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The influence of population size on patterns of natural selection in mammals. Carolin Kosiol < [email protected] > Cornell University 21 st December 2007 Isaac Newton Institute. 0.05. human. chimp. macaque. mouse. rat. dog. Six Mammalian Genomes. - PowerPoint PPT Presentation
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The influence of population size on patterns of natural selection
in mammals
Carolin Kosiol <[email protected]>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
0.05
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
0.05
human
macaque
mouse
rat
dog
chimp0.
05
hu
ma
n
mac
aqu
e
mo
us
e
rat
do
g
chim
p
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