1. The influence of population size on patterns of natural selection in mammals Carolin Kosiol kosiol@cornell.edu Cornell University 21 st December 2007 Isaac Newton Institute

2. 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

3. aggregated models ATT CTT CCT CCG I L P P Leu 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

4. 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

5. Per gene analysis Frequency Nonsynonymous-synonymous rate ratio  P-value: 2.2x10 -16

6. 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.

7. 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  primate branch rodent branch human macaque chimp PSG: 400/16529PSG: 24/14425 PSG: 21/9566 PSG: 10/14558PSG: 18/14558PSG: 16/12499 PSG: 61/10762 PSG: 56/8991 primate clade rodent clade PSG: 7/10980 hominid

8. Bayesian Model selection

9. 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

10. 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

11. Rates of mutations The 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

12. ‘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

13. 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

14. Comparison to estimates from polymorphism data Estimation from 10980 genes: N m /N h = 1.40 95% CI =(1.15, 1.64) Population genetics: N m = 73000 (Hernandez et al.,2007) N h =40,000-70,000 (Wall, 2003) => N m /N h = 1.04-1.82 0.05 human macaque mouse rat dog chimp NhNh N c = N h NmNm

15. LRT for population size ratios Model1:  h =  c,  m Model2:  h =  c,  m = c(N m /N h ) 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.

16. 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.

17. Mammalian (Xmas) Tree 0.05 human macaque mouse rat dog chimp 0.05 human macaque mouse rat dog chimp Re-interprete the mammalian tree !

18. 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