1. Rates and Fitness Effects of Mutations Adam Eyre-Walker (University of Sussex)

4. Types of Mutation Deleterious Neutral Advantageous 0 +ve-ve

5. DNA Sequence Data Neutral (intron) Selected (exon) Assume all mutations are neutral or deleterious   f XXXXX XX X K = 10% 10% sites mutated K = 2% 80% mutations deleterious

6. Protein Coding Sequences CCC CTG GGT CCT CTG AGT SynonymousNon-synonymous

7. Method 59 human/chimp genes K s - synonymous divergence K a - amino acid divergence N a - proportion of mutations which alter aa (~75%) M’= K S x N a U’= M’- K a Human Chimp

8. Per site to per genome Length of genes - 1340 bp Number of genes - 30,000 genes Divergence time - 6 MYR Generation time - 25 years M = 3.1 U = 2.2

9. Underestimation of U Excluded mutations in non-genic DNA Excluded indels Ignored AA adaptive substitution U > 2.2

10. Estimates of U

11. U versus generation time

12. U ≥ 2.2 Mutation Load = 89%  Each female must have 18 offspring How have we survived?

13. Evolution does not occur http://www.evolutionfairytale.com/ Monkey-Man Hypothesis Thwarted by Mutation Rates “The high mutation rate from the Eyre-Walker & Keightley study was determined under the assumption of common ancestry between chimps and man. Since the rate is clearly too high, there are clearly only two realistic explanations: 1) there is a mistake in their data or analysis (doubtful), or 2) the base assumption that man and chimp share a common ancestor is flawed (most likely).”

14. Selection before birth Germ-line selection Selection before birth –Rate of spontaneous abortion > 50%

15. Dominance & Epistasis Synergistic epistasis –One mutation reduces fitness by 5% –Two mutations reduce fitness by ~10% with multiplicative selection >10% with synergistic epistasis Inbreeding and recessive mutations Sexual selection

16. Distribution of Fitness Effects

17. Random Genetic Drift time frequency

18. Random Genetic Drift time frequency

19. Prediction Bigger populations have fewer deleterious mutations segregating than small populations

20. Distribution of Effects neutraldeleteriouslowhigh

21. The Model f  N e - 

22. Variation in (Effective) Population Size Autosomes > X > Y & mitochondria Natural selection Recombination

23. Dataset - humans Environmental genome project 275 human genes 90 individuals resequenced 549 non-synonymous polymorphisms 15746 intron polymorphisms

24. P n /P i versus  i Human

25. Results - human NesNes 01011  1010  100100  10001000  10000 %232237190.1 Shape = 0.28 N e s = 240

26. Results - human 01011  1010  100100  10001000  10000 0.380000.62 0.230.220.370.190.001 0.170.330.470.030.000 Shape = 0.28 (0.03, 0.48) N e s = 240 (90,  )

27. Dataset - D.melanogaster  44 genes  5-55 alleles sequenced  141 non-synonymous polymorphisms  346 synonymous polymorphisms

28. P n /P s versus  s D.melanogaster

29. Results - drosophila Shape = 0.46 (0.15, 0.65) N e s = 1000 (400,10 7 )

30. Adaptive Mutations

31. The Human Genome Size = 3.4 x 10 9 nucleotides

32. 1% 34,000,000 nucleotide differences 290,000 amino acid differences

33. Random Genetic Drift

34. Last Names Bush Hussein Chirac Blair Hussein Chirac Blair Hussein

35. 1% 34,000,000 nucleotide differences 290,000 amino acid differences

36. Human1 CCC GCA GAG TTA CTA ATC GAA Human2 CCG GCA GAG TTA CTA ATC GAA Human3 CCC GCA AAG TTA CTA ATC GAA Human4 CCC GCA AAG TTA CTA ATC GAA Chimp CCC GCC GAG TTA GTA ATT GAA

37. Expectations Assume - synonymous mutations are neutral - amino acid mutations are deleterious, neutral or advantageous

38. Dataset Environmental Genome Project 232 human genes 90 individuals resequenced Non-synonymous versus intron

39. Human Nuclear Genes

40. Low Frequency Polymorphisms

41. Human SNPs ≥ 10%  = 0.25 (0.05, 0.42)

42. Humans & Chimpanzees 1% 290,000 amino acid differences 25% adaptive 72,500 adaptive differences 1 every 165 years

43. D.simulans & D.yakuba 20% 36,000,000 differences 600,000 aa differences

44. Adaptive Evolution in Drosophila  = 33%  constant across genes 35 genes with multiple alleles in D.simulans and one allele in D.yakuba

45. D.simulans & D.yakuba 600,000 aa differences 33 % adaptive 200,000 adaptive 1 every 60 years

46. Summary Deleterious mutation in hominids > 2 Deleterious mutations leptokurtically distributed in humans and drosophilids 25% of amino acid substitutions between humans and chimps are adaptive 33% of amino acid substitutions in drosophilids are adaptive

47. Thanks Peter KeightleyNick Smith Nicolas BierneGwenael Piganeau Meg Woolfit