Chromosome Structure and Abnormalities

First, some basic terms:

Haploid: One copy of each chromosome…this occurs in gametes and
as part of the normal life cycle of organisms such as yeast
Diploid: Two copies of each chromosome…this is what we are
Triploid: Three copies of each chromosome
Tetraploid: Four copies of each chromosome…occurs naturally during
mitosis and meiosis immediately after diploid set of chromosomes has
been replicated. Occurs in organisms with duplicated genomes.
Hexaploid, octoploid, dodecaploid, etc. Occurs in some plants, liver
cells
Polyploid
Monosomy…one copy of a given chromosome when there should be
two
Trisomy…three copies of a given chromosome when there should be
two
What is on a
chromosome?
List of genes along a
chromosome is a list
of all our parts and,
at the same time, its
like a list of what
goes wrong.

Transmission failure
Windshield wipers
Fan belt
Clutch
Power steering
Haploid vs
Diploid

Some examples
of chromosome
structure that
differ in the
position of the
centromere
Monosomy
Often lethal……why?
1. Unmasks lethal alleles on other chromosome (i.e. you become
haploid for a nonfunctional but critical gene
2. Proper development may require coordinated expression of two
gene copies, one gene copy may be insufficient

Deletion
No examples of complete
chromosomal monosomy in
humans, beyond birth

Example of partial monosomy is the

cri-du-chat syndrome (cry of the cat)
Results from partial deletion of end
of short (p) arm of chromosome 5 5 5
Trisomy
Usually lethal, unless it involves a small
region or a small chromosome. That is
why there is no trisomy 1, 2, etc…too
many critical genes affected

Examples also involve sex chromosomes:

XXY, XYY, XXX

Best known example of trisomy: [trisomy

21; 47, +21]; Downs syndrome

Downs syndrome usually due to

nondisjunction in meiosis I or II (usually I)
Frequency is associated with maternal
age
The reason why is uncertain; one
speculation is that it is due to the long
time the oocyte has been waiting to
complete meiosis
Examination of many
miscarriages shows that at
least 6%, maybe more, of
fertilizations involve
chromosomal abnormalities
Examples of
some
chromosomal
abnormalities
and their
estimated
frequencies

Why these
chromosomes?
…small, with
relatively few
genes, or in the
case of X,
inactivatable.
Polyploidy
Start with normal (diploid) set of chromosomes: duplication of the entire
set gives you a doubled up set of chromosomes. Or, combining with
another similar set, for instance through cross-hybridization, can also give
more chromosomes than before. Such events result in an organism having
two copies of what was before single genes. Often one copy performs the
original role and the other diverges and either becomes inactive or begins
to fulfill another role.
Polyploidy
Polyploidy can be artificially induced in normal somatic cells using
colchicine. This treatment interferes with microtubule/spindle formation
and prevents chromosomes from going to each pole. Chromosomes don’t
segregate properly and so the cell now contains a tetraploid set of
chromosomes.
Such duplications are sometimes possible in cultured cells because they
do not undergo the complete process of development, although
chromosomes may gradually be lost. And, it is possible to fuse human and
mouse cells to make (initially) tetraploid hybrid cells. Amazingly, in plants
polyploidy tends to be tolerated (recall wheat kernel color problem).
Polyploidization is important in agriculture.

Plants tend to be very tolerant of extra chromosomes, unlike organisms

like us. And, even if they are unable to proceed through meiosis and
cannot make pollen/oocytes, polyploid plants can usually still be
propogated without fertilization (grown asexually) both from cells or
from cuttings. FYI, humans cannot be regrown from ‘cuttings’.

(It turns out…) some triploid or tetraploid plants have interesting and
attractive features, such as larger fruit size, seedlessness, etc.

Seedlessness, for instance, is sometimes due to the fact that meiosis

fails due to unequal chromosome types/numbers. As a result of
meiotic failure, seed formation terminates because there are no good
gametes to build a seed around. But, you still get the fruit!

Sometimes polyploidization results in sterility, but sometimes not.

Seedless watermelon
http://edis.ifas.ufl.edu/cv006
Seedless naval oranges are supposedly due to a mutation that arose in a
tree in Brazil in 1820. Because the mutation made the oranges seedless,
further propogation had to be due to cuttings/grafting. (picture from Wikipedia)
Some cells of an organism have multiple chromosome sets

Examples are……
Liver cells, 4n, 8n, 16n

Drosophila salivary glands (polytene chromosomes)

And, gene amplification (replication to make many copies) of

chromosomal regions is sometimes used as a mechanism to allow
higher levels of gene expression. For instance, cells resistant to
chemotherapeutic drugs sometimes display amplification of a
chromosome region that contains drug resistance genes.
Major Types of Changes in Chromosome Structure

Deletions
Duplications
Inversions
Nonreciprocal translocations
Reciprocal translocations
Drosophila polytene
chromosomes
Formed because many cycles
of replication have occurred
without separation of DNAs
by cell division. As a result,
many chromosomes (1000s)
are lined up next to each
other and can be visualized
microscopically. Banding
patterns have been analyzed
in detail.
These occur in Drosophila
salivary glands. Other than
to say it allows production of
more gene products there
isn’t a real good explanation
as to why this happens.
Produce more saliva? Huh?
Example of gene deletion in Drosophila polytene chromosomes
a. Normal banding configuration at chromosome end. Bands are
assigned addresses. Location of genes y, ac, and sc are shown.
b. Deletion 260-1 results in pseudodominance for y, ac, sc. These would
normally be recessive but they exert a phenotype when their
counterparts on the other homolog have been deleted.
c. Deletion 260-2 is smaller than 260-1 and results in pseudodominance
for y and ac
An interesting deletion puzzle….

Notch phenotype
Organism: Drosophila
Notch is an X-linked dominant phenotype with notched wings
let’s call it N for notch, n+ for not notch (i.e. wild type).

Some observations about Notched…

1. Notch is given from a Notched mother to half the females

2. Half of sons of Notched females die

3. Notch females do not breed true (suggests homozygous lethal)

4. white-eye, facet-eye, and split-bristle are (recessive) genes linked to

notch

5. Notched but otherwise normal females bred to white/facet/split males

display half female progeny with white/facet/split
Lets take a look at point 5. We suppose the cross is something like…

FEMALE: N WFS / n+ WFS X MALE: n+ wfs / Y

gives ½ notched females that are white, faceted, split

But wait, that’s odd….what you expect is notched females N to NOT BE white,
faceted, split. That is to say you suppose delivery of N to be accompanied by
wild type W, F, and S which should be dominant over male derived wfs.

Explanation: Examination of Notch and normal polytene chromosomes,

show distinct banding (staining) patterns. In particular, a loop was observed
between two paired chromosomes. The loop represents a chromosomal
region that cannot pair in register with its polytene partner. The absence of
this region (no loop) on one of the chromosomes is associated with the
Notch phenotype. The ‘no loop’ means something is GONE relative to the
chromosome with the loop.
That is, the deletion associated with the Notch phenotype also results in the
deletion of adjacent white, faceted, and split genes. SO, the previous cross is
really more like…

(del NWFS) / n+ WFS X n+ wfs / Y

All the genes

Missing genes
Example where duplication of chromosome region causes a phenotypic
effect
X chromosome linked bar gene….causes small eye (barred)
Normal chromosome structure…wild type
1 copy…intermediate effect (female); severe effect (male)
2 copies…severe effect (female)
Polytene chromosomes could be analyzed to actually ‘see’ a physical
abnormality (a duplication) in chromosome structure associated with the bar
phenotype
Inversions

Why would such a structural rearrangement happen in the first place?

Sometimes it is due to homologous sequences that can interact through
complimentary base pair interactions, allowing the homologous
recombination machinery to act. Such homology is observed between gene
families and in repetitive DNA. Other times we don’t know why, its just a
mistake.
Inversions make a
mess of meiosis
To the right is an
example of what
could happen during
meiosis in the case of
a pericentric
inversion.
Chromosomes have
to loop to regain
homologous pairing.
That ‘might’ not be so
bad, but crossing
over (recombination)
within looped region
generates complex
meiotic products.
Changing the position of a gene along the length of a
chromosome can have an effect on their expression
This is called a Position Effect, or Position Effect Variegation,
and it has important implications for ‘gene therapy’.

Inversion: Position Effect

w+
w RED

w+
w RED/WHITE

Transgenic Mouse: Position Effect

 Translocations

Normally changes in chromosome organization are bad for an individual. But

why not consider what good this could be? The sequence of individual genes
can (often) be readily recognized from species to species. That is, genes are
often quite similar in sequence from yeast to fly to mouse to human. But, the
number and organization of genes on chromosomes can be quite different.
Reorganization of chromosomes is part of the reason why one species is
separate from another. Chromosomes must line up for successful meiosis.
 Comparison of the chromosomal organization of
human and mouse chromosomes

Its pretty much the same set of genes, but the organization is different. We
actually don’t know what effect such organization has on the phenotype.
This chart shows a
comparison of chromosomal
banding patterns between
Human (left)
and
Chimpanzee (right).
The two sets are nearly
identical; one distinction is
that human chromosome 2
is divided into two separate
chromosomes in chimps.
When human and chimp
genomic DNA sequences are
compared, we find about 1%
difference (1/100 nt). Unique
insertions and deletions in
either human or chimp add
another 3% or so sequence
difference.
 Below right a reciprocal translocation generates the
‘Philadelphia’ chromosome. This translocation puts the
ABL protooncogene under the control of new regulatory
sequences and turns ABL into an oncogene that
Chromosome promotes uncontrolled cell growth.
translocations involve
movement of DNA to
other locations on
chromosomes.

22

9
A Robertsonian translocation is where two acrocentric
chromosomes join to make a bigger chromosome and a
small chromosome fragment.
Familial Downs

There is a form of Down’s

syndrome that is not due to the
the standard meiotic
nondisjunction explanation.

In this case a translocation

between chromosomes 14 and
21 result in an extra copy of
chromosome 21 in the genome.

Because this can be transmitted

in the form of a ‘carrier’, it is
called familial Down’s
syndrome.
Fragile X Syndrome
1:4000 males; 1:8000 females
Mental Retardation

Due to changes in the FMR1 gene.

Produces RNA binding protein
that is expressed in the brain

Fragile X provides an example of

genetic anticipation:

CGG sequence repeat numbers of

55-230 in one generation can
generate higher repeat numbers
(and the disease) in the next
generation.

Under some cell culture

conditions the gap region is
fragile and can ‘break’, although
this does not ‘cause’ the disorder.
 FMR1 Gene and Fragile X Syndrome

Normal
CGG X 6-54

Carrier
CGG X 55-230

Affected
CGG X 200-1300

The explanation for the disease is not the fragility of the chromosome seen
when cells are incubated in cell culture, but the fact that the extended CGG
repeats cause lowered expression of the nearby FMR1 gene. The gene
itself has something to do with binding and regulation RNAs and in some
way its lowered expression specifically affects the brain.
Notes on chromosome rearrangements, abnormal chromosome
numbers, and their effects on physiology.

1. effects on meiosis: failure to pair up and recombine results in

meiotic termination and no functional gametes. This is why many
animal hybrids are sterile. Effects on mitotic cells are also possible
but we are often more concerned about effect in the germ line.

2. incorrect gene dose results in too much or too little of certain gene
products causing abnormal development.

3. genes get separated from their correct regulatory elements and

become fused with inappropriate DNA regulatory elements,
resulting in either too much or too little production of a gene
product (e.g. oncogene).
Bilateral Gynandromorph
W and w are alleles for eye color
M and m are alleles for wing morphology
Fly fertilized to be XWM/Xwm
That’s pretty normal...and such a fly should
be red eyed (W is dominant) and should be
normal wing (M is dominant).
But look at the fly here….one side has
normal wing and red eye. The other side
has minature wing and white eye. And, the
patterning on the left side is male while the
patterning on the right side is female. What
gives?
One cell zygote after fertilization is XWM/Xwm.
But through mitotic nondisjunction, division
of this cell produced one cell with XWM/Xwm
and the other with O/Xwm. XX is female, OX
is male! Eye and wing phenotypes depend
on copy number, as shown…
Mules….A mule is a hybrid between a female horse (a mare) and a male
donkey (a jackass). Horses and donkeys are pretty closely related,
genetically, behaviorally, anatomically. But, horses have a haploid
chromosome number of 32, while donkeys have a haploid chromosome
number of 31.
In a horse-donkey hybrid, the 2n number of chromosomes would be 31 plus
32, which is 63. Development is allowed because these organisms are so
closely related, but there is an unpaired chromosome to deal with during
meiosis. Meiosis fails, no gametes formed, animal is sterile.
Now, if a mule was a plant, one might be able to force nondisjunction so that
63 chromosomes turns into 2X63=126, all of which could pair up.
Examples of Hybrids….
Liger, Tigon, Wolf-Dog, Zorse, Zonkey, Zony, Cama, Grolar, Pizzly, Leopon,
Wolphin, Jagalion, Tangelo, Centaur, Mermaid
Organisms that are hybrids of two species are often sterile because of
effects of mispaired/unpaired chromosomes during meiosis. In cases of
closely related species with similar chromosome numbers, such hybrids can
be ok (but are usually not seen due to say geographic isolation, etc).
Sometimes sterility is due to other effects
When a cow has twins the following combinations may occur
1 male and 1 male…… both offspring are fertile
1 female and 1 female…… both offspring are fertile
1 male and 1 female….. male is fertile, female is 90% of time
infertile
such a female is called a freemartin
The thought here is that hormonal influences during gestation when a male
and female fetus are present result in masculinization and sterility of the
female.
Thus a case of environmental rather than genetic sterility.