The influence of population size on patterns of natural selection

in mammals

Carolin Kosiol <kosiol@cornell.edu>Cornell University

21st December 2007Isaac Newton Institute

0.05

human

macaque

mouse

rat

dog

chimp

Based on multiple alignments (RefSeq, Vega, and UCSC Known Genes).

Rigorous filters (spurious annotations, paralogous alignments, pseudogenized).

Include genes where the sequences of up to three species are missing as well as truncated genes.

17489 human / chimp / macaque / mouse / rat / dog orthologous genes.

Six Mammalian Genomes

aggregated modelsATT

CTT

CCT

CCG

I

L

P

P

Leu

Pro

Pro

Ile

< 1 purifying selection = 1 neutral evolution > 1 positive selection

Measuring selective pressures

nonsynonymous substitution

synonymous substitution

is defined as the nonsynonymous-synonymous rate ratio

0.05

human

macaque

mouse

rat

dog

0.249

0.245

0.202

0.191

0.127

0.121

0.125

0.140

0.172 chimp

branch specific nonsynonymous-synonymous rate ratios

Average rates of positive selection

Per gene analysisF

req

ue

ncy

Nonsynonymous-synonymous rate ratio

P-value:2.2x10-16

Likelihood Ratio Tests (LRTs) for positive selection

Branch-site models (Yang & Nielsen, 2001, 2005 ) to find positively selected genes (PSGs) on

-Any branch-Specific internal and external branches-Specific clades

We identify 544 putatively positively selected genes (PSGs) in all test.

0.05

human

macaque

mouse

rat

dog

0.249

0.245

0.202

0.191

0.127

0.121

0.125

0.140

0.172 chimpbranch specific nonsynonymous-synonymous rate ratios

primatebranch

rodentbranch

human

macaquechimp

PSG: 400/16529 PSG: 24/14425

PSG: 21/9566

PSG: 10/14558 PSG: 18/14558 PSG: 16/12499

PSG: 61/10762

PSG: 56/8991

primateclade

rodentclade

PSG: 7/10980

hominid

Bayesian Model selection

Previous scans on mammalian genomes

0.05

human

chimp

macaque

(PNAS, 2007)

“[…] These observations are explainable by the reduced efficacy of natural selection in humans because of their smaller long-term effective population size …”

“[…] The diversity in West African chimpanzees is similar to that seen for human populations. The observed Clint is broadly consistent with West African origin …”

(Nature,2005)

Clint

The effective population size N and probability of fixation

where

s>0 mutation is selectively favoured

s<0 mutation is selectively disfavoured

For the neutral case (s = 0) this is simply the initial frequency of mutation 1/2N.

(Kimura 1969)

Let 2N the number of chromosomes. Then

Rates of mutationsThe fixation rate of a new mutations is the product of the mutation rate per site, the chromosomal population size 2N and the probability of fixation:

The rate of neutral mutations is

‘Popgen Omega’

Rate for selected mutations s = ∙ 4Ns/(1-e-4Ns)

Rate for neutral mutations 0 =

(Bruno &Halpern 1998 Nielsen & Yang, 2003, Thorne et al., 2007).

where = 2Ns

Population genetic interpretation of

Advantages:• Accounts for multiple substitutions per site can be calculated for each lineage (branch model)• Improves understanding of effects of population size N on

the nonsynonymous-synonymous rate ratio

Disadvantages:• Assumes that sites are independent• Instantaneous change of population size at speciation• N and s always come as a product =Ns and cannot be

estimated separately by ML techniques

Comparison to estimates from polymorphism data

Estimation from 10980 genes:

Nm/Nh= 1.40 95% CI =(1.15, 1.64)

Population genetics:

Nm = 73000 (Hernandez et al.,2007)

Nh =40,000-70,000 (Wall, 2003)

=> Nm/Nh = 1.04-1.82

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human

macaque

mouse

rat

dog

chimp

Nh

Nc= Nh

Nm

LRT for population size ratios

• Model1: h= c, m

• Model2: h= c, m = c(Nm/Nh) x h

• For 10496 out of 10980 (95.6%) no significant deviation for was observed.

• The differences in selection pressures are well described by differences in differences in population size.

Summary

• The population genetic interpretation of is helpful to

understand differences between selection pressures.

• For human-chimp macaque trios our estimates of population

size ratios agree with estimates from population genetics.

• An LRT shows that differences in selection pressure are well

explained with the differences in population size.

Mammalian (Xmas) Tree

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hu

ma

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mac

aqu

e

mo

us

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do

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chim

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Re-interprete the mammalian tree !

Siepel Labs (Cornell)Adam Siepel, Tomas Vinar, Brona Brejova, Adam

Diehl, Alex Denby

Bustamante Lab (Cornell)Carlos Bustamante, Adam Boyko, Adam Auton,

Badri Padhukasahasram, Abra Brisbin, Kasia Bryc,

Jeremiah Degenhardt, Ryan Hernandez,

Emilia Huerta-Sanchez, Lin Li, Kirk Lohmueller,

Hong Gao, Amit Indap, Dara Torgeson

Rasmus Nielsen (Copenhagen)Tanja Gesell (Vienna)

NIH and NSF for funding

Thanks