.
Picky eaters and dont-like-vegetables people

Most of the GGs, the homozygous bitter tasters, didnt like vegetables, and were
also likely to describe themselves as picky eaters who would only eat a limited
range of foods.
The CGs who didnt like vegetables were also likely to describe themselves
as picky, suggesting that their heterozygous combination of this SNP leaned
towards bitter tasting.
Conversely, the Ill eat anything crowd was more likely to be CCs or the CGs
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who probably got the heterozygous variant that didnt allow them to over-taste
bitterness.
But theres always gotta be those few outlier people that mess up the data.
We had a couple of predicted bitter tasters with the GG version of the SNP that
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liked vegetables just fine. And they said theyd eat anything.
Once again, its worth asking:
How does being a health-conscious population affect peoples eating habits?

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In the case of the PN sample, the more bitter-averse people have learned to
like many vegetables, or prepare them in ways that taste better (for instance,
by adding a dash of maple syrup to a kale salad dressing, or roasting Brussels
sprouts to amplify their sweetness). They tend to prefer cooked vegetables to raw.
So, theyre still eating vegetables, but in ways that work for them and their taste
preferences.

If youre bitter-taste-averse:
Genetic testing may give you insight about why you dont like bitter foods.
23andMe tests for rs713598, a SNP on the TAS2R38 gene.
Your environment will also affect your preference for bitter foods. As with
sweet and fatty foods, what we grow up with and habitually choose will
shape our taste habits.
You may also notice that your preference for bitter tastes changes as you age.
Try a wide variety of healthy foods. You may discover some that you like
better.
Try foods in season or at different stages. For instance, you may find that
baby kale is fine, but mature kale tastes too bitter.
Try a wide variety of preparation methods. You may discover that small
changes to how you prepare, cook, and/or season foods make a big
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difference.
Cilantro taste
Cilantro, or Coriandrum sativum, is a herb that looks a bit like parsley and is
found in many cuisines. And many people dont like it.
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Fun factoid!
Generally the fresh leaves are known as cilantro, while the dried seeds are known
as coriander.
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Along with our taste receptors, our olfactory (scent) receptors help us perceive
particular chemical compounds. Many volatile chemicals in fragrances are
aldehydes, a particular type of molecule.
A SNP known as rs72921001 is found near a cluster of olfactory receptor genes

(genes involved in recognizing the volatile chemicals that make odors), including
the gene OR6A2, which likes to bind to several of the aldehyde molecules that
give cilantro its recognizable scent.
Two other markers, rs2741762, and rs3930459, also located near the olfactory
receptor gene OR10A2, may help determine whether someone likes cilantro.

In our sample, we didnt have enough people who actively found cilantro
disgusting to make predictions about who might dislike it.
But in terms of actively liking it (thus definitely not disliking it) the OR10A2
rs2741762 SNP was a bit equivocal. Every single person who should have been a
cilantro hater thought it was yummy.
The rs3930459 SNP did a bit better: Out of all the people who actively liked
cilantro, only one person should theoretically have hated it, based on their CC
variation of this allele. Just under half of the cilantro likers were TTs, people with
lower odds of finding cilantro nasty. The rest were CTs and the aforementioned CC.

Genetic testing can tell you whether you carry the genetic variant for
being less likely to appreciate cilantro. But even if you do carry the hatin
on cilantro variant, you might like it anyway.
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23andMe tests for rs2741762, and rs3930459 on OR10A2.
If youre a cilantro hater, you probably dont need a genetic test to tell you.
Ignore the people who mock you for picking off the garnish at Mexican, Thai,
or Indian restaurants. You do you.
If youre a cilantro lover, dont keep insisting that your cilantro-hating

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friends are flavor troglodytes. It really does taste like soap or dirt to
some people.
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Whats up next
In the next chapter, well look at food intolerances, which can also affect our
food preferences.
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CHAPTER 7 CHAPTER 9
What we found: Body What we found: Food
weight and body comp intolerances
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In this chapter, we look at Why dont some foods dont agree

some genetic factors related with you? And how much of that
to energy balance, what makes may be due to genetic factors?
our bodies naturally bigger or
smaller, and how much lean or
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CHAPTER 9
What we found: Food intolerances

the basic physiology of immune system and inflammatory responses;

how food allergies, intolerances, and sensitivities work;
how these can be affected by our genes; and
what you can learn from genetic testing about your reactions to
particular foods.
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In previous chapters, weve explored the idea of whether theres a single best
diet. By now, it should be obvious there isnt.
Two important points to keep in mind as you read through:
Just because a genetic test can tell you about your risk of particular food
sensitivities doesnt mean that it can tell you the perfect diet for you.
And remember our usual caution:
Almost all of us have eaten

something that didnt agree with
us in some way
Of course, this doesnt mean we have any special sensitivity.
It might just mean we should have said no before the third pound of suicide-
spice chicken wings.
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Aside from situations in which We Really Should Have Known Better, many
people find that certain, normally innocuous foods such as bananas,
avocados, berries, shrimp, eggs, etc. are just bad news for them in general.
In general, we might loosely call these food sensitivities or food intolerances,

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but we want to be careful with our language.

Its important to understand the difference between a food allergy, a food

sensitivity, a food intolerance, and a specific disease, such as celiac disease or
Crohns disease, all of which have a genetic basis.
Its also important to understand that these and related digestive and
autoimmune disorders, like most chronic diseases, are polygenic (i.e. many
genes contribute) and emerge from complex interactions between genes,
behaviors, and environment.
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Antibodies, immunoglobulins, and inflammation
An antibody is a type of protein that is produced by the immune system when
it identifies a foreign substance, known as an antigen. Antibodies help identify
pathogens (such as bacteria or viruses) as well as allergens and toxins.
Antibodies can also be known as immunoglobulins, and get the abbreviation

Ig. There are 5 main antibodies: IgA, IgD, IgE, IgG, and IgM.
Antibodies are Y-shaped proteins that share the same general structure, but
their tips vary quite a lot. This helps them match a specific antigen.
Figure 9.1: Antibody structure and antigen binding sites
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If our bodies think a particular food or part of a food is harmful or foreign, itll
create a targeted antibody to defend against it.
Over time, with repeated exposure, these immunoglobulins can build up and
create a physiological response. This response can be acute (immediate,
sudden, often dramatic) or it can be chronic (ongoing, persistent, often lower-grade).
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Typically, the response includes some form of inflammation.
Inflammation can be local restricted to a small area, such as a patch of skin.

Or it can be systemic affecting various parts of our physiology, such as our
respiratory system, our joints, our nervous system, and/or our digestion.
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We can often see inflammation emerge in real time, with redness, swelling,
rashes, hives or a combination of these symptoms. Chemically speaking, we
can also see inflammation by the presence of particular substances, such as
interleukins (IL), histamine, prostaglandins, and so forth.
The expression of all of these, of course, is shaped by our genes.
There are many types of immune

and inflammatory responses
Because many types of food-related immune and inflammatory responses can
have similar symptoms (such as stomach pain or diarrhea), it can be hard to tell
which is which. In addition, people can have more than one health condition (for
instance, a food allergy plus celiac disease).
Food allergy
An allergen is something that causes a histamine response, known as an
immunoglobulin E (IgE) immune reaction. White blood cells (mast cells and
basophils) release histamine molecules when exposed to an allergen and cause
an inflammatory response such as:
hives;
swelling;
trouble breathing; and
a sudden drop in blood pressure.
Allergies are generally characterized by sudden and strong. IgE spikes quickly,
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but also tapers off relatively quickly, generally dissipating within a few days
(though it can last up to a week or two).
Food allergies, like other allergies, do seem to run in families. This suggests that
we can, to some degree, inherit our allergy risk.
Food sensitivity
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Food sensitivities tend to present more with things like abdominal pain and
bloating, which are related to the actions of immunoglobulin G (IgG) rather than
IgE, as in allergies, above. IgG responses tend to be slower than IgE responses,
often taking hours or even days to show up.
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People with health problems such as inflammatory bowel syndrome / disorder
(IBS / IBD), Crohns disease, or ulcerative colitis tend to have higher IgG levels
than healthy controls. IgG antibodies can also infiltrate and affect other tissues,
such as the pancreas, thyroid, respiratory system, kidney, lymph nodes, or
salivary glands.
Food intolerance
Other types of food intolerances, such as the example of lactose intolerance,
below, are typically caused by not making enough of the right types of enzymes
(for instance, lactase). Without enough of a particular enzyme, we cant digest
some foods properly.
Autoimmune-related problems
Gluten sensitivity and celiac disease
Gluten is a protein found in wheat, barley, and rye. Its a type of storage protein
known as prolamins, and made up of two proteins: gliadin and glutenin. (Barley
prolamins are hordeins, rye prolamins are called secalins and oat prolamins
are avenins).
Gluten is what gives wheat its elasticity and viscosity so that it can be made into
bread, pasta, or other baked goods.
You may have heard of gluten intolerance or even gluten allergy. You may
have heard that gluten is the root of all human disorder and dysfunction. (Move
over, money and power! Gluten is the new gangster in town!)
As with all things, humans are diverse.
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Some people those blessed with iron constitutions seem to be able to eat
anything. They munch on the bread basket cheerfully, crumbs falling out of their
mouths, apparently unaffected.
Other people notice some sensitivity to gluten and similar proteins in other
grains. Perhaps their joints hurt a little bit; perhaps they get a bit of a stuffy nose;
perhaps a slight skin rash.
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A few people notice a strong, immediate reaction, even to trace amounts of

gluten or the proteins in other grains.
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Why?
Well, at least part of this is, of course, genetic. But we dont yet know all the
factors involved.
Celiac disease
Celiac disease is an autoimmune condition triggered by gluten. Because its
autoimmune, which means that the bodys immune system attacks its own
healthy tissues, symptoms can be widespread through the entire system.
As weve seen in our chapter on metabolism and thyroid autoimmunity,

genes related to autoimmunity can play many roles. Youll see here that many
autoimmune disorders share common genetic components and there is no
single autoimmunity gene.
As with most diseases, our risk for celiac disease appears to be polygenic. To
date, research suggests that genetic factors can explain about 55% of celiac
disease cases.
Not surprisingly, research has found links between celiac disease and several
genes related to immune and inflammatory responses, including:
CCR3 codes for the C-C chemokine receptor type 3. Chemokines are a
type of cytokine, or cell signaling molecule, that tell other cells to move
somewhere, like directing immune cells to move to the site of an infection.
The CCR3 protein is highly expressed in immune system cells such as
eosinophils and basophils (types of white blood cells), or T-helper cells, as
well as in the epithelial cells of our airway.
HLA-DQ, which well look at more below.

IL12A, which codes for interleukin 12A (interleukins are a family of cytokines).
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IL12A helps to direct the activities of T-helper cells.
IL18RAP, which codes for interleukin 18 receptor accessory protein. Its

involved in the binding and signaling of IL-18. Variations in this gene have
been linked to inflammatory bowel and Crohns diseases, as well as leprosy
and atopic dermatitis.
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MYO9B, which codes for myosin IXB and is involved in maintaining the
integrity of the intestinal lining. It has also been associated with inflammatory
bowel conditions. People with variants of MYO9B may have more intestinal
permeability, aka leaky gut.
PFKFB3, which codes for a protein that plays a role in cancer progression,
circadian clocks, autophagy, and insulin signaling.
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PRKCQ codes for protein kinase C, which is involved in T-cell immune
system signaling.
PTPRK codes for protein tyrosine phosphatase, receptor type K, involved in

cell growth, differentiation, migration, and division. Levels of this protein are
associated with some types of cancer.
RGS1 codes for regulator of G-protein signaling 1, which has been used as
a marker of intestinal tissue quality in studies of colorectal cancer. Its also
been linked to mental health and multiple sclerosis (along with IL12A).
SH2B3: Remember this little guy from Chapter 6 on metabolism and

autoimmune thyroid health? Here he is again!
TAGAP codes for a protein involved in T-cell signaling; like other genes in
this list, is linked to autoimmune disorders such as rheumatoid arthritis, Type
1 diabetes, and multiple sclerosis.
THEMIS-coded proteins are related to T-cell maturation, appear in lymphoid

tissues, and are highly expressed in celiac disease.
These genes, and others like them, are probably involved in a wide variety of
immune system function.
For instance, Type 1 diabetes and celiac disease share HLA-DQ, IL2/IL21, CCR3
and SH2B3 SNPs in populations of European ancestry. And vitamin D seems to
interact with IL2RA and TAGAP.
Theres no test on this, of course.
Just get the general idea: Its complicated.
HLA-DQ
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You may remember that in Chapter 6, we talked about the human leukocyte
antigen (HLA) gene complex that codes for major histocompatibility complex
(MHC) proteins in humans.
These proteins, which are found on the surfaces and membranes of cells,
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regulate our immune system.

HLA-DQ is a type of protein that appears on the membrane of what are known
as antigen-presenting cells, cells that tell other cells of the immune system (such
as T cells) that theres trouble spotted (such as a pathogen), and its time to go
to work.
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The most significant genetic risk factor for celiac disease seems to encode the
HLA-DQ2/DQ8 heterodimers (molecular complexes of two macromolecules
stuck together).
When immune cells that have HLA-DQ2 or DQ8 on their membranes come
in contact with gluten (for instance, in the small intestine), this complex can
incorrectly tell the immune system to attack the threat in this case, healthy
tissues. This creates the symptoms of celiac disease, such as gastrointestinal
pain and diarrhea.
However, as weve seen, other genetic variants may also contribute. There are
several dozen known factors so far. Some genes appear to be altered only in
adults or children with celiac disease, suggesting that age may also change the
genetic expression of the disease.
Not everyone with genetic variations will develop the disease, but most people
who have celiac disease do seem to share some related genetic variants.
For instance, 23AndMe tests for a subtype of HLA-DQ2 called HLA-DQ2.5,

using a SNP called rs2187668 located in one of the genes encoding HLA-DQ2.5
This subtype is found in roughly 15% of the general population but in over 90%
of people with celiac disease, though only about 3% of people with this specific
variation will actually develop celiac disease.
23andMe also tests for rs6822844, a SNP that lies in a block of genes (KIAA1109/
Tenr/IL2/IL21) that, along with another SNP in the same area (rs13119723), are
strongly associated with autoimmune disease, including celiac disease.
Like many chronic diseases with a strong genetic component, the prevalence of
celiac disease varies with geography and population.
Celiac disease is most often found in populations of European descent (North
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America, Europe, Australia, some parts of South America) as well as populations
in India. It is relatively rare in most local populations in Asia.
Yet celiac disease prevalence is increasing quickly. This suggests that

environmental or other physiological factors (such as the health or diversity of
our gut microbiota) may be contributing.
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Getting diagnostically tested for celiac disease is a painful business. In order to

produce enough antibodies to show up on a lab test, patients must eat more
gluten. You can imagine how that feels if you already have a sensitivity. Its sort
of like having to get stung by more bees if you have a potential bee venom allergy.
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So, in this case, genetic testing is a much more pleasant option. However:
The solution would still be the same: remove gluten from the diet.
Research suggests that non-celiac gluten sensitivity (sensitivity to gluten
without overt antibodies) is a thing.
Non-celiac gluten sensitivity

Most people in our co-author Kristas extended family have trouble with wheat
and some other grains. They get skin rashes, coughs and snuffles, even intestinal
bleeding (in worst cases). Youd think that this would be an obvious case of
genetically-determined celiac disease, and perhaps in some folks, it could be.
Krista, too, avoids wheat, because the connection between eating it and
inflammatory symptoms is pretty clear. Yet Kristas 23andMe test for celiac risk
showed that based on a few different markers, she actually had half the average
risk of celiac.
So what gives?
Is Kristas family just full of hypochondriacs who are hating on pasta?
Or is there another explanation?
Many other frustrated people who know they dont respond well to wheat may,
nevertheless, have been told that they dont have legitimate celiac disease, so
they should quit bellyaching (so to speak).
In fact, we are coming to realize that non-celiac gluten sensitivity (NCGS) can
also be a problem.
With NCGS, we dont see the same chemical markers (such as immunoglobulin
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A, or IgA, antibodies), or the destruction of intestinal tissue that we see with full-
blown celiac disease, but we still see inflammation.
At this point, theres no direct-to-consumer test for NCGS, although in research

labs we can look at whether inflammatory markers (such as interleukins or
immune system proteins) are elevated.
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For instance, the researchers in the Nutrigenomix lab looked at the relationship
between genetic markers of celiac and 2-macroglobulin, a protein that goes up
in response to inflammation. They found that eating more gluten was correlated
with more 2-macroglobulin, but this happened regardless of peoples HLA-DQ.
That said, over half of people who have NCGS do carry similar genetic variants
as people will full-blown celiac disease, and both NCGS and celiac sufferers are
much more likely to have these variants than the general population.
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With the HLA-DQA rs2187668 SNP tested by 23andMe, each copy of a thymine
(T) increases celiac risk. So TTs (thymine-thymine) are most at risk.
We had no TTs in our sample, but about 16% of the sample had CT (cytosine-
thymine), a slightly increased risk.
Several people said they were definitely intolerant of wheat. Four of those had
had a celiac test done, which suggests that they had enough wheat intolerance
symptoms to check.
Yet none of these wheat-intolerant folks were CTs. All were CCs the lowest-
risk group for celiac.
Moreover:
All the people who said they were definitely intolerant to wheat were CCs,
which, again, is the group that theoretically shouldnt have problems.
A few people said they were definitely not intolerant, and could crush
croissants with no problems. Most, not surprisingly, were CCs, but one of
those was a CT.

If you suspect you may have celiac disease, see your doctor. Genetic
testing can help you see if your risk of celiac disease is higher, but other
tests can also confirm whether you have active antibodies to gluten.
Research suggests that even if you do not have celiac disease, you may
still have a sensitivity to gluten or other related proteins. This may be
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genetic or may also be related to a wide variety of other factors, such as
your lifestyle, your gastrointestinal health, and your environment.
If you notice gluten intolerance or other food sensitivities, consider

working with a nutrition coach or dietitian to come up with menus that
accommodate these. |
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Food intolerances
Lactase persistence / lactose tolerance
Lactase is an enzyme, secreted by the brush border cells of the small intestine,
that helps us digest lactose, a sugar in milk.
Almost all of us can digest lactose when we are born. We need to: Breast milk is
our only source of nourishment. But not all of us keep this ability as we age.
Being able to make lactase into adulthood a trait known as lactase

persistence is determined almost completely by our genes, although other
factors (such as gut microbiota) can also affect how we digest milk and dairy.
In Europeans, particularly northern and western Europeans (such as

Scandinavians and Irish), the gene that codes for lactase has remained fairly
common, which probably reflects the importance of milk and dairy foods for
European populations. The same is true of particular farming populations in
eastern / northern Africa, the Middle East, or northeast Asia where herding and
dairy consumption are common.
Other populations who dont consume as much milk and dairy for instance,
people with southeast Asian ancestry tend not to carry this gene.
In fact, not being able to digest lactose is more the global norm than the
exception. Some estimates suggest that worldwide, about 65% of adults cannot
digest lactose.
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Figure 9.2: Who can drink milk? Global rates of lactase persistence
The ability to digest lactose probably evolved separately in different populations.

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LCT
At the moment, we know of many different alleles of LCT, the lactose tolerance
gene, that can affect this ability.
These alleles tend to travel with different haplotypes. This means that the
outcome (being able to digest lactose, or not) is the same, but the reason (a
specific gene variant) can be different, depending on a persons ancestry.
For example:
13838G/A, 13906T/A and 13908C/T variations may have appeared

independently in Tibetans, a traditionally cattle and yak-herding population.
Fun factoid!
Tibetans have also crossed domestic cattle (Bos primigenius) with yaks (Bos
grunniens) to create a hybrid called a dzo.
13910*T (aka rs4988235) appears in Europeans, and correlates almost

perfectly with lactose tolerance. This variant almost never appears in Sub-
Saharan African populations, though it does appear among the Fulani of
Sudan, who originally migrated from western Africa. It also appears in South
America among populations with a history of European colonization.
13907*G, which is an East African variation appearing in Afro-Asiatic Beja

populations and in the Afro-Asiatic Kenyan populations.
13915*G, the founder mutation for the unusually high lactase persistence
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in Saudi Arabians and Bedouins which may not relate to cows milk but
to camels milk. (Despite their high lactose tolerance, the characteristically
European 13910*T variation doesnt seem to appear much in this population
either.)
14009 T>G, one of a few Ethiopian variations.

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14010*C, typically found in a single haplotype in Kenya and Tanzania

(known as Nilo-Saharan, from people who lived along the Nile and Sahara).
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Other candidate variations still being tested include:
13779 G>C, found to date only in Amhara people (aka Abyssinians)

originating in the northern and central highlands of Ethiopia.
13806*G, found only in Ethiopian milk drinkers, but actually associated

more with non-digestion.
13909 C>T, another European variation.

You may remember in our previous chapter that we explored the idea of ethnic
ancestry. Superficial characteristics (such as skin color) dont actually tell us
much about a persons full set of genes.
Supporting this idea is the fact that there are at least seven different rare alleles
associated with lactase persistence in one small ethnic group (Somali cattle
herders from Ethiopia). In terms of understanding genetic variation, simply
lumping this group into a large category called African or black would be
useless at best.
MCM6 and enhancers

Along with variations upstream of the LCT gene, there is evidence that related
variants in the minichromosome maintenance complex component 6 (MCM6)
could also play a role.
Although MCM6 doesnt directly affect lactose digestion, it contains two of the
regulatory regions for LCT.
Youll hopefully remember that back in Chapter 2, we talked about how genes
are made, the process that regulates whether a gene is made or not, and a key
region of DNA called the enhancer.
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Enhancers for different genes are different, since you dont want all the genes
to be made at the same time. You want some to be turned on, and others to be
turned off, depending on the situation.
If enhancers vary genetically, expression of other genes can vary too.
Thats what happens with the LCT gene and MCM6. Some people have a
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particular SNP (rs49882359) in the MCM6 gene that increases the activity of the
LCT enhancer and leads to the expression of the LCT gene and most lactase.
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Sweeps, spreads, and selection
These genetic variations, and the other possible variations that we havent
yet found, give us clear evidence of convergent evolution, or a trait emerging
independently, more than once (rather than developing in a straight linear path).
As an example of convergent evolution, consider the concept of food in wrap

format.
For instance, wrap-type foods include sushi hand rolls, rice paper wraps, dosas,
crepes, burritos, shawarma, and so forth all having evolved independently in
world cuisines. Sushi didnt directly evolve from burritos (although now we have
the sushi burrito, another one of Natures magnificent miracles).
In this case, we have a situation where various populations are able to produce
lactase, but by different pathways.
Some of these variations also give us evidence of what is known as a selective

sweep. In a selective sweep, a particular variation becomes much more common
among a population, to the point where the alternative may be completely lost.
Once 100% of the population have a particular form of the gene, that form is said
to be fixed.
Selective sweeps can happen when a beneficial mutation starts out relatively
rare, but quickly moves through the population, pushing out genetic rivals.
This can often happen when environmental conditions change and favor the
new mutation.
For example, if climate rapidly changes, genes that were previously neutral but
now help the organism adapt to the new climate will likely spread.
When the Ice Age suddenly hits, everyone with the genes for a furry pelt, short
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limbs, and plenty of subcutaneous fat will be left standing, while everyone with
the genes for squeaky-smooth-as-a-dolphin skin, lanky heat-dispersing limbs,
and six-pack abs will be quickly wiped out.
Lactase persistence is an example of positive selection: a genetic mutation that

promotes the emergence of new phenotypes, usually by offering some kind of
advantage. (The other type of selection is purifying selection, which helps keep
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an existing phenotype the same.)

Many have speculated that lactase persistence emerged over and over among
various populations because it was helpful for pastoral populations who might
have consumed a lot of milk and dairy from cows, sheep, goats, and camels.
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Genetic studies seem to support this hypothesis, since populations with higher
lactase persistence also tend to include milk and dairy as part of their regular
diets. (After all, try to imagine northern Europe without cheese or yogurt no
Icelandic skyr, no British Stilton, no Swiss fondue.)
Indeed, early humans dont appear to have had much lactase persistence. The
genetic variations that now let some of us enjoy ice cream and milkshakes
emerged relatively recently perhaps 10,000 to 25,000 years ago or so (some
estimates even put it around 3,000 years ago).
This, again, suggests that we actively adapted to innovations in agriculture,

otherwise known as figuring out how to make animals hold still long enough for us
to milk them. Consistent dietary pressure in a small population can actually help us
make pretty quick genetic changes, perhaps within 150-400 generations.
This milk-lactase persistence connection isnt true for all populations.
For instance, Dinka and Nuer in Sudan and Somalis in Ethiopia dont seem
to have lactase persistence despite consuming dairy. In genetically lactose-
intolerant populations that consume dairy but seem to digest it fine, gut
microflora may also be helping out.

23andMe tests for the rs4988235 SNP of the LCT gene. The GG (guanine-
guanine) variant is more likely to be lactose intolerant.
In this case, having the GG variant did seem to predict dairy intolerance. All the
people who said they had significant problems digesting dairy were GGs.
That said:
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Lactose tolerance still varied. One gut-of-steel GG said they had absolutely
no problems with dairy, while other GGs said their tolerance was sometimes
an issue, sometimes not.
Some AAs (adenine-adenine, the lowest-risk group) also said they had some
problems digesting dairy, though nobody said it was as serious as some of
the GGs did.
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AG or CT?
When we were writing up our results for the rs4988235 SNP of the LCT gene, and
checking both 23andMe and Nutrigenomixs reports, we stumbled across something
that seemed confusing.
23andMe listed the SNP variants as A/G. In other words, the 3 options would be
AA, AG, or GG.
Nutrigenomix listed them as C/T. In other words, the 3 options would be CC,
CT, or TT.
Which one was right?
As it turns out, both of them.
Genetic analysis uses what are called reference genomes.
If you ask the question about what variant an individual has, you have to know what
they vary from.
Researchers have settled on reference genomes, which are compiled and released as
a set by the Genome Reference Consortium, an international consortium of experts
from some of the top research institutions.
The current human reference genome is called GRCh38.p11 (GRC human genome build
38, patch level 11), released in July 2017.
(Use that little factoid to stimulate interesting conversations at cocktail parties! It is a

crowd-pleaser!)
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Remember that DNA has two complementary strands.
For example, if theres an A on one strand, you know theres a T at the same position
on the opposite strand. If theres a C on one, you know it has a G buddy.
Sometimes, when a build of a reference genome is released, the opposite strand is

used.
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The identifiers for SNPs are unique to each genome build, so the position might be
reported as A in one build because one strand is sequenced, and a T in the next build
because the complementary strand is sequenced.
For determining SNP variation, this is fine the location varies and you dont really
care about it.
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However, we discovered that 23andMe always uses the letter on the forward (i.e.,
transcribed) strand, independent of the reference genome.
This is an unusual choice. Most research and clinical literature use the genotypes
defined in the reference genome.
You can see why 23andMe might make this choice, though it makes it easy to say
This is the A or T that gets transcribed, so this is the one we will use.

If you cant digest lactase, it may be genetic.
23andMe tests for the rs4988235 SNP of the LCT gene.
If you still want to enjoy dairy but it gives you trouble, you have a
few options.
You can try lactase pills or lactose-free milk.

You may find that fermented dairy (e.g. yogurt, kefir, etc.) is OK, as
the process of bacterial fermentation tends to break down sugars.
Supplementation with a probiotic may also help.
If you can digest lactase, It may be from one (or more) of a number of
different gene variants, depending on your ancestry. Congratulations!
Enjoy the lattes, thanks to convergent evolution.
There are other reasons you may be dairy-intolerant. For instance, your
gut microbiota can play a role; you can also be sensitive to other proteins
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in dairy.
If you have been diagnosed with lactose intolerance, or if youre noticing

other food sensitivities, consider working with a nutrition coach or
dietitian to come up with menu options and strategies to accommodate
your food needs.
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Hereditary fructose intolerance
Hereditary fructose intolerance (HFI), as its name suggests, is a genetic
condition in which people cant break down fructose properly. Fructose is found
in fruit, as well as many processed foods (such as soda).
People with HFI cant make enough aldolase B, an enzyme encoded by the
ALDOB gene that helps metabolize fructose. If aldolase B isnt working properly,
our bodies cant properly convert sugar into energy, which can result in
hypoglycemia (low blood sugar).
Hypoglycemia, if severe and left untreated, can lead to seizures, coma and
death. In addition, the accumulation of partially metabolized fructose molecules
becomes toxic to the cells and causes liver and kidney damage.
People who have HFI may avoid many sweets and fruit instinctively, which
means they may never get properly diagnosed. This also means that researchers
arent completely sure how common HFI really is.
HFI is an autosomal recessive disorder, which means that to have HFI, a person
must inherit two copies of the ALDOB gene variant that causes the problem.
While it can be fatal if not properly treated, people can remain healthy and free
of symptoms if they avoid fructose.
There are at least 40 known ALDOB mutations that have been linked to HFI.
23andMe looks at four of the most common ALDOB mutations in people with
European ancestry:
rs1800546, aka A149P (which accounts for about 65% of all HFI-causing
mutations in this population)
rs76917243, aka A174D (accounting for about 11-14% of mutations)
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rs78340951, aka N334K (about 5-8%)
rs387906225, aka delta4E4 (about 3%)
Together, these mutations make up about 75% of the HFI-causing mutations in
this population.
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Luckily for our PN team members, nobody had two of the ALDOB HFI mutations
tested for: rs1800546 and rs76917243.

If youre concerned about HFI, consult your doctor. You may still have an
ALDOB mutation or have HFI even if your genetic tests for these particular
variations are negative.
Even if you do not have HFI, you may find that you have digestive
symptoms from eating particular types of carbohydrates known as
FODMAPs: fermentable oligo-, di-, mono-saccharides and polyols. This
group includes fructose.
If you have been diagnosed with HFI, or if youre noticing other food
sensitivities, consider working with a nutrition coach or dietitian to come
up with menu options and strategies to accommodate your food needs.
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Whats up next
In the next chapter, well look at how genetic factors other than food intolerances
or sensitivities can affect how we absorb and use nutrients.
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CHAPTER 8 CHAPTER 10
What we found: Food What we found: Nutrient
preferences absorption and use
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Why we might dislike some In this chapter, well examine some

foods, like others, and really like genetic factors that may affect
others? In this chapter, we'll cover how our bodies digest, absorb,
how genetics influence how we and use particular nutrients.
experience the taste of food.
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CHAPTER 10
What we found: Nutrient

absorption and use
genetic variations that may affect how our bodies respond to specific
diets, such as high-carbohydrate or high-fat / ketogenic diets;
methodological problems in drawing clear links between diets and

genes;
MTHFR variants that affect folate (vitamin B9) use;

genetic differences in caffeine metabolism; and
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what genetic testing may tell you about how your body processes
particular nutrients, and what other ways you can discover this.
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What role might genes play in nutrient
processing?
We all know that person who seems to be able to eat anything they want and
stay lean and fit.
Is that genetic? Possibly.
We also know that person who seems to do everything right and ends up with
a nutrient deficiency or health problem.
Is that genetic? Possibly.
Nutrient processing (in other words, how our bodies digest, absorb, and
use both macronutrients like fat, carbohydrates, and protein, along with
micronutrients such as vitamins and minerals) can also be affected by many
factors, such as:
how often we exercise;

how much body fat we have;
the health and diversity of our gut microbiota;
any medications we might be taking;
etc.
In this chapter, well look at what you might learn from genetic testing about the
possible effects of a few dietary patterns.
Two important points to remember as you read through:
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Just because a genetic test may tell you how you might metabolize a
particular nutrient doesnt mean that it can tell you the perfect diet or
supplement for you.
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How do our bodies process
nutrients?
When you eat an orange or some ripe blackberries that are high in vitamin C,
how does that vitamin C get into your cells?
How does your body know how to extract vitamin C or any other nutrient
from your food, absorb it, transport it where it needs to go, use it in various
chemical reactions, and then get rid of any waste products it creates?
What if a nutrient needs to be in two places at once? How does your body know
which one to prioritize?
Does your body prefer a certain form of a nutrient, such as the retinol form of
vitamin A, instead of the plant-based carotenoid forms?
Does your body prefer to store a particular nutrient, use it immediately, or

excrete it?
Does your body completely ignore an important nutrient as it sails by?
All these and many other processes and physiological decisions are governed
by genetics.
Although we are more the same than different, there can be subtle genetic
differences in how our unique bodies digest, absorb, use, and excrete the
nutrients from the food we eat.
We can learn about some of these through genetic testing.
Macronutrients: Carbohydrates
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Carbs have been getting a bad dietary rap lately. Perhaps youve counted
carbs or bought a low-carb product or cut them out altogether. Perhaps
youve been told that to stay lean, carbs are the enemy. Or that needing glucose
is some kind of moral failure.
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As usual, science ruins our conveniently simplistic theories.
For instance, researchers studying indigenous populations living on high-

carbohydrate ancestral diets full of tubers, fruit, beans, squash, honey, and
heritage grains (such as maize or wild rice) reported that these traditional diets
didnt seem to make people fat or sick.
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In fact, the prestigious British medical journal The Lancet recently reported on
one population, the Tsimane of Bolivia, whose diet is over 70% carbohydrate
from foods like manioc (cassava) and plantains, and who have some of the
healthiest hearts in the world.
Such findings of metabolic health in people eating traditional diets have been
consistently reported for decades.
And instead of high-carb diets inevitably making people obese (as is often
suggested about processed-food Western diets), people in many other foraging
societies with a traditional high-carbohydrate diet (such as the Hadza people of
Tanzania) are smaller and lighter than the world average.
(By the way, the !Kung of Namibia, Botswana and Angola, and the Fulani people
of northern Nigeria also have a traditionally low body mass index, or BMI, and
enjoy cardiovascular health, but live on higher-fat diets. Well look more at
potential genetic adaptations to higher-fat diets below.)
Now, of course, there are many environmental factors involved.
For instance:
Traditional societies eat certain types of carbohydrates, generally higher-

fiber, nutrient-dense types such as starchy tubers, whole grains, fruit,
vegetables, and/or beans and legumes. Traditional carbohydrates are almost
always lower in sugar, and digested more slowly, than modern, processed
carbohydrates.
Traditional societies are not known for their high-tech labor-saving

conveniences. People would have had to work hard to get these
carbohydrates (for instance, they might have to dig for tubers, or process
maize or cassava so that theyre digestible).
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Traditional societies get more daily-life physical activity than people in
industrialized, urbanized regions. This can affect nutrient partitioning, or
how our bodies use and store those carbohydrates.
And, of course, there are genetic factors.
People who have lived a relatively traditional lifestyle for hundreds or thousands
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of years may also share genetic features that have made them uniquely suited to
their local, ancestral diet. Over time, genetic selection helps them adapt to their
environmental conditions.
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Amylase and copy number variation (CNV)
In Chapter 2, we looked at the concept of copy number variation (CNV). This
refers to whether chunks of genetic material are repeated. CNVs can also affect
how genes work.
We used the example of genes (AMY1 and AMY2) that make an enzyme
(amylase) that helps us break down the carbohydrate amylose. Digestion starts
in the mouth, where salivary amylase begins the process of breaking down the
starches we eat as we chew them.
Research on various populations has found that those groups with a traditionally
high-carbohydrate diet (for instance, people in Japan, who consumed rice,
buckwheat, sweet potatoes, and so forth) had more copies of AMY1, while
people with a traditionally low-carbohydrate diet (such as people living near the
Arctic Circle in places like Yakut, Russia) had fewer copies of AMY1.
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Figure 10.1: Average number of amylase gene copies in selected populations

Image adapted from Perry GH, Dominy NJ, Claw KG, et al. Diet and the evolution of human
amylase gene copy number variation. Nature Genetics. 2007;39(10):1256-1260.
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Copy number variation of the AMY1 gene has also been linked to BMI. People
who had more amylase-making genes tended to be leaner; while people with
fewer copies of the genes tended to be heavier.
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Figure 10.2: AMY1 copy number and body size
Image adapted from Falchi M, Moustafa JS, Takousis P, Pesce F, Bonnefond A, Andersson-
Assarsson JC, et al. Low copy number of the salivary amylase gene predisposes to obesity.
Nature genetics. 2014 May 1;46(5):492-7.
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AMY1 may also play a role in postprandial (after-meal) glucose digestion and
disposal. People with more copies of the gene tend to have lower blood sugar
after a starch-containing meal.
In short: More copies of AMY1 might mean better starch digestion and more
effective use in our bodies.
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Having more AMY1 may have been a helpful adaptation for populations with
high-carbohydrate diets, and it may mean that people from those populations
may do well on such diets.
We dont know for sure whether all the lean and healthy indigenous populations
of the world eating high-carb diets share this genetic feature of multiple
copies of amylase, or perhaps some other mechanism that helps them digest
carbohydrates effectively. (For instance, a 2017 study that looked at the
relationship between AMY1/2 genes and body mass index also found that
AMY1As effects also interacted with the actions of gut microflora in digesting
starches.) But its an interesting working hypothesis.

Genetic testing may tell you about your ability to digest carbohydrates.
Nutrigenomix tests for the rs4244372 SNP of the AMY1 gene;
people with the AA variant do not digest starch as well people who
are AT or TT.
Most direct-to-consumer tests do not (yet) test for CNVs. So, we dont
have any PN sample data to share here. Many CNVs dont have clear start
and stop points (which would normally help us see where the DNA segment
occurs). However, higher-end labs do have many techniques for identifying
CNVs, and sequencing the exome or genome can help identify CNV.
Genetic testing can tell you about your ancestry. As we saw in Chapter 5
with examples like lactase persistence, knowing your ancestry may suggest
what types of foods or dietary patterns you might be better-adapted to
eat. Research on indigenous populations who have gone back to more
traditional modes of eating and living (for instance, First Nations or Inuit in
Canada who have gone back to hunting, trapping, fishing, and harvesting
wild foods) shows that they become healthier and fitter when following
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dietary patterns that better suit their evolutionary history.
Your ancestry may also teach you about your food heritage. As weve
seen, food isnt just about survival or delivering nutrients; its about history
and culture too. Learning about your genetic heritage may also inspire you
to learn about your cultural food traditions and stories. This knowledge and
practice is part of a healthy diet too.
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Insulin and glucose management
Digestion of starches begins in our mouths, with salivary amylase. Another
important step in carbohydrate metabolism is signaling the pancreas to release
insulin.
This, too, can be affected by genetic factors.
For instance:
The KCNJ11 gene codes for a protein that regulates insulin release.
Gain-of-function mutations in this gene prevent insulin secretion in
response to glucose. This gene has 219 SNPs, six of which have been
linked to diabetes (rs5219, rs5215, rs5210, rs5218, rs886288, and
rs2285676). 23andMe tests for the rs5219 SNP of KCNJ11. Having a T version
of this allele results in a protein that doesnt respond as well to glucose.
When this happens, we cant clear glucose as well from the bloodstream.
More glucose hangs around, causing problems such as hyperglycemia, Type
2 diabetes, and tissue damage.
We arent quite sure yet what the protein encoded by CDKAL1 does, but it
seems to be similar to another protein that plays a role in insulin resistance.
Some studies have linked SNPs in CDKAL1 (such as rs4712523) to problems
with insulin secretion in European and South and East Asian populations,
though other studies havent found the same links.
The TCF7L2 protein, which is encoded by the TCF7L2 gene, seems to play
a role in developing pancreatic islets, where we have beta cells that make
insulin. If we have the T version of the rs7903146 SNP, we may make less
insulin; if we are female we may also have a higher chance of developing
diabetes during pregnancy (known as gestational diabetes). This link
between the TCH7L2 SNP and problems with insulin has been shown in
populations with European, Asian, and African ancestry.
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Chapter 6 on metabolism reviews other factors that can affect glucose and
insulin regulation in our bodies.
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Our diverse pancreas?
The INS insulin gene can contain a variable number of tandem repeats (VNTRs),
which we looked at in Chapter 5.
As per our discussion of African genetic diversity, also in Chapter 5, in African

populations the INS VNTR has been divided into 22 lineages, whereas in non-African
populations there are only three (grouped as class I, IIIA, and IIIB).
This particular feature is an unusually significant genetic difference between African

and non-African populations.
For most polymorphisms, only 10%-15% of genetic variation is due to differences

between population groups.
Yet in the case of this particular gene, estimates suggest that about 28-45% of total
genetic variance is due to differences between Africans and non-Africans.
Its not clear why this specific gene diverged so much, but its consistent with the
hypothesis that Homo sapiens originated in Africa, and that humans who remained in
Africa (while others migrated in smaller, more genetically homogeneous groups) had
plenty of time to diversify.
Even more interesting, we cant find a modern primate relative for this gene. So we
cant tell which line of the gene is the oldest.
Variation in the INS VNTR is associated with a wide range of traits and health
conditions, such as Type 1 and 2 diabetes, polycystic ovarian syndrome (PCOS), birth
weight, and body fat levels. This diversity may also help to explain different rates of
diseases and health concerns in different populations.
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23andMe tests for these genes and variants:
CDKAL1 (rs4712523)
CDKN2A/B (rs2383208),
HHEX (rs1111875),
IGF2BP2 (rs4402960),
KCNJ11 (rs5219),
KCNQ1 (rs2237892),
MTNR1B (rs1387153),
SLC30A8 (rs13266634),
WFS1 (rs10012946), and
PPARG (rs1801282), which we looked at in Chapter 7.
They use the above to create a combined Type 2 diabetes risk score.
Along with genetic data, we asked people whether theyd ever had their blood
sugar tested, and if so, what it was. Not everyone had, but some were able to
share.
The figure below shows the results of our multi-SNP risk score assessment,
along with known fasting blood glucose test results.
Each row is one person. Read across to see each persons risk score by allele,
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and what their actual tested blood sugar levels were (if they had been tested via
blood test; if not, the space will be blank).
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Figure 10.3: Type 2 diabetes-linked variants in PN population
You might notice a few things here:
Nobody had the highest possible risk score. Most people were, in fact,
rather boringly average: a slightly higher risk here, a normal risk there.
A few of us had lower-than-average blood sugar. One of those had a

homozygous risk allele at MNTR1B.
Of the two people who had higher-than-average blood sugar, nobody had
a high-risk homozygous allele. For them, environmental factors were more
relevant.

Genetic testing may tell you if you have gene variants that have been linked
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to problems with glucose regulation. Mutations with gain or loss of function
may affect how your body processes sugars and starches, as well as the
function of other hormones (such as melatonin, in the case of MTNR1B) that
interact with insulin.
23andMe tests for the following and uses them to develop a diabetes
risk score:
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CDKAL1 (rs4712523),
CDKN2A/B (rs2383208),
HHEX (rs1111875),
IGF2BP2 (rs4402960),
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KCNJ11 (rs5219),
KCNQ1 (rs2237892),
MTNR1B (rs1387153),
SLC30A8 (rs13266634),
WFS1 (rs10012946), and
PPARG (rs1801282), which we looked at in Chapter 7.
Again, they use these to create a combined Type 2 diabetes risk score.
We probably dont (yet) know all the genes involved. Even if you dont
have any of the risk SNPs, you may have others that affect your
carbohydrate tolerance.
However, other factors besides genetics can also affect your metabolic
health and digestion of carbohydrates. These include:
The type of carbohydrate you eat;

How much you eat;
How active you are;
How old you are;
Etc.
Blood glucose is an important health indicator. Dont rely only on a
genetic test. At best, a genetic test can only predict possible risk. It cant
tell you what your blood glucose actually looks like. While blood glucose
normally rises and falls as we eat and fast between meals, chronically
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elevated blood sugar can tell you that there is an underlying health problem.
Get regular bloodwork done. Generally, by the time fasting glucose is

affected, people may be well on their way to metabolic syndrome. So having
your fasting glucose tested, along with your blood lipids, as part of your
regular medical checkup (for instance, annually) is a good idea, especially
as you age.
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If you are a do-it-yourself kind of person, you can buy a home glucose
monitor and test your glucose throughout the day, including after meals.
Postprandial after meals blood sugar levels will give you a better idea,
sooner, of what your blood glucose is up to, compared to fasting glucose.
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Regardless of genetic makeup, basic nutritional principles still apply.
Avoiding added sugars, minimizing processed foods, and choosing high-
fiber, nutrient-rich options such as fruits and vegetables, starchy tubers,
whole grains, and beans / legumes is still an excellent strategy.
If you want to know whether your body will thrive on a higher-carb diet,
just try a higher-carb diet for a month or two and see what happens.
Wed define higher-carb as something thats more than 50% of your total
calories from carbs. Track how you feel and perform, as well as your body
weight, body composition, and blood sugar if possible. The data you gather
from this simple experiment will probably give you a clearer answer than
most genetic predictions we could make right now.
If youd like to improve your overall wellness, see our strategies for
healthy metabolism in Chapter 12.
Macronutrients: Fat
High-fat versus low-fat diets: Which is healthier? Which diet helps us stay
leaner, or lose weight better? The debate has raged for decades.
One reason we cant say definitively how much fat people should eat, or what
type of fat is best, is because different people respond differently to different
diets.
Many people are curious about whether genetic testing can answer questions
like:
How might eating a higher-fat diet change our:

body fat / weight?
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risk of premature death?
blood chemistry?
How might these changes be connected to our genetic makeup, if they are?
What specific genetic factors might be involved? (Remember that these are
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only associations, not causes.)

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Methodological problems in studying dietary
responses
Research suggests that there are, indeed, genetic differences in how people
might respond to higher-fat diets.
Yet there is still no clear link between particular genes and particular outcomes.
For one thing, few studies exploring genetic responses to high-fat diets have a
control group. Few are based on data where peoples food intake was strictly
monitored (for instance, people getting a strict menu in a lab).
Instead, many studies about dietary intake are based on people self-reporting
what they ate, which is known to be quite inaccurate.
(What did you eat for lunch last Tuesday? Tuna? What was the exact portion of
tuna? Oh wait, was tuna on Wednesday? And maybe it was salmon? Difficult,
right?)
So, in fact, none of the data in any study that used dietary self-reporting may be
particularly useful.
This is a common problem in nutritional research in general.
Other problems in studying high-fat diets include:
Higher in fat may be 30% of total calories in some studies; in other studies,
it may be more.
Fat type may differ from study to study (for instance, comparing unsaturated
fats to saturated fats, or processed oils to naturally occurring fats such as
butterfat).
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To draw good conclusions, we need good data. So, before you get your genetic
test results, recognize that the scientific research that many of these proposed
genetic links are based on may have significant methodological problems.
High-fat diets and body weight

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All weight loss diets need to control energy balance (energy in versus energy
out). There is nothing magical about eating a given percentage of any particular
macronutrient.
Yet some people swear that a high-fat diet helped them lose weight.
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This may be because some people find higher-fat diets more satiating due to
the effects of gastrointestinal hormones such as CCK, which respond to the
presence of fat and protein in the gut. More satiating means people eat less,
which then creates an energy deficit that helps them lose weight.
Other people, hearing the exciting tales of the miraculous high-fat diet, might
leap on the lipid bandwagon, only to discover that, sadly, cheese and butter
were not their personal path to getting ripped.
Heres what 23andMe suggests as potential genetic markers and how they
might work in European populations:
APOA2 SNP rs5082: Associated with increased odds of obesity in those

who ate a diet high in saturated fat.
APOA5 rs662799: Having 2 copies of the G version was associated with

higher BMI among those eating a diet high in fat (30% of calories from fat).
The GG version of this SNP is also associated with double the risk of early
heart attacks.
Other studies have looked at other links between dietary fat, other SNPs, and
BMI. Results are equivocal.
For example:
Some earlier research suggested there may be a link between the PPAR-
gamma (usually written as PPAR- ) pathway (which youll remember from
Chapter 7), dietary fat, and BMI. Yet a later 2016 study involving about
11,000 European men and women found that the influence of dietary fat
on associations between SNPs in the PPAR- pathway and body size was
probably absent or marginal.
A study that looked at whether consumption of fried food interacted with
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a genetic risk score of 32 combined genetic variants found that yes, if
people ate more fried foods they were likely to be heavier. But was this due
to the greater energy intake (in other words, the fact that fried foods are high
in calories), or other factors (such as other behaviors of people who eat a
lot of fast food) as well? (If youre curious, the full list of variants is here:
http://www.bmj.com)
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This doesnt mean theres no genetic link, just that we havent closed in on a
precise connection just yet.
We have a lot of informed hypotheses and areas for further research. And we
can pretty confidently say that different people have different responses to
different diets.
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High-fat diets and metabolic health
The rs662799 and rs662799(C) alleles of APO5 have been shown to be
associated with weight gain and higher triglyceride levels on high-fat diets in
a variety of ethnic groups, such as Han and Guangzhou Chinese, Pakistanis,
Caribbean Hispanics, and Israelis of European (Ashkenazi), Middle Eastern
(Sephardic) and Yemenite origin.
This suggests that for some people at least, high-fat diets may result in a poorer
blood lipid profile.
One study in a South Korean population looked at people with a variant of the
APOA5 gene that made them more likely to have high blood triglycerides. (We
looked at triglycerides in Chapter 6.)
Researchers asked participants to increase their vegetable intake to six servings

a day, and replace processed carbohydrates in this case, the familiar Korean
staple of white rice with higher-fiber carbohydrate sources: whole grains
(such as barley) and legumes. This higher fiber intake resulted in better blood
sugar and triglycerides, and improved markers of insulin resistance (HOMA-IR),
regardless of their genotype.
In other words, no matter what genes you have, eating more vegetables and
fiber is a good idea for most people.
This study didnt track weight loss. But, given what weve seen in our PN
Coaching program, wed guess that improving food quality and fiber intake might
have loosened some peoples belts.

In our PN sample, only one person had the GG allele of APOA2 rs5082, so it was
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hard to draw any conclusions.
However, the APOA5 rs662799 SNP was a different story.
With this SNP, AAs were considered normal because theyd theoretically gain
weight on a high-fat diet. GGs would be theoretically more likely to lose weight.
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Nearly 80% of our sample were AAs. Some AAs did say theyd usually gain
weight on a high-fat diet. This would be expected, since high-fat diets are often
also high in calories. Other AAs said theyd just stay the same.
A few people did, however, report that they typically lost weight on a high-fat
diet. All were AGs, not GGs.
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We had no GGs in our sample. The potential rarity of this allele may help explain
why some people in the fitness industry sing the praises of high-fat diets for
weight loss, but also why many other people find that their personal reality
doesnt match the promise.
Of course, again, there are many other factors involved, such as:
the energy density of fat: it packs a calorie punch and is easy to over-eat;
peoples individual preferences for eating more fat, which may also be
affected by genetics (see Chapter 8 for more on fat taste preference);
why people might be eating a high-fat diet in the first place, since some of
our PN population might be looking to gain weight on purpose; and
how people are defining and measuring a high-fat diet; or

how they were tracking their intake and observing the results.
So, we cant really say with certainty that the APOA2 or APOA5 variants really
made that much of a difference.

Genetic testing may tell you whether you might gain or lose weight on a
high-fat diet, or whether a high-fat diet might negatively affect your blood
lipids. But right now, the research still isnt definitive.
You may need to watch your total fat intake how much fat you eat
in general.
You may need to watch your saturated fat intake.

You may gain weight on a high-fat diet. But energy balance (calories in vs.
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calories out) is still the most important factor. This doesnt mean that if you
have the wrong genes, youre doomed to never enjoy butter or bacon
again. You might simply have to moderate your intake, stay active, and make
generally healthy choices you know, all the boring non-magical stuff.
Other dietary factors are probably also important for managing

triglycerides, such as getting enough fruits and vegetables, as well as fiber
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from whole grains and beans / legumes.

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If you want to know whether your body will thrive on a higher-fat diet
try a higher-fat diet for a month or two, and see what happens. Wed
define higher-fat as something thats more than about 35-40% of your
total calories from fat. Track how you feel and perform, along with your body
weight, body composition, and blood lipids if possible. The data you gather
from this simple experiment will probably give you a clearer answer than
most genetic predictions we could make right now.
Include a blood lipid profile as part of your regular medical checkups (e.g.,
annually or biannually). Again, this will give you a much clearer picture of
what is actually happening right now, rather than simply speculating based
on genetic markers without clear data.
Ketogenic diets
High-fat diets are often discussed together with terms like ketosis and
ketogenic diet. A high-fat diet is not necessarily a ketogenic diet.
However, given that people commonly equate them, and that some form of
ketogenic diet regularly comes in and out of fashion, we thought wed discuss
ketogenic diets here as well.
Ketone bodies are particular types of molecules (acetoacetate, beta-

hydroxybutyrate, and acetone) that our liver can make from fatty acids. We can
use these for energy, especially at times when other sources of energy arent
readily available, such as when weve gone without food for a while (when
fasting, most people go into ketosis within 2-3 days).
Dietary ketosis simply means that blood levels of ketones are above a certain
level. Again, this most often happens when we are fasting, or when we are
eating a very low carbohydrate diet (which tends to be a high-fat diet, hence the
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confusion between high-fat, low-carb, and ketogenic diets).
We can also raise our blood levels of ketones without changing our diets by
taking ketone supplements, though this isnt necessarily the same physiological
state as ketosis via fasting or carbohydrate restriction. (Heres a link to more
reading about ketogenic diets.)
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A quick skim of diet support groups will reveal that ketogenic dieting has its
raving fans people who tried ketosis-stimulating ways of eating, felt terrific,
and now want everyone else to do it.
However, as with most other ways of eating, variation in key genes involved in
certain metabolic pathways may shape how we respond to this or any other diet.
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FGF21 and HMGCS2
You might remember FGF21 from Chapter 8 on food preferences. The FGF21
gene codes for FGF21, a protein that helps to regulate energy balance and
insulin sensitivity.
Early work in mice found that the FGF21 protein increased in the liver in
response to one of three states: fasting, ketogenic diets, or low-sugar / low-
protein diets. This increases fat oxidation, decreases inflammation, increases
energy expenditure and increases glucose tolerance. (Generally, all good things.)
However, in humans, FGF21 is only stimulated by fasting for more than 72 hours,
not with other diets.
Lab models suggest that FGF21, along with other genetic and epigenetic factors,
may also affect our response to ketogenic (low-carbohydrate / high-fat) diets.
The models show that:
1 | FGF21 protein production is turned on by ketone bodies (namely,

acetoacetate) through epigenetic remodeling by a protein called SIRT3.
2 | This then increases the production of a protein called HMGCS2 (3-hydroxy-

3-methylglutaryl-CoA synthase 2, in case you need to win biology trivia
night). HMGCS2 is the first enzyme in a chain of enzymes needed to make
ketone bodies.
3 | Ketone bodies make more FGF21 and HMGCS2.
4 | HMGCS2 then is able to make more ketone bodies, unless theres a

polymorphism in the HMGCS2 gene (rs28937320). There are several types
of polymorphisms, one of which can be completely inactive. In that case, a
ketogenic diet wouldnt trigger FGF21, as little to no ketone bodies will be
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made.
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Figure 10.4: Ketone body metabolism and regulation
Image adapted from Newman JC, Verdin E. Ketone bodies as signaling metabolites. Trends in
Endocrinology & Metabolism. 2014 Jan 31;25(1):42-52.
Mutations in the HMGCS2 gene are associated with a genetic condition known
as HMG-CoA synthase deficiency.
When eating normally, people with HMG-CoA synthase deficiency are fine. But
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when fasting, they cannot go into ketosis properly (aka hypoketotic); they may
become hypoglycemic enough to go into a coma.
HMG-CoA synthase deficiency isnt a medical condition that needs treatment.

Affected people simply need to avoid long periods of fasting and probably also
need to quit reading diet support groups. |
If youre worried you might have this, probably dont worry too much: Its a
relatively rare, autosomal recessively inherited disorder (in other words, you
need two copies of the mutant gene) that only affects fewer than 1 in 1,000,000
people.
Most of us wont have this rare genetic disorder. Yet given the complexity of
metabolism, its still quite possible that we may differ in our responses to a
ketogenic diet.
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Genetic testing may tell you whether you have the HMGCS2 rs28937320
variant that could affect your response to a ketogenic diet and fasting.
23andMe doesnt test for the variant, but other commercial services may.
Again, this variant is quite rare, so theres a strong chance you dont have it.
If you want to know whether your body will thrive on a ketogenic diet
try a ketogenic diet for a few weeks, and see what happens. A standard
ketogenic diet protocol that is used to treat childhood epilepsy typically
uses a 4:1 ratio of dietary fat to protein and carbohydrate combined (in other
words, 4 grams of fat per 1 gram of combined protein and carbohydrate).
Generally, it takes 2-3 days of eating this way to get into ketosis. If you try
several weeks of keto dieting and feel terrific or terrible or meh then
you have your answer. The data you gather from this simple experiment will
probably give you a clearer answer than most genetic predictions we could
make right now.
Experiment and discover the diet that is right for you. Other peoples
results with a given diet may not match yours, in part due to possible
genetic factors.
Micronutrients: Folate and MTHFR

variations
The MTHFR gene codes for the enzyme methylenetetrahydrofolate reductase
(MTHFR).
This enzyme helps us process Vitamin B9, or folate (specifically, folic acid), which
occurs naturally in a wide variety of foods and is involved in many physiological
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processes, including having a healthy pregnancy.
Two common MTHFR polymorphisms (rs1801133 and rs1801131) affect how our
bodies metabolize this nutrient. Approximately 60 to 70% of people will have
one of these variations. About 10% of people will have both polymorphisms. |
When MTHFR protein levels are lower (particularly when one has two copies of
the rs1801133 polymorphism), we dont process folic acid as well. Homocysteine

levels may go up. Higher homocysteine is linked to inflammation and chronic
diseases such as heart disease and stroke.
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Table 10.1: Two common MTHFR polymorphisms and their effects
rs1801133 (677 C>T) rs1801131 (1298 A>C)
Allele What it means Allele What it means
CC Normal folate metabolism AA Normal folate metabolism
CT 65% efficiency in AC Possibly impaired folate

processing folic acid metabolism
TT 10-20% efficiency in CC Number of risks. Complex.

processing folic acid
However, these more common MTHFR polymorphisms dont cause severe

MTHFR deficiency, which is a rarer, genetically recessive condition that can
result in major neurological, movement, and psychiatric disorders as people age.
MTHFR, like most genes, doesnt act alone.
For the MTHFR protein to do its job, it also needs riboflavin (aka vitamin B2)
as a cofactor, a substance thats required for an enzyme to work. Riboflavin is
involved as a cofactor in a wide range of reactions and biological processes.
Thus, genes involved in the absorption, metabolism and utilization of riboflavin

will influence the effect of whatever MTHFR gene variant one has.
Right now, we know of about 90 genes in the human genome that code for
proteins that depend on riboflavin. There are six genes for riboflavin uptake and
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conversion to the active coenzymes flavin mononucleotide (FMN) and flavin
adenine dinucleotide (FAD), and two for converting the enzyme to another form,
dihydroflavin.
This means that our ability to use MTHFR effectively may depend on many
complex factors beyond having a genetic MTHFR variant.
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While there are quite a few genetic testing services out there that offer advice
on B vitamin supplementation based on genetic data, the U.S. Academy of

Nutrition and Dietetics argues that currently, there isnt enough evidence about
MTHFR polymorphisms to change current folate recommendations.
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Likewise, the American College of Medical Genetics and Genomics actively
discourages testing for the two common polymorphisms in the MTHFR gene,
arguing that:
it has minimal clinical utility;

there is no evidence that specific treatments lower the risks of high
homocysteine or other health conditions linked to MTHFR variants; and
concerned patients might be better off simply testing their homocysteine

levels directly.

23andMe tests for a variety of MTHFR polymorphisms. Heres what we found for
the two most common risk variants.
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Figure 10.5: MTHFR variants in PN population
However, it wasnt clear whether having any of these variants had actually led to
any health problems for the affected people. |
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As usual, its complicated. Genes, proteins, and nutrients interact in highly
complex ways.
If you have a MTHFR polymorphism, your body may not be as efficient

as others at processing folate. This is especially important for women
considering pregnancy. However, its worth exploring if you have other
health concerns that have been definitively linked to low folate, such as anemia.
Work with a qualified healthcare provider if you have concerns. You can
get your homocysteine levels tested directly with a blood test. Dont rely
only on genetic testing data, which at best is simply a prediction of risk
rather than a definitive measure.
Caffeine metabolism
You might have noticed conflicting reports in the media about whether caffeine
is good or bad for you.
One problem in judging research studies on things like the link between, say,
coffee and heart disease, is that we vary genetically in how we process caffeine.
The gene CYP1A2 codes for the cytochrome P450 superfamily of enzymes,
involved in the breakdown of drugs along with cholesterol, sterols, and other
lipids. Caffeine is mainly metabolized by the liver enzyme known as P450 1A2, and
breaks down into byproducts like theophylline, paraxanthine, and theobromine (the
compound in dark chocolate that is supposed to make us feel good).
Variations in the CYP1A2 gene at the rs762551 SNP determine how quickly a
person will metabolize caffeine.
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If you have the slow version, more caffeine seems to raise your chronic
disease risk.
If you have the fast version, more caffeine seems to lower your chronic
disease risk.
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However, this is just about how your body processes caffeine.
It doesnt mean that your caffeine consumption habits are determined by your
genes, though there may be some genetic basis for that as well.
Studies comparing genetically identical twins suggest that inheritance may

explain between 34-58% of caffeine-related effects and consumption patterns
unless youre a heavy caffeine user, in which case the contribution of inheritance
went up to around 77%.
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For people who were light or moderate caffeine consumers, inheritance
seemed to matter less than environment for instance, what people around
them were doing, whether they liked the taste of coffee or tea (for more on
food preferences, see Chapter 8), etc. But for people who were heavy caffeine
consumers, heredity seemed to play a bigger role though still not 100%.

Many of us at PN are big coffee and tea fans so much so that having high-end
coffees and teas is a much-coveted part of PN gatherings. People roast their
own beans, argue over the best coffee roast or place in a given city, and would
never be caught drinking cheap green tea.
Youd think that given this love for the magical alkaloid caffeine, all of us might
be fast metabolizers.
In fact, only half of us are.
Would we change if we knew our caffeine processing type?
Its hard to say, but
If were being honest probably not.
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Figure 10.6: Differences in caffeine metabolism in PN population

This one might be worth getting tested for but only if youll actually do
something about it. If you have the slow version but wont give up your
daily pot of coffee, well you might as well save your testing money and
spend it on espresso instead.
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Whats up next
In the next chapter, well look at how genetic variation might affect our athletic
performance and response to exercise.
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What we found: Food What we found: Exercise
intolerances and muscle performance
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Why dont some foods dont agree In this chapter, we look at some of
with you? And how much of that the genetic factors that may shape
may be due to genetic factors? our response to (and recovery from)
exercise and training, and whether
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CHAPTER 11
What we found: Exercise and

muscle performance
In this chapter, well look at what genetic testing can tell us about:
how we might respond to or recover from exercise; and

whether we can predict our athletic performance or talents from the
makeup of our muscle fibers.
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Just because a genetic test can tell you (for instance) what kinds of
muscle fiber types you might have, it doesnt mean that it can tell you the
perfect exercise plan for you.
What determines our physical

capacity?
Maybe youve looked out your window early one morning, watched the
dedicated runners glide past, sleek and lean, and thought, That will never
be me.
Maybe likely around December 31 each year youve thought, I should take
up running. Then you abandoned it around January 12 when your knee said,
Bad idea. Smarten up next year.
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Maybe you are a runner, and wondering how you could be better.
Maybe your personal trainer is telling you that sprinting is awesome, but all you
want to do is chill out with an easy trail run. Or the other way around every
time you try to run more than 5 minutes, you want to lie down until the world
stops spinning. |
Maybe youve already run 3 miles in the time it took us to read this.
Have you ever wondered whether you are naturally meant to run (as
Christopher McDougall suggests in his book Born to Run)?
Or to do any other type of sport?
Its a good question, one without clear answers. (Yet.)

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Human physical capacity is complex.
Human movement is complex.
There are no known golf genes, parasailing genes or hip-hop dance genes.
Yet genetic data can give us some clues about how we might play to our
potential.
Are you a tortoise or a hare?

Sprint versus endurance performance
You might have seen some version of a photo series floating around the Internet
that compares a sprinters muscular, powerful body to an endurance athletes
lean, sinewy one.
Heres an example we found:
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Figure 11.1: Sprinter versus endurance athlete
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The usual implication is that if you want to look like a sprinter, train like one.
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Indeed, fitness media is full of workout programs that promise you the body
youre seeking:
Want long, lean muscles? Do Pilates or yoga.

Want to be tall, slim, and graceful? Do ballet.
Want to be jacked and lean? Do Crossfit.
Want to be a human tank? Do rugby.
And so on.
Is it that simple? Nope.

Of course, nobody is genetically gifted enough to just roll out of bed and into
an Olympic-caliber performance or a magazine-cover-worthy physique. In other
words, training and nutrition matter a lot.
Certain types of training do, indeed, amplify physical abilities and characteristics
such as muscle size or mobility. So you could probably become more graceful
after years of ballet classes, more muscular after years of bodybuilding, or more
likely to grind other peoples faces into the mud after years of rugby.
Yet athletically ideal bodies in other words, bodies that demonstrate elite,
world-class performance and physique development involve a statistically
unusual collection of physical characteristics that are, for the most part, present
on Day 1 of training.
In other words, as Lady Gaga sings, genetically speaking, these top athletes
were born this way.
This is particularly true with events at the polar ends of the running continuum
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(e.g., 100-meter sprints compared to endurance or ultra-endurance), or the
size continuum (e.g. gymnastics and horse racing versus basketball and sumo
wrestling).
Yet other events that include sprint or endurance performance also include
other elements, such as hand-eye coordination and reaction speed. Our co-
contributor John, a highly-ranked masters-level sprinter, reports that although
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he could easily match NFL skill position players in a 40-meter sprint, he got
obliterated when competing in a reaction time contest against them.
Although most youth coaches know intuitively that some athletes show up with
better physical raw material than others, its hard to say exactly what the genetic
basis of those gifts might be.
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What parts of athletic performance
come from our so-called genetic
potential?
And what parts are a result of training and practice?
Exercise physiologists have suggested that many factors could contribute to

running performance in particular, such as:
Creatine kinase (CK), an enzyme involved in cellular energy production

cycles and in passively moving this energy from mitochondria to myofibrils
(muscle fibers) in contracting muscle. Some studies suggest that having the
AA version of the rs8111989 SNP in the CK-MM gene, which codes for CK,
may improve physical performance in various tasks. CK-MM polymorphisms
have also been linked to differences in muscle damage after exercise.
Maximal oxygen uptake, aka VO2 max, which may be responsible for the
better endurance performance of athletes from mountain populations,
such as the East African highlands, the South American Andes or northern
Mexicos Sierra Madres, home of the famed indigenous Rarmuri /
Tarahumara runners. Although we can improve VO2 max a fair bit with
training, theres also a significant genetic contribution: researchers
speculate that between 40-50% of variance in oxygen uptake is genetically
determined.
Tendon stiffness, particularly in the lower leg, which could offer more elastic
spring to a stride.
Skeletal structure, including narrower hips.

Mitochondrial gene expression, mitochondrial DNA and mitochondrial
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enzyme activity: Since mitochondria are the power generators of a cell,
better mitochondrial function may mean more sustained energy for athletic
activity.
PGC-1 is a protein that binds to and activates transcription factors,

including most nuclear receptors. Its strongly expressed in skeletal muscle,
particularly Type I oxidative fibers. Transgenic mice with more PGC-1
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have improved endurance performance and preserve muscle mass better,

particularly as they age. (More on muscle types below.) In humans, PGC-1
increases when we exercise, and may coordinate the activation of metabolic
genes in muscle in response to exercise. It may also improve the function of
mitochondria and peroxisomes, which break down fatty acids.
These are a mix of environmental and heritable factors.
Even something that may seem as fixed as skeletal structure can be affected
by our environment.
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For instance, lets say we have genetically-identical twins separated at birth.
One grew up in an affluent region with plenty of good nutrition and early-life
sports training.
The other grew up in a poor region with frequent food deprivation and
malnutrition, where sports training was kicking an old soccer ball around
and walking miles to get fresh water.
Although there will obviously be a family resemblance, the second twin will
probably end up with a somewhat different build likely lighter and smaller than
the first twin.
Theres no single sprinter gene or

marathoner gene.
At last count, researchers have found more than 200 genetic variations that may
contribute to physical performance, or how well people respond to training.
Even capacities that may seem fairly simple, like endurance, are actually
complex abilities that depend on many factors.
For instance, among endurance athletes from East Africa, how much do cultural
factors contribute to developing endurance capacity and performance for
example, is there a running culture where children are encouraged and
supported to run early in life? Do strong runners have a high social status?
What about the diverse geography of countries like Ethiopia and Kenya, which
contain both highlands and lowlands is there an oxygen advantage for
athletes who grow up at higher altitudes?
Similarly, Chris McDougalls book Born to Run looks at the Rarmuri / Tarahumara
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population, who have physiological features that make them good runners, but
who also live in mountainous regions where running is a favored activity.
Do athletes from these isolated regions have distinct genotypes?
Or have they simply adapted their fitness and behavior to match to lower-oxygen
environments and/or movement cultures?
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The Spanish ultra-athlete Kilian Jornet is an example of why its hard to answer such
questions.
Jornet specializes in FKTs, or fastest known times for ultra-endurance activities

for instance, he set the record for a round trip up Mount Kilimanjaro in 2010 (7
hours 14 minutes). His VO2 max is around 85-90 mL per kg of body weight per
minute, compared to the average fit males VO2 max of between 45-55.
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This sounds like hes a genetic freak designed for endurance work, and maybe
he is but he also grew up as the son of a mountain guide in the Spanish
Pyrenees, in a rustic mountain hut at an altitude of about 6,500 ft (2,000 m).
So what is responsible for his performance?
His genes?
His lifetime physiological adaptation to living at high altitude?
His upbringing?
His family environment?
His training?
Of course, the answer is probably All of the above, and more.
One study looked at genetic polymorphisms that may be involved in endurance

performance. Using 46 world-class endurance athletes and 123 controls (all
white Europeans in Spain), this study set out to explore whether there was an
ideal endurance type.
Researchers tested the subjects for the following seven genetic variants,
involving many factors that are part of endurance performance:
The insertion / deletion variant of ACE, which codes for angiotensin-

producing enzyme (ACE). ACE helps control blood pressure and
inflammation. The relationship between variants in this gene and endurance
performance were first noticed in high-altitude British mountaineers who
were able to climb higher than 7,000 meters without using supplementary
oxygen.
The Arg577Ter variant of ACTN3, which codes for alpha-actinin-3, and which
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well look more at below.
AMPD1 Gln12Ter, which codes for an enzyme that deaminates AMP

(adenosine monophosphate) to IMP (inosine monophosphate); variations can
lead to impaired exercise performance or myopathy (damage to or diseases
of muscle tissue).
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Muscle-specific creatine kinase (CKMM 1170 bp/985 + 185 bp variant), a

genetic variant associated with aerobic performance.
HFE His63Asp mutation; HFE codes for the human hemochromatosis protein
and is involved in iron uptake.
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GDF-8 Lys153Arg mutation, aka MSTN, which codes for myostatin, a major
determinant of how much muscle mass we can have.
PPAR- (PPARGC1A Gly482Ser), related to genes involved in energy

metabolism, muscle fiber type, blood pressure, cholesterol metabolism, and
obesity.
Would endurance athletes likely have more of the particular variations that
promote athletic performance than average? Yes.
But only three of the 46 top world-class endurance athletes had the best
possible score for up to six genes.
More significantly, none of them had the perfect profile of genetic variations.
Other researchers took this speculation one step further, asking:
Could the perfect endurance athlete (at least based on what we currently
know about genetic polymorphisms that favor endurance) theoretically exist?
These researchers put together 23 polymorphisms that were strong contenders

for individually influencing endurance, and considered how likely it was that this
perfect endurance athlete could exist. They speculated that among people of
white European backgrounds, only 0.0005% of them might have this profile.
In the United States, there are around 224 million people who report their main
ethnicity as white European. This means that using this model, 1,120 people
might have this genetic profile.
Should those 1,120 people report for marathon training immediately? Well, even
if we could find them, lots of other factors might affect their performance, such as:
Whether they actually like endurance exercise;
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Whether they are motivated to train;
Whether they have the mental skills to stay focused during long events;
Whether they want to spend hours pounding the pavement, or would rather
watch Netflix;
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Whether they live near somewhere they can train;

Whether people around them are doing the same activity;
Etc.
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Some researchers suggest that among top athletes, about two-thirds of their
athletic capacity can be explained by genetic factors that add up, with the
remaining one-third being explained by environmental factors.
Yet that theoretically perfect profile may also depend on an athletes ancestry.
In a study that compared white European and East Asian swimmers, top
swimmers did have the ACE Ins/Del variation, but top Europeans tended to have
the D allele, while the top East Asians tended to have the I version (ACTN3 was
also tested, and it didnt seem to make a difference).

Its complicated. (Darn it.) Most sports and physical activities involve a mix
of capacities, only some of which are strongly genetically influenced.
While we might be able to predict which people have the highest ceiling
for athletic development, we cant predict if a person will ever hit that
ceiling. We have some compelling clues and strong hypotheses, but not
enough data yet to build a model.
Most coaches will probably tell you that they would get better data from
simply knowing, observing, and understanding their athletes than from
genetic testing. Standing in a field with a clipboard, watching an athlete
train for several months or years, is probably the best data of all.
Heredity is not destiny. Even if you come from a population of people that
have traditionally done well at a certain activity, its no guarantee that you
will do the same, or that you have any intrinsic natural ability by virtue of
heredity. Conversely, even if you come from a population of people that
traditionally havent done well at a certain activity, its no guarantee that you
cant succeed at that activity.
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The genetic makeup of muscle
fibers
Muscles are made up of fibers. Within each muscle fiber are many myofibrils,
bundles of long polymers of the proteins myosin and actin. When myosin and
actin filaments slide past each other, we get muscular contraction.
Figure 11.2: Muscle fibers
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Actin is an ancient protein that has long been conserved through evolution. In
mammals, there are six actin paralogs: different yet related forms encoded by
separate genes. One study describes actin as cellular steel, because actin can
act as an alloy to form various mixes of protein-based structures in cells.
There are likewise many classes of myosin proteins; myosin II is the type
involved in muscular contraction. Nearly 20 known genes contribute to myosin II.
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ACTN3
The ACTN3 gene makes a protein called alpha-actinin-3, which (unlike its buddy
ACTN2) is only expressed in fast-twitch muscle fibers, which we use for speed
and power movements like weightlifting, sprinting, and/or jumping.
Research suggests that particular forms of this gene correlate to sprint and
endurance performance. 23andMe looks at a particular SNP (rs1815739) on the
ACTN3 gene.
The T form of the rs1815739 SNP prevents the full alpha-actinin-3 protein from
being made, and people with two copies of T lack alpha-actinin-3 completely.
Thus, many elite sprinters and strength athletes have the CC type, while few
have the TT type. CT is a mixed type.
Among athletes, power athletes were much more likely to have at least one
working copy of the gene than non-athletes, and at elite levels, nearly everyone
has at least one working copy (in other words, they were either CC or CT).
Seems pretty straightforward: If you have the right ACTN3 variant, you should be
crushing all the strength-power events, right?
As it turns out, so far, only running seems to be strongly affected. It doesnt seem
to make a difference for other movements like throwing and jumping. Nor does it
seem to matter for team sports.
This doesnt necessarily mean that TT makes you a better endurance athlete
(since research suggests that being a TT gives elite cyclists no advantage), but
rather that if youre a TT, you may perform less well in sprint and power-type
events.
On the plus side, while TTs started out weaker in workout programs, they often
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made significant gains when trained.
Nor does a TT type seem to cause any type of disease. This may be because
there are other related proteins that can do the job, though less well. For
instance, ACTN2, which is expressed in all muscle fibers, might compensate for
the loss of ACTN3 in fast Type II fibers. |
Alpha-actinin-3 may also affect how muscles use oxygen. Research suggests
that having less ACTN3 might make muscles greedier for oxygen, which might
be metabolically costly and slow the CT or TT people down. Studies in mice
have found that muscle fibers lacking alpha-actinin 3 are weaker and smaller, but
more efficient and fatigue-tolerant a perfect recipe for an endurance athlete.
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About one-third of us have the pure fast-twitch or sprinter CC type of
ACTN3 SNP variation
About one-sixth of us have the TT, or endurance-type, variation.

The rest of us are CT, or mixed.
Figure 11.3: Distribution of ACTN3 rs1815739 alleles within survey population
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How does this compare to real-world
experience?
Among the people we surveyed:
About half of them matched their expected genetic profile, i.e.:

CCs preferred sprint-type activities.
TTs preferred long slow endurance-type activities.
CTs preferred a mix.
A little less than half of them sort of matched their profile in other words,
they were CTs who preferred either sprint or endurance-type activities. We
counted this as a partial match, since in terms of their muscle fiber makeup,
CTs could likely go either way.
5% of them were the opposite: either CC hares who nevertheless preferred

endurance-type activities, or TT tortoises who nevertheless preferred
sprinting-type activities.
Our PN sample is a handy one for this particular SNP, because it contains
many people who have achieved significant athletic success (i.e., who were
competitive at the national or international level).
Interestingly, there was no clear correlation between a given SNP combination

and a predicted match for a given sport.
In fact, this high-achieving athlete group included someone with the opposite
SNP to what they should have been doing.
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Genetic testing can tell you what form of the ACTN3 variant you have.
Both 23andMe and Nutrigenomix test for the rs1815739 SNP in the
ACTN3 gene.
Youll likely notice a difference in your sprint versus endurance

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preferences and abilities if you have a pure form of the ACTN3

variant in other words, either a CC (sprinter type) or TT (endurance type).
If youre a mixed type, you might notice you could go either way.
If you like particular activities but arent genetically destined to do them,

enjoy them anyway. You probably wont get to the Olympics (though based
on our sample, who knows?), but if youre a CC who appreciates a leisurely
Sunday morning jog, have fun.
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How well can you recover from
exercise?
Being good at movement, sports, and exercise isnt just about how well you
perform during those activities. Its also about how well you recover afterwards.
After all, its hard to become a world-class athlete if most of your training time is
spent sitting on an ice pack.
When we move with vigor, we do minor damage that must be repaired, and we
put stress on our structures, which then remodel themselves to manage the
strain. Its this repair and remodeling process that makes us stronger and fitter,
not the workout itself.
Non-genetic factors in recovery

Age and life stressors play a major role in recovery. You simply cant recover as
well at 81 as you did at 18, nor will you be able to sustain a tough training load if
youre also working full-time as an emergency room doctor with a newborn baby
at home.
Biological sex is also a factor, though this is usually hormonal rather than genetic
per se (in other words, these are not necessarily characteristics linked to X or Y
chromosomes).
For instance:
Women tend to have more tissue laxity than men (which may mean more
joint injuries) as well as a higher rate of many autoimmune diseases (which
are typically aggravated by stress, including training stress).
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Mens higher average testosterone, which helps with protein synthesis,
means that they build more muscle faster.
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Then there are emotional, social, and cultural components.
For instance:
Are you a perfectionist, type-A, second place is first loser kind of thinker
who would rather tango with an alligator than miss a workout? (Or maybe
tangoing with the alligator is your workout?)
Do you choose sports and activities that push your limits? Or are you more
of a chill out with a restorative yoga class kind of person?
Do you train on a team where the motto is Pain is weakness leaving the
body or Tape it up and get back in there, ya baby?
Did you grow up doing manual labor from an early age, and/or in a family
where sports, exercise, and movement were encouraged? (In other words,
did you start building titanium tendons as a toddler?)
Genetic factors in recovery

And, of course, many factors in recovery are shaped by our genetic expression.
For instance:
How fast and effectively can your body make connective tissue proteins to
repair damage in structures like ligaments, tendons, and cartilage?
How fast and effectively can your muscles clear waste products and repair
themselves?
How fast and effectively does your immune system respond to the stress of
exercise? (Or does it over-respond and start attacking healthy tissues?)
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How does your body manage inflammation? Is it a constantly raging forest
fire? Or a carefully controlled tactical operation, complete with fast and
efficient cleanup crew?
Given all the factors involved in recovery, there are naturally many potential
genetic contributors. Here are just a few. |
We wont look at all of these in depth. Just get the main ideas:
Its complex.
We still have a lot to learn about what genetic factors affect our recovery
from exercise.
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Gene / variation What its related to
Angiotensin gene Creatine kinase and recovery from eccentric

ACE (I/D) (rs4646994) muscle lengthening
Actin protein gene See above for more on ACTN3; some forms
ACTN3 (rs1815739) may predispose people to exercise-induced
rhabdomyolysis (excessive muscle tissue
breakdown)
Chemokine (cell signaling) Markers of exercise-induced skeletal muscle

ligand and receptor genes damage; soft tissue injuries
CCL2 3441(C>T) (rs3917878)
CCL2 289 (G>C) (rs2857656)
CCR2 941(A>C) (rs3918358)
CCR2 4439 (T>C) (rs1799865)
Collagen repair genes Remodeling of connective tissues; variants

COL1A1 rs1800012, (especially in COL5A1) are associated with higher
COL5A1 rs12722, rs3196378 rates of anterior cruciate knee ligament injury,
BstUI RFLP tennis elbow, carpal tunnel and Achillles tendon
COL27A1 rs4143245, rs1249744, tears
rs753085, rs946053
TIMP2 rs4789932
TNC
Creatine kinase gene Creatine kinase as well as C-reactive protein

CKM Ncol (A>G) (rs1803285) (CRP), a marker of inflammation
Insulin-like growth factor genes Associated with muscle damage (particularly in
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IGF-II (C13790G, rs3213221) men)
IGF-II (ApaI, G17200A, rs680)
IGF-II antisense (IGF2AS)
(G11711T, rs7924316)
IGF binding protein gene
IGFBP-3 (C1592A, rs2132570)
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Interleukin genes Inflammatory response to exercise and muscle

IL1B 3737 (C>T) (rs4848306) damage
IL1B 511 (C>T) (rs16944)
IL1B 3954 (C>T) (rs1143634)
IL6 174 (G>C) (rs1800795)
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Gene / variation What its related to
Insulin gene Codes for the insulin protein, which transports

INS 1045 (C>G) (rs3842748) nutrients into cells
Myosin light chain kinase genes Myosin muscle protein phosphorylation; may
MLCK 49 (C>T) (rs2700352) affect how well muscle fibers can tolerate
MLCK 37885 (C>A) (rs28497577) mechanical force
Osteopontin promoter gene Muscle size and weakness; muscle damage

OPN 66 (T>G) (rs28357094) marker
Solute carrier family 30 Zinc transport and insulin secretion; associated

(zinc transporter) gene with recovery
SLC30A8 (C>T) (rs13266634)
Superoxide dismutase 2 gene Recovery from oxidative stress

SOD2 (C>T) (rs4880)
Tumor necrosis factor gene Creatine kinase (CK) response to eccentric

TNF 308 (G>A) (rs1800629) exercise; also regulates muscles ability to repair
and grow
COL and TNC genes

One interesting genetic contribution to recovery is our ability to regenerate
collagen proteins, which make up much of our tendons, ligaments, and other
connective tissues.
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The gene COL5A1 codes for the alpha-1 chain of type V collagen.
Variations of this gene have been linked to connective tissue disorders such as
osteogenesis imperfecta (aka brittle bone disease) or Ehlers-Danlos syndromes,
a group of connective tissue disorders that can range from mild joint laxity to
potentially fatal complications if the connective tissues of major organs are affected.
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The rs12722 SNP on the COL5A1 gene has been linked to chronic connective
tissue injuries such as Achilles tendinopathy.
COL5A1 gene variants also seem to affect the mechanical properties of

collagenous tissues, such as its stiffness during moderate to intense contractions
(for instance, running, jumping, or other explosive movements).
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For many sports, having stiffer tendons and ligaments is an advantage, as these
tissues can bear more load and produce more elastic energy to help generate
force. Conversely, looser joints with laxer tissues may be more prone to injuries, as
the tendons and ligaments are less able to maintain stability around the joint.
Similarly, variations in the COL1A1 gene, which codes for collagen type I, are
associated with several complex connective tissue disorders, as well as shoulder
dislocations and ruptures of the anterior cruciate knee ligament (ACL) and/or
Achilles tendon.
Tenascin-C, encoded by the TNC gene, is a glycoprotein that is also involved

in wound healing as well as formation of tendons, ligaments, cartilage, and
bone. Like variations in the COL genes, variations in the TNC gene are linked
to tendon injuries.

We didnt test for any recovery-related genetic variants such as the COL genes,
but we did ask people about their experiences of joint injury.
There were clear variations in peoples experiences: Some people felt like they
were always injured; others said they almost never had problems despite regular
and rigorous workouts.
In addition, only one person whod been a high-achieving athlete (but started
athletics later in adulthood, rather than in childhood, as most others had)
reported frequent joint injuries. Most other athletes in the sample said they
rarely suffered from joint pain or injuries (or only had problems if they were really
pushing their training hard).
Does this mean that athletes naturally have better recovery?
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Or perhaps that people who started athletics young had better-conditioned
connective tissue?
In our sample, its hard to say whether theres any definite connection, but one
possible hypothesis could indeed be that to succeed in athletics, you need to
survive the training, and this includes joints as well as muscles. |
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Genetic testing services may be able to tell you about some of the gene
variants linked to recovery from exercise. If youre considering using
genetic testing to explore this question, try to find a service that offers as broad
an analysis as possible, rather than just one or two exercise-related SNPs.
Even if you dont know your genetic makeup, or dont have genetic
variants that put you at risk, you still have to train intelligently. The freebie
of a genetic advantage (such as some theoretical mutation that gives
you Wolverine-like recovery powers) will run out eventually with age and
cumulative stress.
Pay attention to how well you recover from exercise. Look for how often
you feel joint pain or other aches and pains, and how strongly. These may be
related to your genetic makeup; they may be related to other environmental
factors. Regardless, you still have to address them. If youre always dealing
with some minor problem, consider addressing your recovery more
aggressively. You may not be recovering as well as you could be, or you may
be following inappropriate training methods for your body.
Time is a thing. Tissues remodel on their own schedule, no matter what

you want. Good nutrition and regular movement help (by getting blood
flow to the tissues as well as a mechanical signal to kick-start remodeling).
Yet aside from aggressive supplementation with illegal drugs, we cant do
much about our natural tendencies. Give your tissues the time they need to
build a strong foundation, and recover from training.
Follow YOUR bodys cues, and dont try to stick to a rigid workout
schedule, or someone elses workout plan. It might be too much work for
you, or not enough. Schedules and plans are only as good as the bodies
that can manage them.
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Does exercise help you lose weight
easily?
As weve seen, exercise and daily-life movement are part of a healthy lifestyle
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plan for everyone.
Exercise does many good things: improves our fitness and strength; build lean
mass (muscle, bone, connective tissues); helps us beat stress; and so forth.
But does exercise always help us lose weight easily?

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Many people who want to be smaller or leaner find themselves frustrated when
they hit the gym regularly, and dont seem to make much progress.
This may be due to poor training practices (in fact, it often is).
It may be due to other factors, such as not addressing energy balance.
It may also, in part, be influenced by genetic factors.
The FTO gene seems to be involved in various aspects of energy balance

regulation, body size and fatness, along with other possible functions. For
instance, recent research in mice suggests that it also contributes to skeletal
muscle differentiation. (For more on FTO, see Chapter 7.)
One SNP on the gene is associated with both a higher BMI, and seeing different
benefits from exercise, at least among people of European descent.
In one large study of several thousand people:
People with the AA variant at rs9939609 tended to have a higher BMI (in
other words, they were heavier), but also lost weight more readily when they
exercised.
People with the TT variant tended to be lighter, but lost less weight when
they exercised.
But wait: Theres a wrinkle.
In the study used to support this finding, the effect was seen in people living in
North America, but not in Europe. This may be because on average, Europeans
tend to get more daily-life physical activity, such as walking or cycling, than
North Americans.
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In other words:
People with the same ancestry and genetic variant see different effects
depending on their environment and choices.
At first glance, you might think this research says that exercise isnt as helpful for
weight loss people with a TT variant, and some people shouldnt bother.
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In fact, it suggests that exercise is more important, and more helpful, for
people who might be genetically predisposed to being heavier.
In our experience coaching over 45,000 clients, weve found that the simplest
explanations are often the most common.
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While exercise alone doesnt necessarily help people lose weight (if thats
their goal), exercise plus a few basic nutrition and behavioral habits, done
consistently, does.
In other words, no matter what your genetic makeup involves, if you want to
lose weight, the pathway to get there is still the same as everyone elses.
Of course, exercise isnt just about losing weight.
Indeed, there are two key problems with predictions about exercise and
weight loss:
There are many ways to exercise. Exercise can be all kinds things, ranging
from yoga to extreme sports. Different types of exercise will affect our
bodies differently.
There are many reasons to exercise, such as having better metabolic

health, better movement quality, less pain, more physical capacity, more
strength, more muscle and bone mass, better athletic performance,
and so forth.
Weight loss is just one of many possible effects of exercise, but certainly not an
inevitable one, regardless of our genetic makeup.

In our PN sample, this FTO variant seemed to have little relationship to peoples
response to exercise.
Only about 22% of our sample matched their predicted FTO profile; about 78%
did not.
People who should have lost weight quickly didnt (or perhaps even put on
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mass when exercising); people who shouldnt have lost weight quickly did.
So, at least in our sample FTOs ability to predict weight loss from exercise meh.
What this means for you |
You might find that exercise helps you lose weight quickly or
moderately or not so much. This might mean you need to adjust your
workout plan, be more consistent with exercise, or simply enjoy the health
and stress-busting benefits of movement while looking for other ways to
keep your body fat and body weight so that its in a healthy range.
Movement is important for all of us, regardless of whether we are genetically

optimized to benefit from it, or whether it helps us lose weight. (More on this
in the next chapter.)
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Whats next: Real-world strategies
By now, you may be wondering what you can do about your genetic makeup,
whether you know you have risk factors or advantages.
In the next chapter, well look at all the things that you can do to give yourself
the best chance of living a healthy, happy, functional life no matter what your
genetic code is.
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What we found: Nutrient What does this
absorption and use mean for you?
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In this chapter, well examine some Chapter 12: Now that you've
genetic factors that may affect learned more about genetic
how our bodies digest, absorb, testing, or even gathered your own
and use particular nutrients. data, what should you do next?
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CHAPTER 12

Wow. You made it all the way through.
Congratulations.
That was heavy stuff, right? A lot to know and remember.
In this chapter, youll learn what to do with it all.
Which is:
Keep your sense of wonder.

Keep it simple.
Keep asking good questions.
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Keep practicing the basic good habits that you know are helpful,
regardless of your genetic makeup.
Keep contributing to the cause of science, if you can.

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At the edge of possibility
In 1868, Swiss doctor Friedrich Miescher extracted a compound from the nuclei
of cells, which he called nuclein. Today, we call this DNA, the code of life.
Around this time, Czech monk Gregor Mendel was breeding peas and
developing ideas about how these plants inherited their traits.
In 1944, American scientist Oswald Avery created what we might consider

the first transgenic bacteria by transferring nuclear material from one type of
bacteria to another.
In the early 1950s, British scientists Rosalind Franklin and Maurice Wilkins used
X-rays to explore the structure of DNA molecules.
Chemist Linus Pauling took a crack at proposing the shape of DNA as a triple helix.
Eventually, with a landmark research paper in 1953, James Watson and Francis
Crick laid claim to the double helix format that we recognize today.
Its hard to believe its been only 64 years since then.
A baby boomer could have been born the day that Watson and Crick published
their paper, and not even be old enough to get the seniors discount at their local
movie theater by the time theyre able to enjoy the benefits of genetic science.
Were writing this book in 2017.
And we are standing on the edge of major scientific discoveries that will
forever change the way we think about ourselves. Our connections to a larger
ecosystem. And our potential.
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Weve gone from making ball-and-stick models of a molecule that we barely
understood to fully mapping the human genome.
Now we can literally watch our cells work. Now we can see DNA unzip itself.
Now we can look at long tangles of chromatin tucked into tiny nuclei. Now we
can see proteins folding.
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We can now see processes inside our bodies that previous generations could
barely imagine.
We can now create a child with three parents, and treat or even cure diseases
that have plagued humanity forever. And we are just a few years away from
perfecting the technology that can let us remove genetic diseases or grant
additional abilities to our species.
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Every day, we discover new genes, new proteins, new pathways, new chemical
reactions, new possibilities and opportunities.
Our computing and bioinformatics processing are becoming faster, stronger,

more accurate.
And, of course, genetic testing becomes cheaper and more available.
We can speculate about the future. We can imagine great things.
But:
What does this mean for you, right

now?
Lets go back to the fundamental questions we asked earlier in the book.
4 simple questions to ask about genetic testing

Youll hopefully now remember our 4 questions about how to decide whether a
particular genetic test is a good idea.
Is this particular test:

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Hopefully by now youve gotten some general ideas about genetics, genetic
testing, and how these might relate to your health, fitness, physical makeup, and
performance.
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We also hope that youve gained a new appreciation of how incredible it is to be

a complex biological organism with so many moving parts.
There is so much more to learn about genetics.

We are just getting warmed up.
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Whats next for you?
Reading through this book, you probably wondered things like:
Whats in my genes?
What happens if I discover stuff I dont like in my genetic test results?
I got my test results back how do I make sense of them?
What am I supposed to do with all this stuff?
Im a health and fitness professional what do I tell my clients about their
genetic potential and risk factors?
Heres our suggested road map through the

land of genetics.
There are many ways to navigate this terrain.
This is just one way.
We think its a pretty good one, though.
1. If youre thinking about getting your genetic

code tested, start with why.
Get clear on your objectives and reasons.
Ask yourself questions like:
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What would I like to find out? Why?
What would be useful to me? Why?
What do I plan to do with the results? Why?
What am I comfortable with knowing or not knowing? Why?
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What emotional response might I have to my test results? Why?

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2. If youve already had genetic testing done,
start with how.
Understand how things work and what that means.
How was this sample collected?

How was the test done?
How were the results presented?
How was research and evidence used to support any claims made?
How were the possibilities and risks discussed?
How might the results be shaped by the agenda of the testing agency? (In
other words, what else is the testing agency looking to sell?)
3. Once you have your results, start with what.

Consider what you need to move forward with what you have learned.
Ask yourself questions like:
What information is useful, and what is not?

What does this information mean for how I think about my potential, and my
risks?
Will the results change my future choices? If so, how?

What more do I need to know in order to make informed decisions?
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What kind of health professional can help me answer the questions I have?
Who can coach me through my choices in the future, once I know what (if
anything) might help me?
Genetics: The game of probability

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Few genetic tests offer clarity or certainty.

If you have survived to healthy, functional, and relatively fit adulthood,
congratulations! You have probably escaped most of the congenital genetic
conditions with major, inevitable effects.
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You probably have few for-sures in your genetic code.
More likely, you have complex probabilities.
You have possibilities. Maybes. Risks. Could-bes.
Your game, should you choose to play it, is optimizing your genetic potential
while reducing your risks.
The problem is, we dont know exactly what this means for every single genetic
combination, or even most individual variations.
However, based on the research we do have, we can say what optimizes some
potentials and reduces some risks.
Here are some solid, evidence-based strategies for doing that.
What to do next
Think like a scientist.
Appreciate the complex, wondrous universe of biology.
DNA unites us with all living things in the world. We are all connected.
Your cells carry ancient stories, and at least parts of those stories can also be
understood by every other organism whether octopus or orchid, mouse or
mushroom, bird or bacteria.
Be critical, skeptical, and curious.
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Ask what evidence supports any claims made.
Be aware of your own biases and desires.
Notice when you may be engaging in magical thinking (Maybe genetic testing
will solve all my problems!) or becoming emotionally attached to the results
that you get.
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If you have a mysterious health problem, or are someone whos always looking
for the edge, you will naturally want to find solutions, or connect dots that
arent related.
If you are someone who likes data and exploration, you might also be tempted
by the utopian promise of quantifying the self and optimizing or hacking
human function.
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This isnt bad. Its normal.
Simply be aware of your own perspective and potential prejudices.
No amount of testing on its own will change your habits. A genetic result will not
somehow scare or motivate you into sustainable behavioral modification.
Expect complexity.
Theres no single, simple explanation.
Distrust one size fits all or one factor explains all solutions, and people trying
to sell you something based on them.
If someone is giving you an answer that sounds too straightforward (such as

You have Gene X, so you should do Exercise Program Y), thats probably not
the whole picture.
Gather your research team.
If you dont have enough training to interpret the evidence, look for a genetic
counsellor and/or other qualified healthcare provider who is informed and
relatively unbiased.
Help research be better.
Share your data, if youre comfortable.
23andMe asks users to answer survey questions about their experiences, to

better correlate the genetic data with what actually happens.
You can also contribute to things like the Personal Genome Project, Human
Longevity Inc. (HLI), 1000Genomes, or National Geographics Genographic
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Project.
The more data we gather, the better science works.
Embrace and discover your ancestry. |
Recognize that your ethnicity, heredity, and ancestry will affect your results.
Some genetic tests might not even apply to you if your specific ethnic group
hasnt been well-studied.
(And, if possible, demand that your group is studied. Science should not be an
elite club.)
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Be curious about the paths your ancestors travelled.
A very long and complicated series of events led to you being here right now.
Infinite biological equations and social choices had to happen to make you (or
even to give you eyes and a brain so you could read this).
Where are your people from? How did they get here?
Learning about your history can add to your own sense of identity and pride.
Be curious about food, movement, and health traditions in the regions where
youre from.
Some traditions may be about convenience or belief. Others may reflect actual
data on what has worked in the past for a specific population.
For instance, if people where youre from never drink milk but always win
weightlifting events, this may tell you that your population of origin likely doesnt
have the lactase persistence gene, but could have an inherited tendency for
being strong.
Start gathering data for your Owners Manual.

The Owners Manual is a concept that we use at Precision Nutrition to help
clients and coaches create an individualized, data-based handling instructions
for themselves and their lives.
An Owners Manual isnt a real thing (although it could certainly be if you kept a
physical file of your observations). It just means noticing and gathering evidence
from your own experiences, and recording it (whether mentally or literally).
Corroborate any genetic test results to observed reality.
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If your genetic test says you may have one trait, but you dont seem to, thats
useful data.
If your genetic test says you may have a high risk for a certain health condition,
but youre not sure, thats useful data too. Go and get other types of tests done,
such as blood work.
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Be an informed assessor of your own health and fitness.
Medical tests can be extremely helpful. They can give us an objective picture
of what is actually happening in our bodies, based on known and relatively
reliable indicators.
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At the same time, you can also observe many simple and important indicators on
your own. Such as:
What is your daily energy level like?

How much pain or inflammation do you have day-to-day?
How well do you sleep, and for how long?
Whats your general mood like?
Hows your digestion?
How much body fat versus lean mass do you have? (Even if thats just a
general guess.)
How often do you get sick?

Are you able to handle physical challenges of daily life? What about more
strenuous challenges?
And so on.
In our coaching programs, we teach clients to identify and interpret their own
basic physical cues in order to get a simple snapshot of their own overall health.
Exercise regularly.
Recognize that everyone benefits from exercise, movement, and activity.
Regardless of your genetic makeup, your body will work better when youre
consistently active.
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For instance, exercise and movement help us:
stay mobile and functional;

keep our balance and stay agile, preventing falls;
manage stress;
process and partition nutrients (in other words, food does its job properly);
build lean mass (muscle, bone, and connective tissues);
keep our brains smart and nervous system responsive;
prevent age-related muscle loss (aka sarcopenia);
digest our food better by promoting gastrointestinal motility;
think in different ways with our kinesthetic movement brains; and
maintain healthy body fat levels.
Exercise can also help us prevent, treat, and/or manage many chronic diseases
as well as slow the aging process.
Exercise may be one of the most powerful tools in our toolbox, as it improves
almost everything, often relatively quickly.
For instance, exercise:
may briefly decrease methylation in skeletal muscle;

increases messenger RNA (mRNA) expression; and
changes the protein levels of many genes that regulate metabolic factors
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such as mitochondrial function and fuel use (e.g. PGC-1, transcription
factor A, mitochondrial (TFAM); peroxisome proliferator-activated receptor
(PPAR-); and pyruvate dehydrogenase kinase, isoenzyme 4 (PDK4) and
so forth).
At the same time

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Recognize that genetically speaking, not everyone sees exactly the same
results from exercise.
So dont get frustrated or criticize yourself if youre working hard but not seeing
the same results as your buddy who seems to be a natural athlete.
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Or, if your body naturally seems to respond well to exercise, dont expect other
bodies to do the same (especially if youre a coach who works with all kinds of
clients).
Exercise helps us metabolize sugar and fat properly, but we vary genetically in
how well or quickly we respond to exercise in this way.
For example:
One study looked at the rs1801282 variant on the PPARG gene that codes
for PPAR-, which helps regulate metabolism of glucose and fatty acids.
While some people with a particular variant of rs1801282 (also known as the
Pro12Ala variant) were better at clearing glucose during exercise, everyone
benefited metabolically from exercise.
In another study, people with the -514C allele of LIPC were more likely to
significantly improve their insulin sensitivity if they exercised regularly.
Various APO genotypes affected peoples lipase (fat-mobilizing enzyme)

activity.
And so on.
Other genetic variants may affect a wide variety of exercise results, such as
heart rate, vascular function during exercise, and other measures of aerobic
performance.
If you have a particular variant of the AMPD1 gene, which codes for an enzyme
known as adenosine monophosphate deaminase (one of the enzymes used
to process ATP), you might get more muscle pain and cramping during intense
exercise. Though you arent alone: At least one world-class runner has this variant.
Your body is your body.
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And not someone elses.
Your mileage may vary.
Choose physical activities that suit your body as

much as possible.
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If youre looking for the best results possible, then try to match your physical
activities to your most informed hypotheses about what your unique body prefers.
Over time, gather data about your hypotheses and refine your action plan.
If its pretty clear youre a fast-twitcher, enjoy your strength and power sports, and
dont feel like you should be doing distance running.
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If its pretty clear that youre a slow-burner, enjoy your endurance sports, and
dont try to beat the world high-jump record. (Well, you can try, just dont get
mad if you dont succeed.)
Of course, if you enjoy a sport that you arent naturally well-suited for, go and
have fun doing it. You probably wont be the best in the world at it, but who cares?
Control what you can control.

We cant control what mom and dad (or, these days, maybe mom, mom, and dad)
gave us.
We also cant necessarily control many environmental factors, such as airborne

pollution, chemical contaminants in our food and water, occupational hazards,
early-life trauma, and other things that may affect our epigenetic expression.
We may find ourselves struggling to maintain a healthy body composition if we

dont have the skills and habits to do so, or if we have underlying genetic factors
that make this more difficult. Our skeletons may be wider or narrower; denser or
lighter; shaped this way or that way.
But, for the most part, we have a fair bit of control over such factors as:
what we eat;
whether we drink alcohol;
whether we smoke;
what drugs we take (assuming that these are non-life-saving medications,
of course);
how often and intensely we exercise and move around;
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how we respond to daily-life stressors; and
how and whether we choose to reproduce and pass on our DNA
to offspring.
Consider your environment.

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You may have heard the expression, Genetics loads the gun; environment pulls
the trigger.
Now, thats a bit of a disturbing analogy that makes genetics sound like a
professional but ambivalent hitman, but it gives you the idea:
Whats around you matters.

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This includes real things like chemicals as well as more intangible things like
social support. (See below.)
One researcher has coined the term exposome to describe all the
environmental factors that might affect genetic expression throughout our lives.
Environmental stressors (such as pollution, toxic chemicals, medications, or
pathogens like viruses) can all affect expression. This, in turn, can affect things
like our metabolic health.
Regardless of your genetic makeup, its probably not a great idea to stew in a
soup of potentially toxic or DNA-altering chemicals.
Look around your immediate environment and consider the products youre
using, and/or what youre exposed to. Consider whether any of this can be
improved.
Consider your ability to respond to stress.

Environmental stressors also affect the length of our telomeres, which work at
the ends of our DNA strands like the little caps on the ends of your shoelaces
that prevent them getting frayed. (The term comes from the ancient Greek telos,
or end, and meros, or part. So telomeres are literally end parts.)
The longer our telomeres are, the healthier were likely to be, and the less
cellular aging we likely have.
Shorter telomeres, on the other hand, indicate more aging and degeneration
again, sort of like a shoelace fraying.
So, how long our telomeres are can tell us about how healthy our DNA is, and
how quickly or slowly were aging in a biological sense.
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Figure 12.1: Telomere shortening
Being exposed to environmental stressors like chemicals can shorten our

telomeres, but so can social stress.
For instance, a study that looked at women caring for a child with a major
disability or serious chronic illness found that the long-term stress of caregiving
and worry over a childs health was linked to shorter telomeres. Feeling socially
isolated and lonely can change our genetic expression too.
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However, stress isnt just whats around us. Its how we respond to whats around us.
So even if youre exposed to a social stressor (such as something bad happening

to you as a child), if you can respond resiliently to that stressor and have other
people supporting you, youll have better DNA health than someone who is
isolated and panicking.
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If youre a parent, choose wisely.

When humans and other mammals get ongoing social support in an interesting
and engaging environment with a small dose of growth-promoting good stress,
they thrive.
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Parents can play a major role here, not just in offering their own genetic
material, but also in creating surroundings that help their children optimize their
epigenetic expression.
For instance:
Build your own healthy habits. Many of our clients come to us because
theyve decided to be healthy role models for their children. And, as a parent
(especially if your children are younger and they live with you), you can
shape their food and activity choices which will be a lot easier if your own
fundamental habits are in place.
Make wise choices before conception and during pregnancy. This goes for
you too, dad. Both parents genetic material can be affected by their own
health habits. So if youre hoping for a baby but havent gotten started on
the project yet start building those healthy habits now. And, of course, if
youre currently pregnant, choosing healthier options will improve whats
known as the maternal effect the role that the mother plays in her
offsprings epigenetic expression. (More on this below.)
Introduce your child to a wide range of tastes. (If youre currently pregnant,
try a wide range of tastes yourself.) Evidence suggests both prenatal and
early childhood exposure to various foods helps set taste preferences
for later on. If you want your kids to eat healthy foods, eat healthy foods
yourself, and make them readily available.
Introduce your child to a wide range of microbes. Research suggests

that pre- and post-natal exposure to diverse microbial environments (like
bacteria, viruses, and fungi) can change the epigenetics of the immune
system. Dont keep your house too antiseptically clean, and its probably OK
if your kid licks the dog.
Be active as a family. Whatever your genetic makeup, were healthier when
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were moving, and when were connected to other people. Even if you
got every single one of the exercise nonresponder / metabolic disruptor
/ excess adiposity genes, you can still (to some degree) change the
expression of these, especially if you start as early in life as possible. (But of
course, its never too late to make some healthy changes.)
Dont smoke. This should be obvious, but its pretty clear: Smoking changes
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our epigenetic expression in a bad way. It affects both the smoker and
anyone else exposed to secondhand smoke, especially a child with a

developing system.
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Maternal effects
Although, of course, both parents contribute genetic material to their offspring,
given the mothers role in gestation, she can have a powerful effect on her
developing fetus epigenetic expression.
In particular, what she eats and the environment shes in can affect the outcome.
For instance:
If mothers have persistently high blood sugar (known as hyperglycemia)

during pregnancy, this may affect methylation of the fetus leptin gene, and
potentially the childs body fat levels as they mature.
High-fat diets during pregnancy may affect expression of the fetus

adiponectin genes; in particular, methylation may go up while acetylation
may go down. This may mean that later in life, the child may have a higher
risk of some types of metabolic problems such as Type 2 diabetes or
cardiovascular disease. (It isnt clear whether the type of fat matters here,
though.)
In a famous study on the effects of undernutrition during pregnancy,

offspring of mothers whod endured the so-called Dutch Hunger Winter
famine during WWII showed hypomethylation on the IGF2 gene, later
correlated with higher risks of cardiovascular disease.
Along with physical health, mothers mental and emotional health is also
important.
For instance, the NR3C1 gene codes for the glucocorticoid receptor (GR).
Glucocorticoid hormones, such as cortisol, are involved in our stress response
and inflammation.
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Our stress response is organized by a complex set of feedback loops known as
the hypothalamic-pituitary-adrenal (HPA) axis. HPA axis function shapes how we
are able to respond to stress, and how generally anxious and physiologically or
psychologically reactive we tend to be.
When mothers were anxious, depressed, or otherwise distressed during

pregnancy, this often affected methylation of their fetuses NGFI-A binding site
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in NR3C1. This epigenetic change then predicted increases in infants HPA stress
reactivity.
In other words: A stressed mother may mean a stressed child.

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Other research suggests that there are similar links between mothers mood or
distress level during pregnancy, and their offsprings epigenetic expression of
other genes such as HSD11B2, which codes for a protein that converts cortisol to
cortisone and vice versa, as well as protecting other tissues from the damaging
effects of corticosteroids.
Of course, as a parent, you cant control all the factors involved in your childs
epigenetic expression. (See above: Control what you can control.)
Rather than worrying too much about the genetic blueprint you or your
child got, focus on how you can help build the best house possible from
those blueprints.
Whats next for you?

At Precision Nutrition, our motto is Life-changing, research-driven nutrition
coaching for everyone.
Genetics (and genetic testing) highlight one of the fundamental tensions of

coaching:
The outer limits of our health, ability, function, and performance are
determined by factors outside our control (factors that include genetics).
At the same time, we have tremendous potential for change, growth,

improvement, and adaptation.
So, for instance, a person who is 5 feet tall can learn to run, jump, and throw a
basketball better perhaps even at a world-class level of shot accuracy. But
that person will never be able to dunk a basketball like a 7-footer.
At some point, we bump up against our own limits, and some tasks are simply
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impossible for some people.
On the other hand, most of us will never find most of those limits, because the
playing field of our physiology is wider and bigger than we can imagine.
Disciplines that specialize in finding the boundaries of human function and

performance have discovered that the human body has far greater resources of
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recovery, resilience, and capacity than most of us realize.
We contain limits, but also opportunities and potential.

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So, if youre curious about what that looks like for you:
Treat your body as a set of possibilities rather than limitations. Explore,

build, practice, and see what you can do after putting in the reps.
Consider coaching. Coaches specialize in finding, bettering, and amplifying

the raw material you already have.
Check back on our site for updates. Research is always evolving.

Be curious. Ask us questions on our Facebook page.
And, of course: Keep science-ing!
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What we found: Exercise Glossary of terms
and muscle performance
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Confused by codons? Mystified by

In this chapter, we look at some of mutations? No worries, weve got a

the genetic factors that may shape handy glossary for all the technical
our response to (and recovery from) terms weve used in this book.
exercise and training, and whether
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PRECISION NUTRITION | GENETICS: THE UNIVERSE WITHIN |
Glossary of terms
CHAPTER 13
#
6-n-propylthiouracil (PROP): A compound that tastes bitter to some people, but
is tasteless to others; the ability to detect it is genetically determined.
A
Absolute risk: In terms of health conditions, the prevalence of a disease within
an entire population (e.g., 3% of all people will get Disease X in their lifetime).
Actin: A protein within muscle tissue.
Adenine: One of the nucleotides that forms DNA / RNA, along with cytosine,
guanine, and thymine (uracil in RNA). Often abbreviated as A. In base pairing,
adenine pairs with thymine (T) and uracil (U).
Adipocyte: A fat cell.
Adiponectin: A protein produced in adipose (fat) tissue that helps to regulate

many processes, including glucose metabolism and fatty acid oxidation.
Alkaline lysis: A process for breaking down cell membranes in order to extract
genetic material, using a base like sodium hydroxide and a surfactant.
Allele: A variant of the same gene (usually emerging through mutation), found at
the same place on the chromosome.
Allelic heterogeneity: When related genetic variants, or alleles, in the same
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location are associated with the same trait or outcome.
Allergen: Something that causes a histamine response, known as an

immunoglobulin E (IgE) immune reaction.
Allergy: A hypersensitive immune system response.

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Amino acid: The basic building block for a protein.
Amplicon: A piece of DNA or RNA that has been amplified or copied, especially
through the polymerase chain reaction (PCR).
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Amplicon sequencing: A technique that uses the polymerase chain reaction
(PCR) to make billions and billions of copies of a previously-identified stretch of
DNA, and sequence these copies (known as amplicons).
Amplification: An increase in the number of copies of a gene, possibly along

with the RNA and protein made from that gene. Gene amplification is common in
cancer cells.
Anabolism: Metabolic pathways of molecular and tissue growth, synthesis, and

development. Opposite of catabolism.
Androgen insensitivity syndrome (AIS): A type of intersexuality that happens

when a chromosomally male (XY) body does not respond to masculinizing
hormones (i.e., androgens), and develops with a body that looks female.
Antibody: A type of protein that is produced by the immune system when it

identifies a foreign substance, known as an antigen. Antibodies help identify
pathogens (such as bacteria or viruses) as well as allergens and toxins.
Antigen: Any foreign substance that stimulates an immune response, particularly

antibody production.
Antigen-presenting cells: Cells that tell other cells of the immune system (such
as T cells) that theres trouble spotted (such as a pathogen), and its time to go to
work.
Apolipoproteins: Protein-based components of lipoproteins. Theyre encoded by

genes that start with the letters APO (such as APOB or APOE).
Apoptosis: Programmed cell death.
Assay: A method for determining the presence or quantity of a particular

component, or a method to analyze or quantify a particular substance in a
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sample.
Autoimmune thyroid disease (AITD): A form of thyroid disease in which the

body attacks normally healthy thyroid tissue.
Autonomic nervous system (ANS): The branch of the nervous system that
controls basic functions such as heart rate and breathing.
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Autosomal dominant: A form of inheritance in which you need only one copy of
a gene from a parent to express a trait.
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Autosomal recessive: A form of inheritance in which you need two copies of a
gene (one from each parent) to express a trait.
Avenins: A protein in oats that is similar to gluten in wheat, and which can cause
an immune system reaction in some people.
B
BamforthLazarus syndrome: A rare genetic disease in which thyroid tissue is
underdeveloped or missing entirely.
Basal metabolic rate (BMR): The bodys idling speed, i.e., the rate at which
metabolic reactions take place and use energy to do so.
Base excision repair (BER): A method that our cells use to repair damaged DNA.
Base pair: A pair of complementary nucleotides (bases) on a strand of DNA or RNA.
-adrenergic receptors: Receptors that respond to catecholamine hormones

like adrenaline, and activate processes to help us free up stored energy, get our
muscles moving, and do other autonomic nervous system jobs.
Bioactive form: A form of a molecule or compound that has an effect on a

biological organism (e.g., Before we can absorb Substance X, it must be
converted into its bioactive form).
Biochemical genetic tests see Genetic test types.
Bioinformatics: The analysis and interpretation of biological data using methods

drawn from computer science, statistics, mathematics, and engineering.
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Biological sex: The collection of physical characteristics (such as chromosomes
or reproductive organs) that identifies a body as male, female, and/or intersex.
Body composition: The relative amount of fat mass to lean mass.
Body mass index (BMI): A measure of weight relative to height.

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C
Carbohydrate: A family of biological molecules that includes sugars, starches,
and soluble and insoluble fiber.
Catabolism: Metabolic pathways of molecular and tissue breakdown for energy

or disposal. Opposite of anabolism.
Catecholamines: A group of hormones that includes epinephrine (adrenaline),

norepinephrine (noradrenaline) and dopamine, which have similar effects on the
nervous system.
Celiac disease: An autoimmune disorder in which the body makes antibodies to

gluten, causing damage to the gastrointestinal lining.
Central dogma of molecular biology: The fundamental concept of how genetic

information and instructions flow from DNA to RNA to proteins. Thus, DNA
contains all the information and instructions required to make proteins via the
action of RNA.
Chemokine: A cell signaling molecule (cytokine) that attracts white blood cells
to the site of tissue damage.
Chip: See microarray.
Cholesterol: A waxy lipid that we can make in our liver or consume from food.
We use cholesterol to make many important molecules that our bodies use,
including our sex hormones.
Chromatin: The material, composed of DNA, RNA, and proteins, that makes up
our chromosomes.
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Chromatin immunoprecipitation (ChIP): A molecular biology technique that
identifies proteins that interact with known DNA sequences.
Chromosomal genetic tests See Genetic test types.
Chromosomal inversions: Occurs when a single chromosome breaks and

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rearranges itself, reversing end to end.

Chromosomal translocations: Occurs when material from one chromosome

migrates to another, and/or is swapped between chromosomes.
Chromosome: A long strand of tightly wound chromatin that contains genetic

information. Humans have 23 pairs of chromosomes.
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299
Chylomicrons: Small lipoprotein particles that circulate in the blood after fat is
absorbed from the small intestine.
Clinical Laboratory Improvement Amendments (CLIA) regulations: A set

of federal standards applicable to all US facilities or sites that test human
specimens for health assessment or to diagnose, prevent, or treat disease.
Closed assay: An assay that identifies beforehand what its seeking, such as a
particular mutation or gene variant.
Codon: A set of three nucleotides that codes for a specific protein.
Cofactor: A substance thats required for an enzyme to work. Riboflavin (vitamin

B2) is an example of a cofactor.
Convergent evolution: Occurs when unrelated species develop traits

independently of each other, without a common root of that trait (for instance,
bat, bird, and insect wings evolved independently from one another).
Copy number variation (CNV): Repetition of specific sections of genetic

material; the number of repetitions can vary from person to person.
Cruft: A computer term for crud or leftover bits of stuff; poorly designed,
unnecessarily complicated, or unwanted code or software.
Cytokine: A cell signaling molecule.
Cytoplasm: The fluid within a cell.
Cytosine: One of the nucleotides that forms DNA / RNA, along with adenine,
guanine, and thymine (uracil in RNA). Often abbreviated as C. In base pairing,
cytosine pairs with guanine (G).
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D
Deletion: A mutation in which some genetic material is lost during the process of
DNA replication.
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Deoxyribose: The sugar-based structural backbone of DNA.
Diploid: Containing two sets of chromosomes. (Opposite: haploid.)
DNA: A biological molecule that holds the code for making all living things.
Dominant traits / genes: Traits and/or genes that are more likely to be
expressed, and which require only one copy to do so.
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Double-strand breaks: A mutation or damage that occurs when both strands of
DNA are severed. This often happens in response to ionizing radiation.
Duplication: Reproduction of chunks of DNA that contain genes, resulting in

multiple copies of those genes. A common basis for genetic evolution.
Dyslipidemia: Having a poor / unhealthy blood lipid profile.
E
Electrolytes: Dissolved salts such as sodium or potassium.
Epigenetics: The study of factors that affect genetic expression for instance,
how the same genetic blueprint may actually be used to build different things.
Endocrine system: The coordinated system of glands that secrete hormones

that act elsewhere in the body.
Energy balance: The relationship between energy (calories) in (from food) and
energy out (from metabolism / excretion / activity).
Energy sensing: Mechanisms in the body that monitor how much energy
is available.
Enhancer: A part of the genome that, when bound by a given transcription

factor, increases the likelihood that a particular gene will be transcribed.
Enzyme: A substance that helps initiate a particular biochemical reaction, often

breaking things down (e.g. protease enzymes break down proteins).
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Eukaryote: Organisms that have cells with a nucleus and organelles surrounded
by a membrane. The nucleus contains genetic material in the form of
chromosomes. Organisms without this are known as prokaryotes.
Evolutionarily conserved: Preservation of genetic information and gene function

over time, even through the division into different species. Evolutionarily
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conserved genes tend to keep their functions.

Exon: The parts of the gene that code for protein sequences (the opposite
of introns).
Exome: The part of the gene formed by exons.

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Exposome: The combination of all environmental factors that might affect
epigenetic and genetic expression.
Expressing sequences: Another term for exons.
F
Feedback loop: A coordinated series of if-then actions in which output
determines future input; information at a given outcome is used to determine the
next action.
First messenger: A substance that binds to the outside of a cell, stimulating

certain actions from second messengers within the cell.
Fixation: When multiple alleles from a gene pool are removed and only one
remains. Once this happens, the gene is said to be fixed in the population.
Forkhead box (FOX) proteins: FOX proteins are transcription factors that
control the expression of other genes. They are typically involved in regulating
cell growth, development, differentiation, and survival.
Fusion gene: A single gene formed from two separate genes.
G
Gain of function mutation: A type of mutation that results in the altered gene
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having new or enhanced activity, a new molecular function, or a new pattern of
gene expression. These mutations are often dominant.
Gametes: A haploid germ cell of sexual reproduction (i.e., egg / ovum or sperm).
Gel electrophoresis: A technique used in molecular biology where an electrical

current is applied across an agarose gel to separate DNA, RNA and/or protein
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fragments by size.
Genes: Regions of DNA that have instructions for making specific proteins.
Genetic sequencing see Genetic test types.

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Genetic test: A laboratory assay specifically for clinical testing purposes that
is used to identify specific genotype(s) to diagnose a specific disease in a
specific group of people for a specific purpose. Genetic testing is very targeted
compared to a genetic assay, which may be scanning, or may be targeted.
Molecular genetic tests look at the smallest chunks of DNA, perhaps a

single gene or short pieces of DNA, usually looking for a specific variation or
mutation.
Chromosomal genetic tests look at longer pieces of DNA, such as whole

chromosomes, to look for larger-scale genetic changes (such as an extra
chromosome copy).
Biochemical genetic tests look at how much of a certain protein we have, or

how active that protein is. Here, the test doesnt look at the DNA but rather
the protein that it might be coding for. By looking at differences in the pro-
teins, testers can speculate about genetic variations.
Genetic sequencing involves reading a strand of DNA by looking at its

nucleotides, one by one.
Genetics: The study of genes, how they work, and how particular traits (such as
eye color) are passed from parent to offspring (known as heredity).
Gender identity: Ones deeper sense of self as having a particular gender (or not).
Genome: An organisms total set of genetic material.
Genome-wide association studies (GWAS): A type of genetic test that examines

locations across the entire genome to identify potential associations with a
particular phenotype or phenotypes.
Genotype: The genetic code of an organism.
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Gliadin: A protein found in wheat; one of the components of gluten.
Glucose: A simple sugar that is the raw material for building ATP, our cells energy.
Glucose transporter (GLUT): A family of proteins found on cell membranes that help
move glucose across those membranes. GLUT4 is the insulin-regulated glucose
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transporter.
Glutamine: An amino acid.
Gluten: A protein found in wheat to which some people (such as those with
celiac disease) have an immune system reaction.
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Glutenin: A protein found in wheat; one of the components of gluten.
Glycoprotein: A type of protein with a carbohydrate attached.
Guanine: One of the nucleotides that forms DNA / RNA, along with adenine,
cytosine, and thymine (uracil in RNA). Often abbreviated as G. In base pairing,
guanine pairs with cytosine (C).
H
Haploid: Containing one set of chromosomes. (Opposite: diploid.)
Haplotype: A common set of genetic variants that tend to be inherited across

generations. Often used to track ancestry or to identify population groups with
shared ancestry or common disease risk.
Hematopoiesis / hemopoiesis: The production of platelets and blood cells,

which occurs in bone marrow.
Hereditary fructose intolerance (HFI): A genetic condition in which people cant

break down the sugar fructose properly. HFI is an autosomal recessive disorder,
which means that to have HFI, a person must inherit two copies of the ALDOB
gene variant that causes the problem.
Heredity: The transmission of particular characteristics from one generation to

another.
Heterodimer: A complex, or dimer, of two large molecules, such as proteins,

bound together. A heterodimer occurs when the two proteins are different.
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Heterozygocity / heterozygous: Inheritance of two different copies of the same
gene. (Opposite of homozygous.)
Heterozygote advantage: Having a better evolutionary adaptation than a

homozygous combination, due to having two different copies of the same gene.
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Histamine: A substance released by cells in allergic and inflammatory reactions

(and injury), which causes contraction of smooth muscle and dilation of blood
vessels.
Histones: A type of protein found in chromatin, which acts like a spool or

bead around which the strings of DNA are wound. Because of this structure,
they can affect genetic expression.
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Histone modification: Changes to histones (such as acetylation or various types
of methylation) after RNA translation that can affect genetic expression.
Homeostasis: A dynamic state of balance within the body.
Hominin: The taxonomic group that contains genera that have descended from a
common ancestor, the genus Homo (e.g. modern humans H. sapiens, H. habilis,
H. neanderthalensis) and the extinct genera Australopithecus, Paranthropus and
Ardipithecus. Some taxonomists also consider the genus Pan to be hominin. Pan
includes our closest living relatives: chimpanzees and bonobos.
Homology/homologous: A state of similarity.
Homologous recombination repair (HRR): A method of repairing DNA by

exchanging nucleotide sequences between two similar or identical molecules
of DNA.
Homozygous: Inheritance of two of the same copies of the same gene.

(Opposite of heterozygous.)
Hordeins: A protein that occurs in barley and can trigger the same type of
immune response as gluten.
Horizontal gene transfer: The exchange of genetic material between organisms

(e.g., between bacteria and humans).
Human leukocyte antigen (HLA): A gene complex that codes for major
histocompatibility complex (MHC) proteins in humans. These cell surface
proteins regulate our immune system by helping our cells recognize foreign
molecules.
Hydroxylate: To add a hydroxyl group (an oxygen-hydrogen pair) to a molecule.
PRECISION NUTRITION
Hypercholesterolemia: Excess cholesterol in the bloodstream.
Hyperthyroidism: Increased thyroid function.
Hypertriglyceridemia: Elevated triglycerides (fats) in the bloodstream.
Hypomethylation: A natural modification of DNA involving loss of a methyl group.

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Hypothalamus: A small gland in the brain that controls many key metabolic
functions.
Hypothyroidism: Decreased thyroid function.

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305
I
Immunoassay: A biochemical test that measures the presence of proteins or
other substances through their properties as antigens or antibodies.
Immunoglobulin: A type of protein in the serum and cells of the immune system
that functions as an antibody.
Immunoglobulin E (IgE): A type of immunoglobulin, only found in mammals, that

is involved in allergic reactions.
Immunoglobulin G (IgG): A type of immunoglobulin that binds to and

neutralizes pathogens and toxins.
Imprinting: An epigenetic modification inherited from only one parent, with the
other gene copy from the second parent being turned off.
Inactivating mutations: See loss-of-function mutations.
Inflammation: A complex and coordinated process of response to injury and

illness that is characterized by elevated inflammatory chemicals (such as
interleukins) and pain, heat, redness and swelling.
Insulin: A crucial hormone for nutrient storage and anabolism that is released by
the pancreas in response to higher blood sugar (glucose) levels.
Insulin resistance: A condition in which our cells cannot respond appropriately

to the presence of insulin by transporting glucose into cells. As a result, we have
high circulating insulin and high circulating glucose. This is often a precursor to
Type 2 diabetes.
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Insulin sensitivity: How able our cells are to respond appropriately to insulin. We
want this to be working well, and to have high insulin sensitivity. If we have poor
sensitivity, we develop insulin resistance.
Interleukins (IL): A group of cytokines, expressed by white blood cells, that are
involved in regulating the immune system response.
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Intersex: A normal, though less common, biological phenomenon in which

people have variations in reproductive or sexual characteristics that do not
match typical definitions of male or female.
Interstitial deletions: Deletions that dont involve ends of chromosomes.

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306
Intervening sequences: Another term for introns.
Intron: A part of the gene or gene transcript that is removed before the mature
RNA is translated to a protein (the opposite of exons).
L
Lactase: An enzyme that allows us to digest lactose, a sugar in milk.
Lactase persistence: Presence within a population of the ability to digest lactase

as an adult, which is largely genetically determined.
Lactose tolerance: The ability to digest lactase.
Lethal mutation: A mutation that kills the organism, and/or results in the
organism being unable to reproduce.
Leucine: An amino acid.
Ligand: A molecule that binds to another for some biological purpose (such as
initiating a biochemical reaction).
Lipids: Fat-based molecules.
Lipodystrophy: Disorders of fat metabolism that result in wasting of fat stores, or

fat deposits in unusual places (such as on the hands).
Lipolysis: The breakdown of fats (lipids).
Lipoproteins: Proteins that transport lipids. Since lipids cant dissolve in water
PRECISION NUTRITION
but proteins can, lipoproteins help many fat-based molecules move around the
body through the blood.
Locus (plural: loci): A position of genetic material on a chromosome that

describes exactly where that genetic material is located. |
Loss of heterozygosity: A major mutation that results in loss of an entire gene

and its surrounding region. This often happens in cancer.
Loss-of-function mutations: Mutations that result in a gene being inactivated

or silenced.
Lyse: To break down the membrane of a cell. This occurs in genetic testing to
allow the researcher or technician to remove the genetic material from the cell.
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307
M
Macrophage: A type of immune system cell thats part of our cellular cleanup
crew.
Major histocompatibility complex (MHC): Cell surface proteins that regulate our
immune system by helping our cells recognize foreign molecules.
Maternal effect: The role that the mother plays in her offsprings epigenetic
expression, whether through her genetic material, in the environment she
provides, or both.
Maternal haplogroups: A family of mitochondrial DNA that can be traced back to

a single common female ancestor.
Mendelian genetics: A simple model of genetic inheritance originally developed

by Gregor Mendel in the 1860s.
Messenger RNA (mRNA): See RNA.
Metabolic syndrome: A collection of physical risk factors that are related to a

cluster of chronic diseases, such as Type 2 diabetes and stroke. These include
elevated blood pressure, elevated triglycerides, high fasting blood sugar, and
significant deposits of fat around the midsection and internal organs.
Methylation: The addition of a methyl group (a carbon and 3 hydrogens, aka

CH3) to a molecule. Two important processes in epigenetics are the methylation
of bases in DNA (usually cytosine, or C) and the methylation of histone proteins
that affect gene expression. When DNA or histones are methylated, certain
PRECISION NUTRITION
genes are often switched off, which can be a problem if you want those genes
to be transcribed and protein made.
Microarray: A chip with a large array of sensors to detect certain DNA or RNA
sequences.
Microsatellite instability (MSI): Increased likelihood of genetic mutation due to

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poorly functioning DNA mismatch repair (MMR); microsatellites are repeated

sequences of DNA.
Mismatch repair (MMR) a system for identifying and fixing errors in DNA
replication and recombination.
Missense mutations: A mutation in which a single nucleotide change results in a

codon that codes for a different amino acid.
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308
Mitochondria: An organelle within a cell thats involved in energy production
and respiration.
Mitochondrial DNA (mtDNA): A form of non-nuclear DNA that is round and

transmitted maternally. We can use mtDNA to trace maternal ancestry.
Mitosis: Division of one cell into two genetically identical cells.
Mobile genetic element: A type of DNA that can move around the genome.
Molecular genetic tests see Genetic test types.
Muscle-specific creatine kinase (CKMM): A test used to measure levels of

creatine kinase, a marker of muscle damage.
Mutation: Changing the structure or function of a gene in a way that can

potentially be transmitted to future offspring.
Myosin: A protein found in muscle tissue.
N
Neurotrophins: Chemicals involved in the growth, development, and survival
of neurons.
Non-celiac gluten sensitivity (NCGS): An inflammatory response to gluten that

does not depend on making IgG antibodies, as in celiac disease.
Noncoding regions / noncoding DNA: Parts of the genetic code that dont
code for any proteins, but that might be involved in other genetic regulatory and
PRECISION NUTRITION
structural functions.
Nonhomologous end-joining (NHEJ): A pathway for repairing DNA double-

strand breaks.
Nonsense mutation: A mutation that creates stop codons and can truncate the
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protein in the process of being created. This means that a cells ribosome (the
protein-making factory), will stop producing the protein before that protein has
all of its amino acids.
Nuclear exporting: Chaperoning mRNA through a nuclear pore, using nuclear

transport receptors.
Nuclear pore: A channel between a cells nucleus and cytoplasm that regulates
movement of substances in and out of the nucleus.
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309
Nuclear receptor: A type of protein found in the nuclei of cells that can bind
directly to DNA and regulate the expression of genes.
Nuclear transport: Entry and exit from a cells nucleus.
Nucleic acid: Linked chain(s) of nucleotides. DNA stands for deoxyribonucleic acid.
Nucleotide: The basic structural unit of DNA and RNA; a nitrogen-containing

base plus a phosphate and sugar molecule (such as deoxyribose or ribose).
Nucleotide excision repair (NER): A method of repairing DNA, particularly

damage from ultraviolet light.
Nucleus: An organelle within a cell where genetic material is stored (in

eukaryotes).
Nutrient partitioning: What our bodies do with the food we eat (e.g., use it for
repair, use it for energy, and/or store it).
O
Open-ended assay: An assay that looks for anything of interest, like scanning a
landscape to see what pops out.
Organelle: A structure within a cell that has a specialized function (e.g., a

nucleus, mitochondrion, or ribosome).
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P
Paralog: One of two or more genes that come from the same ancestral gene as
a result of gene duplication.
Paternal haplogroup: A haplogroup traced through the Y chromosome.

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Phenotype: The combination of traits and features that results after an

organisms genetic code interacts with its environment; how a genetic
blueprint is actually expressed.
Perilipin: A protein that surrounds lipid droplets in fat cells, helping to control the
metabolism of adipocytes by regulating how fat-mobilizing enzymes (lipases)
interact with the stored fat.
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310
Pituitary: A small endocrine gland within the brain thats involved in regulating
many other endocrine glands, such as the thyroid.
Pleiotropy: From the ancient Greek pleion, or more, and tropos, or way, one
gene influencing two or more apparently unrelated processes or traits.
Polygenic: Many genes involved (e.g., in the cause or progression of a disease).
Polymerase: An enzyme that synthesizes long chains (polymers) of nucleic acids.
Polymerase chain reaction process (PCR): A laboratory technique used to make

multiple copies of a specific region of DNA, for instance for genetic testing.
Polymorphism: Multiple forms or variants of a gene at the same location.
Polypeptide chain: A long strand or set of strands of peptides, amino acids

strung together.
Positive selection: a genetic mutation that promotes the emergence of new

phenotypes, usually by offering some kind of advantage.
Post-transcriptional modification: The modification of an RNA transcript into

mature mRNA.
Post-translational modification: The modification of a protein after it is

translated from mRNA.
Prader-Willi Syndrome: A congenital genetic syndrome caused by the loss of

function of genes in a particular region of chromosome 15.
Predictive value: How well a given factor, such as a genetic variant (or set of
variants), can explain an outcome, such as a disease or trait.
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Prokaryote: Simple organisms whose cells do not contain specialized organelles
or a nucleus with genetic material bound into chromosomes. Many bacteria, for
instance, are prokaryotic. Compare to eukaryote.
Proline: An amino acid.
Promoter: A region of DNA that binds with RNA polymerase and transcription
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factors to initiate transcription of mRNA.
Pronuclear transfer: A method of 3-parent artificial reproduction that uses

two eggs (one egg from the mother, and one egg from a donor) that are both
fertilized with the fathers sperm. Once eggs are fertilized, but before they start
dividing, their nuclei are removed; the nucleus from the donors fertilized egg is
replaced with the nucleus from the mothers egg.
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311
Prostaglandins: A group of lipid-based chemicals that have hormone-like
effects, including regulating inflammation.
Protease: An enzyme that breaks down proteins.
Protein: A biological molecule, made of amino acids, that a gene codes for.
Pseudogene: Segments of DNA that are related to real genes, but are not
functional.
Purifying selection: Removal of genetic variants that are maladaptive.
R
Reactive oxygen species: Waste products generated from the normal process of
cellular metabolism, which contain oxygen and are chemically reactive.
Reading frame: A method of separating nucleotide sequences into a set of

consecutive, non-overlapping triplets, aka codons.
Receptor: A structure that is able to respond to and bind specifically with

something else, such as a molecule.
Recessive traits / genes: Traits that require two gene copies one from each
parent, to express that trait.
Reference genomes: A database of a representative genome of a species,

used as an example or relative comparator for other genomes of the same species.
Relative risk: The risk of a given outcome as compared to another person or

group (e.g., Disease X occurs 2 times more in Group Y than Group Z).
PRECISION NUTRITION
Retroviral sequences: A segment of genetic material that is an artifact of
ancestral retroviral infections, but which is now incorporated into current DNA.
Reverse transcription: Performing the normal steps of transcription in reverse

order, going from RNA to DNA. This occurs in some RNA viruses.
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Ribose: A sugar that forms one of the components of DNA / RNA. In DNA, the
molecule is deoxyribose; in RNA its ribose.
Ribosome: An organelle that is the site of protein synthesis within a cell.
Ribosomal RNA (rRNA): See RNA.

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312
RNA
Messenger RNA (mRNA): A form of RNA that transmits genetic information

to a ribosome.
Ribosomal RNA (rRNA): An RNA enzyme that links amino acids together in
the ribosome to make a polypeptide chain, and makes up some of the struc-
ture of ribosomes.
Transfer RNA (tRNA): RNA molecules that carry specific amino acids to the
ribosome. They match mRNA codons with their respective amino acid.
Small nuclear RNA (snRNA): Short RNA segments that form small nuclear
ribonucleoprotein particles (snRNPs), that then are part of RNA processing.
MicroRNA (miRNA): A small segment of RNA involved in RNA silencing and

regulation of gene expression.
Small interfering RNA (siRNA): A short segment of RNA that can interfere
with the expression of specific genes.
RNA export: Exporting mRNA out of the cells nucleus.
RNA processing: See RNA splicing.
RNA splicing: Stitching together segments of RNA in a variety of ways by

removing introns and joining exons.
RNase: An enzyme that breaks down RNA.
PRECISION NUTRITION
Secalins: A type of protein found in rye, which may trigger an immune system
response similar to gluten.
Second messenger: A molecule that responds to a first messenger molecule in

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a signaling pathway.
Secosteroid: A type of steroid, or cholesterol-based hormone.
Selective sweep: A decrease in genetic variation, particularly near a specific

mutation.
Sequencing: Examining the genome to build a list of specific nucleotides, in order.

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313
Sexual dimorphism: Having two biological sexes with distinct physiological
characteristics within a species (e.g., male and female).
Sexual orientation: Whom we prefer as sex partners.
Signaling pathways: A series of interactions that trigger each other in a

step-by-step process.
Silencer: A part of the genome that prevents gene expression, particularly

during certain stages of the cell cycle.
Silent mutations: Mutations that dont significantly alter the phenotype or health
of the organism.
Single nucleotide polymorphism (SNP): A variation in a single nucleotide (for

instance, having a cytosine, or C, where theres normally an adenine, or A).
SNP genotyping arrays: Arrays that look at a series of predetermined locations

on the genome (usually hundreds of thousands to millions) to look for SNP variations.
Spindle nuclear transfer: A method of 3-parent artificial reproduction that is

similar to pronuclear transfer, but occurs before fertilization.
Substitution mutation: A type of mutation in which a single nucleotide is

exchanged for another.
T
T-helper cells: A type of immune system cell that assists other cells by releasing
cytokines.
PRECISION NUTRITION
Telomere: The structures on the ends of chromosomes that function much like
the plastic end of a shoelace, preventing degradation of chromosomes.
Terminal deletion: Removal of the end of a chromosome.
Terminator: A section of DNA that marks the end of a gene.

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Thermogenesis: The production of heat (i.e., by the body).
Thymine: One of the nucleotides that forms DNA, along with adenine, cytosine,
and guanine. Often abbreviated as T. In base pairing, thymine pairs with adenine
(A). In RNA, thymine is replaced by uracil (U).
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314
Trait: A particular characteristic of an organism (such as eye color or hair texture)
that is expressed by gene(s) as well as influenced by the environment.
Transcription: Making RNA using the instructions from DNA.
Transcription factor: A protein that controls the rate of transcription.
Transfer RNA (tRNA): See RNA.
Transgenic: Artificially introducing genetic material from one unrelated organism

into another.
Translation: Making protein using the instructions from RNA.
Translesion synthesis (TLS): A type of DNA damage control that allows repair
of genetic material to occur past damaged sites (aka lesions).
Transmembrane protein: A protein that spans the membrane of cells, (e.g., to

help transport materials from outside to inside of the cell, or to act as a receptor
relaying information from outside to inside).
Transposon: Segments of DNA that can move around within the genome.
Triglyceride: The storage and transport form of fatty acids, formed with three
fatty acids attached to a glycerol backbone.
Type 1 diabetes (T1D): Often called early-onset diabetes, an autoimmune

disorder where destruction of the pancreas leads to problems with insulin
secretion.
Type 2 diabetes (T2D): A disease in which the body cannot use insulin properly,
and blood glucose (sugar) remains consistently high.
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U
Uracil: One of the nucleotides that forms RNA, along with adenine, cytosine, and
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guanine. Often abbreviated as U. In base pairing, uracil pairs with adenine (A). In
DNA, uracil is replaced by thymine (T).

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315
V
Variable number tandem repeat (or VNTR): Repetition of codons different
numbers of times (e.g., the same codon may be repeated 3 times versus 5
times).
Variant: A different version of the same gene. See also allele.
Vitamin D receptor (VDR): A nuclear receptor that can bind to vitamin D and
affect genetic expression.
W
Whole-genome sequencing: Reading and analyzing an organisms entire
genome.
PRECISION NUTRITION
What does this References
mean for you?
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Dont believe us? Want to learn

Now that you've learned more more? Enjoy the hundreds of

about genetic testing, or references weve collected.
even gathered your own data,
what should you do next?
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316
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317
PRECISION NUTRITION GENETICS: THE UNIVERSE WITHIN
References
CHAPTER 14
#
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Glossary of terms Contributors and
acknowledgments
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Confused by codons? Mystified by

mutations? No worries, weve got a Science is a collaborative endeavor.

handy glossary for all the technical We are most grateful to all of those
terms weve used in this book. who contributed their data and
expertise to help us write this book.
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acknowledgments
Contributors and
CHAPTER 15
Science is a collaborative endeavor.
We are most grateful to all of those who contributed their data and expertise to
help us write this book.
Authors and Contributors
Dr. Krista Scott-Dixon

Dr. Krista Scott-Dixon developed Precision Nutritions PN Coaching /
ProCoach and PN Level 2 Master Class Certification curricula. She
is also a co-author of the 3rd edition of the PN Level 1 Certification
textbook, The Essentials of Sport and Exercise Nutrition.
With a PhD from York University in Toronto and 10 years of university

teaching, Krista has over 20 years of experience in research, adult
education, curriculum design, and coaching and counselling. Krista is
the author of several books, dozens of popular articles, and many academic
publications.
Alaina Hardie
Alaina Hardie is a programmer, maker, and biology enthusiast. She
has worked in software development, data security, and network and
systems engineering.
After graduating in 2011 from Singularity Universitys prestigious

Graduate Studies Program, she studied molecular and computational
biology. As the Chief Maker and director of the iLab at Singularity
University, she is responsible for educating the current and upcoming
generations of leaders on using exponential technologies to address
humanitys greatest challenges.
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As PNs original tech person and resident bioinformatician, she was responsible
for a lot of the details in chapters 2 and 3, and for most of the computational
analysis of the data we gathered for this book.
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Dr. Helen Kollias
Dr. Helen Kollias is a researcher and regular content contributor for
Precision Nutrition. She is also a co-author of the 3rd edition of the
PN Level 1 Certification textbook, The Essentials of Sport and Exercise
Nutrition as well as an advisor for the Precision Nutrition Level 1
Certification.
As a regular content contributor to the blog, she uses her witty

and articulate writing style to make complex science accessible and
entertaining.
Helen holds a PhD in Molecular Biology, specializing in the area of cell signaling
in muscle development and regeneration, and a Masters degree in Exercise
Physiology and Biochemistry.
She has also held research positions at some of the most prestigious institutions
in the world, including John Hopkins University and Torontos Hospital for Sick
Children. At Johns Hopkins, she researched muscle signaling of myostatin and
IGF-1 in muscle. At the Hospital for Sick Children she researched the role of
genetics in the emergence of brown fat.
Dr. John Berardi

Dr. John Berardi is a co-founder of Precision Nutrition, the worlds largest
online nutrition coaching and certification company.
JB has been recognized as one of the top exercise nutrition experts

in the world. He earned a PhD in Exercise Physiology and Nutrient
Biochemistry at the University of Western Ontario, Canada. His work
has been published in numerous textbooks, peer-reviewed academic
PRECISION NUTRITION
journals, and countless popular exercise and nutrition books and
magazines.
As an elite nutrition coach and exercise physiologist, JB has worked with over
50,000 clients in over 100 countries, including Olympic gold medalists, world
champion UFC fighters, and professional sports teams. He is also an advisor to
Apple, Equinox, Nike, and Titleist.
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Judy Rubin
Growing up, Judy was always trying to draw the bugs and creatures
found in her backyard, and the cells seen under the microscope in her
mothers lab. This unusual childhood hobby later turned into a career.
After receiving a BA in Biology from University of Maryland Baltimore

County, she trained first as a fine artist at the Schuler School of Fine Arts
and then as a medical illustrator at University of Toronto in the Biomedical
Communications program. She hopes to continue creating accurate,
effective, and beautiful visuals for a range biomedical and health topics.
More examples of her work can be found at jrubinvisuals.com.
Reviewers, editors, and people who keep us

honest
Ryan Andrews
Ryan Andrews is a world-leading educator in the fields of exercise
science and nutrition. Ryan is a Registered Dietitian with two Masters
Degrees. He completed his education in exercise and nutrition at the
University of Northern Colorado, Kent State University, and Johns
Hopkins Medicine.
A highly-respected coach who has been a part of the Precision Nutrition

team since 2007, Ryans body of work includes an impressive number
of articles, presentations, books, and certification manuals most recently
as a co-author on the 3rd edition of the PN Level 1 Certification textbook, The
Essentials of Sport and Exercise Nutrition.
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A nationally-ranked competitive bodybuilder from 1996-2001, and now a
certified yoga instructor, Ryan is also an active volunteer with non-profit
organizations to help promote a sustainable future.
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Cam DePutter
Camille DePutter is an author, speaker, and communications consultant
with a rich portfolio of experience in marketing, public relations, and
storytelling.
Camille received her HBA in English from the University of Toronto and
trained at the Humber School for Writers. She lends her communication
expertise to Precision Nutrition publications, course materials and
marketing content.
As a consultant, Camille has helped dozens of top brands and business leaders
refine their messaging and improve their customer relationships. Her work has
been published extensively in popular websites, magazines and newspapers.
Camille is a frequent contributor to the Precision Nutrition blog. She is also the
author of the workbook Share Your Story, and self-publishes at
camilledeputter.com.
Dr. Trevor Kashey

Dr. Trevor Kashey, PhD is a biochemist who began his scientific career in
high school where he dedicated to non-small cell lung cancer research
at the Translational Genomics Research Institute in Phoenix, AZ.
On top of setting some American strongman records of his own, hes

dedicated to improving the performance of all the other athletes he
consults and makes a mean oatmeal cookie to boot.
On top of regularly reviewing and publishing lay content, he contributes

critical analysis of technical research data as a research reviewer for public and
private institutions. He is a regular guest lecturer at local colleges and business
PRECISION NUTRITION
seminars and is dedicated to the education and outreach in the field of sports
nutrition and dietary supplements.
Trevor has worked with Worlds Strongest Man competitors, 150-mile ultra
marathon runners, and everything in between. Trevor blends anecdotal,
academic, and clinical data, harmonizing it into practical dietary information for
the general public. You can find him at trevorkashey.com.
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Kenny Manson
Kenny Manson is a performance coach and graduate of the PN Level 2
Master Class Certification. In addition to his PN qualifications, Kenny
holds numerous international fitness certifications and is a PTA Global
accredited coach, for whom he has co-presented at the mentorship
level.
Kenny has worked directly alongside wellness leaders such as OD on

Movement, Human Fitness and Performance and The Kaizen Institute of
Health, and is also qualified as a chartered and certified accountant. Kenny has
applied his corporate experience in the fitness world in a variety of roles, from
coaching clients and fellow fitness professionals to providing fitness business
management solutions.
Kenny is currently mentor to students of the PN Level 2 Master Class

Certification and Digital Health Producer and presenter at Soulgenic.
Dr. Victor Pea

Dr. Victor Pea has a decade of clinical and surgical experience in
Ireland and the UK.
He has published widely in international peer-reviewed medical

journals, and continues to review the latest research in the fields of
health, wellness, fitness, nutrition, and disease prevention on a daily
basis to continue to bring the most reliable strategies to his clients.
After deciding that he would like to prevent rather than treat the
consequences of poor health, Victor changed careers from surgery to the field
of lifestyle medicine.
PRECISION NUTRITION
His work is accredited by respected organizations such as the Harvard Medical
School, Yale University School of Medicine, the American Medical Association
and the George Washington University Medical School.
Victor is regularly interviewed on international radio to promote healthy lifestyle

choices in Spanish-speaking communities in North America and beyond. You
can find him at ElitePersonalizedHealth.com.
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Alex Picot-Annand
Alex Picot-Annand is a holistic nutritionist and writer who studied
psychology at Dalhousie University and nutrition at the Canadian
School of Natural Nutrition. She is also Precision Nutrition Level 1
and Level 2 certified, and a key contributor to the Precision Nutrition
Encyclopedia of Food.
Although they did not earn her any degrees, she would also argue that
she learned many textbooks worth of life wisdom by living in Ecuador for
seven months, and by working on the frontline of the health industry for nearly
a decade. Thankfully, neither Alex nor her husband carry the OR6A2 gene, so
agree on loading their guacamole with cilantro.
You can find her at alexpicotannand.com.
Jennifer Petrosino
Jennifer Petrosino earned a BSc in Exercise Science from the University
of Miami (FL) and an MSc in Kinesiology from The Ohio State University,
while powerlifting for EliteFTS as a raw lifter in the 105-pound weight
class.
She is currently a PhD student in the Biomedical Sciences Program at

The Ohio State University, where she studies post-transcriptional and
translational control of protein synthesis in hypertrophying muscles.
PRECISION NUTRITION
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Dr. Jennifer Zantinge
Dr. Jennifer Zantinge is a Molecular Cereal geneticist at the Field Crop
Development Centre (FCDC) in Lacombe Alberta.
Graduating with a PhD in molecular biology and genetics from the

University of Guelph, Jennifer has had the opportunity to experience
the rapid advancement of the field of genomics, along with its new
technologies and practical applications.
As lead scientist of the cereal biotechnology lab, her primary goals include
the development and evaluation of molecular genetic based tools such as DNA
marker panels to help plant breeders select genetically superior plants.
Additional thanks
Dr. Ahmed el-Sohemy
Dr. el-Sohemy is a pioneer in the field of nutrigenomics. His early
research paved the way for our current understanding of how
genetic and dietary factors interact to regulate various metabolic and
biochemical pathways involved in the development of cardiometabolic
disease, as well as athletic performance.
Widely published, he is considered a leading researcher in the field of

nutrigenomics / nutrigenetics.
His genetic testing organization, Nutrigenomix, is a University of Toronto

start-up biotechnology company. It is dedicated to empowering healthcare
professionals and their clients with comprehensive, reliable, genomic
information, with the ultimate goal of improving health through personalized
nutrition.
PRECISION NUTRITION
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384
Dr. Mariane Hroux
Dr. Mariane Hroux received her PhD in Kinesiology and Health Studies
from Queens University, Canada where she was part of the physical
activity epidemiology lab and studied the relationship between
nutrition, physical activity, and obesity in children from different
countries. Before this, she completed her MSc in Community Health
Epidemiology, and studied the relationship between dietary patterns
and chronic disease.
Dr. Hroux has published her work in numerous scientific journals and has
presented at several scientific conferences. Her interest in how nutrition and
physical activity affect the body developed at an early age, when she started
noticing that what she ate influenced her performance as a competitive gymnast.
Dr. Hroux continues to explore the importance of nutrition and physical activity
at Precision Nutrition where she contributes to research and analyses, and
manages key projects.
PRECISION NUTRITION
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385
Singularity University
Special thanks to Singularity University, its faculty, and facilities for their support
of this project.
Alaina would like to personally thank SUs Chair of Digital Biology, Raymond
McCauley, for checking on her the first day of the Graduate Studies Program,
and providing countless opportunities to learn and teach the wonders of biology.
Without Raymonds inspiration and friendship, this book would not exist.
The PN team
Tim Jones, for so freely sharing his genetic data and letting us tell his family
secrets.
Jenny Brook, Ruby Giulioni, Holly Monster, and Lisanne Thomas, all of whom
read and commented on earlier drafts of the manuscript.
The anonymous genetic data contributors

You know who you are.
Thanks for helping us science.
PRECISION NUTRITION
CHAPTER 14
References
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Dont believe us? Want to learn

more? Enjoy the hundreds of

references weve collected.
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386

Precision Nutrition Ebook Genetics The Universe Within

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Genetics:

The Universe Within

By Krista Scott-Dixon, PhD

By Krista Scott-Dixon, PhD

John Berardi, PhD Alaina Hardie Helen Kollias, PhD

Ryan Andrews Dr. Victor Pea

2017 Precision Nutrition. All Rights Reserved.

CHAPTER 1 CHAPTER 2 CHAPTER 3

CHAPTER 4 CHAPTER 5 CHAPTER 6

CHAPTER 7 CHAPTER 8 CHAPTER 9

CHAPTER 10 CHAPTER 11 CHAPTER 12

CHAPTER 13 CHAPTER 14 CHAPTER 15

Our fate cannot be taken from us. It is a gift.

Oh, I am fortunes fool!

Would you do anything differently?

Human beings have wondered about destiny for

Do we have free will? Can we do anything we like? Or are there limits?

If theres a plan, who or what creates it?

In 2017, we might say: Genetics.

Human beings have also wondered about who

Why is so much of ourselves often hidden from us?

Why dont we know why we do things?

basically just carbon copies of our ancestors, or are we a blank slate?

Again, in 2017, we often try to answer these questions with: Genetics.

If we find something we dont like, how much can we change? How

Genetics is an exciting area of

Genetic testing looks to answer Big Questions like:

What if we could know not just speculate, or guess, or wonder, but

Do this genetic test, and well tell

Its an exciting promise. PRECISION NUTRITION

A plan based on our unique, special blueprint? A one-in-seven-billion program,

Wow. That would be amazing. Wouldnt it?

Were not quite there yet.

But we are at a thrilling crossroads in human

But the window is too small to show you everything.

You just cant see it all

In this book, well peek into the toy

What genetic testing is, and how it works.

What genetic testing can do and not do.

All of this is right now.

Of course, right now will change.

We want to dream, and we also want to be

We encourage you to read this book with the following mindset:

There is stuff we know, and stuff we dont know.

Thats how science works.

Get excited, but keep it real.

Science is a collaborative endeavor.

This project is no different.

We shared our own genetic data.

At other times, well present their data in anonymous aggregate.

Heres our team.

Thanks to everyone who contributed a little part of themselves for their

We need to look at this from many angles.

the molecular biology of genes and how they work;

how genetic testing relates to nutrition and exercise physiology;

how probability and risk work;

The science is neat. But this isnt

As you read this book, remember an important caution:

Heres what the rest of this book

An overview of how genetics works, and an introduction to some of the

Specific topics of interest

What this all means and what to do next

contributed their data and expertise to help us write this book.