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Rates and Fitness Effects of Mutations

Rates and Fitness Effects of Mutations. Adam Eyre-Walker (University of Sussex). -ve. +ve. 0. Types of Mutation. Deleterious Neutral Advantageous. K = 10% 10% sites mutated. K = 2% 80% mutations deleterious. DNA Sequence Data. Assume all mutations are neutral or deleterious.

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Rates and Fitness Effects of Mutations

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

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

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

  4. Protein Coding Sequences CCC CTG GGT CCT CTG AGT Synonymous Non-synonymous

  5. Method • 59 human/chimp genes • Ks - synonymous divergence • Ka - amino acid divergence • Na - proportion of mutations which alter aa (~75%) • M’= KS x Na • U’= M’-Ka Human Chimp

  6. 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

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

  8. Estimates of U

  9. U versus generation time

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

  11. 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).”

  12. Selection before birth • Germ-line selection • Selection before birth • Rate of spontaneous abortion > 50%

  13. 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

  14. Distribution of Fitness Effects

  15. Random Genetic Drift frequency time

  16. Random Genetic Drift frequency time

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

  18. Distribution of Effects deleterious neutral low high

  19. The Model f  Ne-

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

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

  22. Pn/Pi versus i Human

  23. Shape = 0.28 Nes = 240 Results - human

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

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

  26. Pn/Ps versus s D.melanogaster

  27. Shape = 0.46 (0.15, 0.65) Nes = 1000 (400,107) Results - drosophila

  28. Adaptive Mutations

  29. The Human Genome Size = 3.4 x 109 nucleotides

  30. 1% 34,000,000 nucleotide differences 290,000 amino acid differences

  31. Random Genetic Drift

  32. Last Names Hussein Bush Blair Hussein Hussein Blair Blair Hussein Hussein Hussein Chirac Chirac

  33. 1% 34,000,000 nucleotide differences 290,000 amino acid differences

  34. 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

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

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

  37. Human Nuclear Genes

  38. Low Frequency Polymorphisms

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

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

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

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

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

  44. 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

  45. Thanks Peter Keightley Nick Smith Meg Woolfit Nicolas Bierne Gwenael Piganeau

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