1.the Early History of Population Genetics

8/3/2019 1.the Early History of Population Genetics

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Copyright: Gilean McVean, 2001 1

An introduction to populationgenetics

JPMedical applications of population genetics13th MarchGMPopulation structure6th March

PFRecombination27th Feb

MPHuman population genetics20th Feb

GMNatural selection13th Feb

GMThe coalescent6th Feb

GMNeutral mutations in populations30th Jan

GMAn introduction to population genetics23rd Jan

TopicDate

GM Gil McVean MP Molly Prseworski

PF Paul Fernhead JP 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.

Books


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The early history of population genetics

Morgans experiments on Drosophila1915

Fishers paper on phenotypiccorrelations between relatives1918

Sturtevants artificial selection

experiments on Drosophila

1918

Fishers The Genetical Theory ofNatural Selection(Fundamentaltheorem)

1930

Wrights Evolution in Mendelianpopulations

1931

Haldanes The Causes of Evolution1932

Kimura diffusion equation solution to

the distribution of allele frequencies

1955

Pearl, Jennings and Wrights work on

inbreeding

1912-1920

Nilsson-Ehles experiments on wheat1909

Rediscovery of Mendels laws1900

Mendels experiments on peas1856-63

Darwins Origin of Species1859

EventDate


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Definitions

Gene or locus

Molecular: Open reading frame and associated

regulatory elements.

Classical genetic: Chromosomal region to which aphenotypic 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


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Mendels peas

Nilsson Ehles wheat

x

x

AA x aa

Aa x aa

21

21

Aa & aa

bb

Bb

BB

aaAaAAGenotype


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Quantitative trait variation

Three types of quantitative trait

Continuous (weight, height, milk yield)

Meristic (bristle number in Drosophila)

Discrete with continuous liability (diseasesusceptibility)

Trait value

FrequencyMean = =

i

iNx1

Variance = = 2P i

iNx

21 )(

22222

EIDAP +++=

Phenotypic Additive

genetic

Dominance Epistatic Environmental

Genetic


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Estimating the genetic component of

quantitative traits

XX

XX

X

X

X

X

XX

X

X

Mid-parent value (x)

Offspring

value (y)y = a + b x

Cov(x, y)Var(x)

b = = h2 = 2

2

P

A

S

Trait value

= h2

(S - )

Trait value

Selection response


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Heritabilities of human traits

1.0

0.8

0.6

0.4

0.2

0

Height

Weight

Fertility

IQ

Extrovertism

Handedness

Twin concordance in human disease

0.53-0.6515.337.2Tuberculosis

1.04-1.055.067.0Manic-depressive psychosis

0.53-0.626.625.0Arterial hypertension

0.23-0.332.66.8Cancer

MZDZDisease

Genetic

Determinism

Concordance

From Cavalli-Sforza & Bodmer (1971)


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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

JBS Haldane

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

Sewall Wright Evolution in Mendelian populations (1931)

Developed the use of diffusion theory in populationgenetics

Importance of genetic drift

Selection at multiple-loci

Shifting-balance theory of evolution

Four volume Evolution and the genetics of populations(1968-1978)


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Serological techniques for detecting

variation

Human

Rabbit

A

A B AB O

Polymorphic blood groups in the

white English population (no. types)

ABO (4) Kidd (3)

Rh (7) Dombrock (2)MNS (6) Auberger (2)

P (3) Xg (2)

Secretor (2) Sd (2)

Duffy (3) Lewis (2)

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


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HLA diversity at the MHC locus

DP DQ DR C4 C2 TNFa,b HLA-B HLA-C HLA-A

HLA-D

Class II Class III Class I

6p21.34 Mbp c. 127 genes

(18 genes)

0.00

0.05

0.10

0.15

0.20

0.25

0.30

A2

A1

A3

A24

Aw29 A

11A26

A28

Aw30

Aw32 A

23A25

Aw31 N

ull

Aw33

Aw43

HLA-AEuropean Caucasoids

African Blacks


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Protein electrophoresis

++

+

--

- --

-

++

--

- --

--

Starch or agar gel

Direction of travel

Polymorphism = 0.75

Heterozygosity = 0.30

PGM 6PGD

GPDGPI


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The phylogenetic distribution of

allozyme variation

Plants

Drosophila

Other insects

Land snails

FishesAmphibians

Reptiles

Birds

Other mammals

Humans

0 1.0

Polymorphism

Humans Polymorphism = 0.31

Heterozygosity = 0.06

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


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The rise of the neutral theory

Observations

Constancy of rate of molecular evolution(the molecular clock)

More important regions of proteins evolve at aslower 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)/NasN

s = selective advantage


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Genetic load

wFitness

Frequency

optw

Load =

opt

opt

w

ww

Haldanes cost of natural selection

Fitness (w)

= Expected number of offspring given genotype

N N* N

Nsx selective deaths occur

every generation

To fix there must be a

total of 4.6Nselective deaths

if it has a 1% advantage

w( ) = 1

w( ) = 1+s


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Segregation load due to balanced

polymorphisms

Genotype AA Aa aa

Fitness 1 - s 1 1 - s

Frequency x2 2x(1-x) (1-x)2

)1(2 xsxw

ww

opt

opt=

2,5.0if

sLx ==

To maintain 30,000 polymorphisms, each of which has a

heterozygote advantage of 1% creates a load of

66000,30 1051995.01 ==L

Frequency

15,000 99.5%0.5%

450 loci

Variation

01.0)01.01( 450

5.0

5.99 ==w

w


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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 ofneutral mutation

The level of polymorphism in a population is a

function of the effective population size and the

neutral mutation rate

Polymorphisms are transient rather than balanced

fk neutral =

N

N

e

e

41

4

+=

Time

Frequency Frequency

Balanced Transient


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RFLPs

Probe

+

-

PCR analysis of microsatellites

.....CAGCAGCAGCAGCAG.....

.....CAGCAGCAGCAGCAGCAGCAG.....

Full sequence analysis

ATGTGAATGCTAATG

...A..T........

.C.A.......G...

.C......--.G...

...A..T.--.....


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No. segregating sites (S) = 4

Average pairwise differences () = 2.4= 0.16 per site

No. haplotypes = 4

SNPs ATGTGAATGCTAATG...A..T........

.C.A.......G...

.C......--.G...

...A..T.--.....

44

313

0432

22321

5432Seq

Statistics of polymorphism

Segregating site Indel


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Patterns of variation at the DNA level

Synonymous & nonsynonymous mutations

Nucleotide variation v. protein variation?

Arg Gln Val

AGA CAA GTA

AGA CAG GTA

Arg Gln Val

Arg Gln Val

AGA CAA GTA

CAG CGA GTA

Arg Arg Val

D. simulans total = 0.010 per site

silent = 0.038noncoding = 0.023

1%0.1%Nucleotide

14%6%Allozyme

D. melanogasterHumans


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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

Documents

1.the Early History of Population Genetics