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An introduction to population genetics

Date 23rd Jan 30th Jan 6th Feb 13th Feb 20th Feb 27th Feb 6th March Topic An introduction to population genetics Neutral mutations in populations The coalescent Natural selection Human population genetics Recombination Population structure GM GM GM GM MP PF GM JP

13th March Medical applications of population genetics

GM PF Gil McVean Paul Fernhead MP JP Molly Prseworski Jon Pritchard

Crow JF &Kimura M. 1970. An introduction to population genetics theory. Harper and Row, New York. Gillespie JH. 1998. Populations genetics: a concise guide. The Johns Hopkins University Press, Baltimore. Hartl DL & Clark AG (1989). Principles of population genetics. Sinauer Associates, Sunderland, Mass.
Copyright: Gilean McVean, 2001 1

The early history of population genetics

Date 1859 1856-63 1900 1909 1912-1920 1915 1918 1918 1930 Event Darwins Origin of Species Mendels experiments on peas Rediscovery of Mendels laws Nilsson-Ehles experiments on wheat Pearl, Jennings and Wrights work on inbreeding Morgans experiments on Drosophila Fishers paper on phenotypic correlations between relatives Sturtevants artificial selection experiments on Drosophila Fishers The Genetical Theory of Natural Selection (Fundamental theorem) Wrights Evolution in Mendelian populations Haldanes The Causes of Evolution Kimura diffusion equation solution to the distribution of allele frequencies

1931 1932 1955

Copyright: Gilean McVean, 2001

Gene or locus Molecular: Open reading frame and associated regulatory elements. Classical genetic: Chromosomal region to which a phenotypic mutation can be mapped. Evolutionary: A stretch of hereditary material sufficiently small such that it is not broken up by recombination, and which can be acted on by natural selection (the unit of selection).

Allele One of two or more possible forms of gene (locus).

Polymorphism The presence of multiple forms in natural populations

Copyright: Gilean McVean, 2001

Mendels peas
x x AA Aa Aa
1 2 1 2

x x &

aa aa aa

Nilsson Ehles wheat

Genotype AA BB Bb bb Aa aa

Copyright: Gilean McVean, 2001

Quantitative trait variation

Three types of quantitative trait

Continuous (weight, height, milk yield) Meristic (bristle number in Drosophila) Discrete with continuous liability (disease susceptibility)


Mean =

1 N

x =
i i

1 Variance = N ( xi i

)2 =


Trait value
2 P

2 A

2 D

2 I

2 E


Additive Dominance genetic



Copyright: Gilean McVean, 2001 5

Estimating the genetic component of quantitative traits

Offspring value (y)


Mid-parent value (x)

2 A 2 P

Cov(x, y) b= = h2 = Var(x) Selection response S

= h2 (S - )

Trait value
Copyright: Gilean McVean, 2001

Trait value

Heritabilities of human traits

1.0 0.8 0.6 0.4 0.2 0 IQ Weight Handedness Fertility Extrovertism Height

Twin concordance in human disease

Concordance Disease Cancer Arterial hypertension Manic-depressive psychosis Tuberculosis DZ 6.8 25.0 67.0 37.2 MZ 2.6 6.6 5.0 15.3 Genetic Determinism 0.23-0.33 0.53-0.62 1.04-1.05 0.53-0.65

From Cavalli-Sforza & Bodmer (1971)

Copyright: Gilean McVean, 2001 7

Fisher, Haldane, and Wright

RA Fisher
The Genetical Theory of Natural Selection (1930) Fishers fundamental theory Geometric model of adaptation The concept of likelihood in statistical analysis Experimental design The Causes of Evolution (1932) Fixation probabilities of advantageous alleles Theory of sex-linked loci Eloquent exponent of the theory of evolution by natural selection

JBS Haldane

Sewall Wright
Evolution in Mendelian populations (1931) Developed the use of diffusion theory in population genetics Importance of genetic drift Selection at multiple-loci Shifting-balance theory of evolution Four volume Evolution and the genetics of populations (1968-1978)

Copyright: Gilean McVean, 2001

Serological techniques for detecting variation

Rabbit Human A


Polymorphic blood groups in the white English population (no. types)

ABO (4) Rh (7) MNS (6) P (3) Secretor (2) Duffy (3) Kidd Dombrock Auberger Xg Sd Lewis (3) (2) (2) (2) (2) (2)

Pr{2 people same blood type} 3 in 10,000

Copyright: Gilean McVean, 2001 9

HLA diversity at the MHC locus

6p21.3 4 Mbp c. 127 genes




(18 genes)

Class II

Class III

Class I

0.30 0.25

European Caucasoids African Blacks


0.20 0.15 0.10 0.05 0.00

A 3 A 24 A w 29 A 11 A 26 A 28 A w 30 A w 32 A 23 A 25 A w 31 N ul l A w 33 A w 43 A 2 A 1

Copyright: Gilean McVean, 2001


Protein electrophoresis
Starch or agar gel

-- +-+ +- - -- - -+ +- - Direction of travel





Polymorphism Heterozygosity
Copyright: Gilean McVean, 2001

= 0.75 = 0.30

The phylogenetic distribution of allozyme variation

Polymorphism 0 1.0

Plants Drosophila Other insects Land snails Fishes Amphibians Reptiles Birds Other mammals Humans


Polymorphism Heterozygosity

= 0.31 = 0.06

Two haploid genomes are expected to differ at c. 6,000 loci

Copyright: Gilean McVean, 2001 12

The rise of the neutral theory

Constancy of rate of molecular evolution (the molecular clock) More important regions of proteins evolve at a slower rate than less important domains High levels of protein polymorphism High rates of molecular evolution (about 1.5x10-9 changes per amino acid per year)

Theoretical considerations
Haldanes cost of natural selection Segregation load of balanced polymorphisms

Some population genetic terminology

Population = set of inter-mating/competing individuals N = Number of individuals in a population x = allele frequency = N(x)/N as N s = selective advantage
Copyright: Gilean McVean, 2001 13

Genetic load
Fitness (w) = Expected number of offspring given genotype
Frequency Load =

wopt w wopt



Haldanes cost of natural selection

N N* N Nsx selective deaths occur every generation To fix there must be a total of 4.6N selective deaths if it has a 1% advantage
w( ) = 1 w( ) = 1+s
Copyright: Gilean McVean, 2001 14

Segregation load due to balanced polymorphisms

Genotype Fitness Frequency AA 1-s x2 Aa aa

1 1-s 2x(1-x) (1-x)2

wopt w wopt

= 2sx(1 x)
s 2

if x = 0.5, L =

To maintain 30,000 polymorphisms, each of which has a heterozygote advantage of 1% creates a load of

L = 1 0.99530, 000 = 1 5 10 66
450 loci


w99.5 = (1 0.01) 450 = 0.01 w0.5

Copyright: Gilean McVean, 2001



Features of the neutral theory

The majority of changes in proteins and at the level DNA which are fixed between species, or segregate within species, are of no selective importance The rate of substitution is equal to the rate of neutral mutation

k = f neutral
The level of polymorphism in a population is a function of the effective population size and the neutral mutation rate

4Ne = 1 + 4Ne
Polymorphisms are transient rather than balanced
Balanced Frequency Frequency Transient

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PCR analysis of microsatellites

Full sequence analysis

ATGTGAATGCTAATG ...A..T........ .C.A.......G... .C......--.G... ...A..T.--.....
Copyright: Gilean McVean, 2001 17


ATGTGAATGCTAATG ...A..T........ .C.A.......G... .C......--.G... ...A..T.--.....


Segregating site

Statistics of polymorphism
No. segregating sites (S) Average pairwise differences ()
Seq 1 2 3 4 2 2 3 3 3 4 2 4 1 5 2 0 3 4

= 4 = 2.4 = 0.16 per site

No. haplotypes
Copyright: Gilean McVean, 2001


Patterns of variation at the DNA level

Synonymous & nonsynonymous mutations

Arg Gln Val AGA CAA GTA CAG CGA GTA Arg Arg Val D. simulans Arg Gln Val AGA CAA GTA AGA CAG GTA Arg Gln Val total = 0.010 per site silent = 0.038 noncoding = 0.023

Nucleotide variation v. protein variation?

Humans Allozyme Nucleotide 6% 0.1% D. melanogaster 14% 1%

Copyright: Gilean McVean, 2001


Current issues in population genetics

Medical applications
Disease gene identification by association mapping Understanding genetic basis of quantitative variation

Statistical issues
Methods for detecting natural selection Full likelihood methods for estimating evolutionary parameters from sequence data The design of population genetic experiments

Theoretical and empirical issues

The maintenance of quantitative genetic variation Interactions between alleles at selected loci The molecular clock Reproductive isolation and speciation

Copyright: Gilean McVean, 2001