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The Distribution of Fitness Effects of Mutations in Humans and Flies

The Distribution of Fitness Effects of Mutations in Humans and Flies. Adam Eyre-Walker (University of Sussex). -ve. +ve. 0. Types of Mutation. Deleterious Neutral Advantageous. Deleterious Mutations. Mutation accumulation and Mutagenesis expts. d n /d s in primates. <30%. <10%.

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The Distribution of Fitness Effects of Mutations in Humans and Flies

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  1. The Distribution of Fitness Effects of Mutations in Humans and Flies Adam Eyre-Walker (University of Sussex)

  2. -ve +ve 0 Types of Mutation • Deleterious • Neutral • Advantageous

  3. Deleterious Mutations Mutation accumulation and Mutagenesis expts dn/ds in primates <30% <10% 1/100 1/10,000

  4. Distribution of Effects deleterious neutral low high

  5. Theory Neutral sites (e.g. introns / synonymous) Selected sites (e.g. non-synonymous) -assume all mutations neutral or deleterious

  6. Simplication

  7. Theory Neutral sites Parameters n - known Ln - each gene Ls- each gene  - each gene  - shared  - shared Estimation assume free recomb , ,  Bayesian estimation using MCMC Selected sites

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

  9. Pn/Pi versus i Human Pn/Pi i

  10. Shape = 0.28 Nes = 240 Results - human

  11. Shape = 0.28 (0.03, 0.48) Nes = 240 (90, ) Results - human

  12. Low Frequency Polymorphisms

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

  14. Pn/Ps versus s D.melanogaster Shape = 0.46 (0.15, 0.65)

  15. Adaptive Mutations

  16. Human1 CCC GCA GAG TTA CTA ATC GAA Human2 CCGGCA 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

  17. Model Assume - synonymous mutations are neutral - amino acid mutations are deleterious, neutral or advantageous

  18. Estimation Parameters n, Ln, Ls - known without error  - each gene  - each gene  - shared, beta distributed or one per gene Estimation by ML

  19. Drosophila 35 genes with multiple alleles in D.simulans and one allele in D.yakuba

  20. Result  = 0.26 (0.08, 0.41)

  21. Proportion Constant

  22. D.simulans & D.yakuba 600,000 aa differences 26 % adaptive 160,000 adaptive 1 every 75 years

  23. Human-Chimp • Environmental Genome Project • 232 human genes • 90 individuals resequenced • Non-synonymous versus intron • Human sequence aligned against chimpanzee genome

  24. Human Nuclear Genes

  25. Low Frequency Polymorphisms

  26. Dealing With Deleterious Mutations • Use estimate of distribution of fitness effects from SNP data • Assume adaptive and slightly deleterious mutations governed by one distribution • Ignore low frequency variants

  27. Excluding SNPs

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

  29. Conclusions • Distribution of fitness effects of slightly/moderately deleterious mutations is highly leptokurtic in humans and drosophila • ~25% of amino acid substitutions are driven by positive selection in humans and drosophila • Proportion does not vary between genes

  30. Thanks Gwenael Piganeau Nick Smith Meg Woolfit Nicolas Bierne

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