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Rates and Fitness Effects of Mutations

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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. - PowerPoint PPT Presentation
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Rates and Fitness Effects of Mutations Adam Eyre-Walker (University of Sussex)
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Page 1: Rates and Fitness Effects of Mutations

Rates and Fitness Effects of Mutations

Adam Eyre-Walker

(University of Sussex)

Page 2: Rates and Fitness Effects of Mutations
Page 3: Rates and Fitness Effects of Mutations
Page 4: Rates and Fitness Effects of Mutations

Types of Mutation

• Deleterious

• Neutral

• Advantageous

0 +ve-ve

Page 5: Rates and Fitness Effects of Mutations

DNA Sequence Data

Neutral(intron)

Selected(exon)

Assume all mutations are neutral or deleterious

fX X X XX X XX

K = 10%10% sites mutated

K = 2%80% mutations deleterious

Page 6: Rates and Fitness Effects of Mutations

Protein Coding Sequences

CCC CTG GGTCCT CTG AGT

Synonymous Non-synonymous

Page 7: Rates and Fitness Effects of Mutations

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

Page 8: Rates and Fitness Effects of Mutations

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

Page 9: Rates and Fitness Effects of Mutations

Underestimation of U

• Excluded mutations in non-genic DNA

• Excluded indels

• Ignored AA adaptive substitution

• U > 2.2

Page 10: Rates and Fitness Effects of Mutations

Estimates of UDiv. time Gen. time U

Human - Chimp 6 25 2.2

OWM - NWM 40 11 0.90

Sheep - Cow 25 6 0.34

Dog - Cat 38 4 0.60

Chicken - Quail 34 2 0.18

Mouse - Rat 30 0.5 0.080

Hawaiian Drosophila 3.7 0.2 0.071

D.mel - D.simulans 2.5 0.1 0.058

D.mel - D.pseudo 35 0.1 0.069

Page 11: Rates and Fitness Effects of Mutations

U versus generation time

0.01

0.1

1

10

0.01 0.1 1 10 100

Generation time (Yrs)

U

Page 12: Rates and Fitness Effects of Mutations

• U ≥ 2.2

• Mutation Load = 89%

Each female must have 18 offspring

How have we survived?

Page 13: Rates and Fitness Effects of Mutations

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).”

Page 14: Rates and Fitness Effects of Mutations

Selection before birth

• Germ-line selection

• Selection before birth– Rate of spontaneous abortion > 50%

Page 15: Rates and Fitness Effects of Mutations

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

Page 16: Rates and Fitness Effects of Mutations

Distribution of Fitness Effects

Page 17: Rates and Fitness Effects of Mutations

Random Genetic Drift

timefr

eque

ncy

Page 18: Rates and Fitness Effects of Mutations

Random Genetic Drift

timefr

eque

ncy

Page 19: Rates and Fitness Effects of Mutations

Prediction

Bigger populations have fewer deleterious mutations segregating than small

populations

Page 20: Rates and Fitness Effects of Mutations

Distribution of Effects

neutraldeleterious low high

Page 21: Rates and Fitness Effects of Mutations

The Model

f Ne-

Page 22: Rates and Fitness Effects of Mutations

Variation in (Effective) Population Size

• Autosomes > X > Y & mitochondria

• Natural selection

• Recombination

Page 23: Rates and Fitness Effects of Mutations

Dataset - humans

• Environmental genome project

• 275 human genes

• 90 individuals resequenced

• 549 non-synonymous polymorphisms

• 15746 intron polymorphisms

Page 24: Rates and Fitness Effects of Mutations

Pn/Pi versus i

Human

-0.5

0.0

0.5

1.0

1.5

2.0

2.5

-0.002 0.002 0.006 0.01 0.014

Page 25: Rates and Fitness Effects of Mutations

Results - human

Nes 01 110 10100 1001000 100010000

% 23 22 37 19 0.1

Shape = 0.28Nes = 240

Page 26: Rates and Fitness Effects of Mutations

Results - human

01 110 10100 1001000 100010000

0.38 0 0 0 0.62

0.23 0.22 0.37 0.19 0.001

0.17 0.33 0.47 0.03 0.000

Shape = 0.28 (0.03, 0.48)

Nes = 240 (90, )

Page 27: Rates and Fitness Effects of Mutations

Dataset - D.melanogaster

44 genes 5-55 alleles sequenced 141 non-synonymous polymorphisms 346 synonymous polymorphisms

Page 28: Rates and Fitness Effects of Mutations

Pn/Ps versus s

D.melanogaster

-0.5

0.0

0.5

1.0

1.5

2.0

2.5

3.0

-0.01 0 0.01 0.02 0.03 0.04 0.05

Page 29: Rates and Fitness Effects of Mutations

Results - drosophila

Shape = 0.46 (0.15, 0.65)Nes = 1000 (400,107)

Page 30: Rates and Fitness Effects of Mutations

Adaptive Mutations

Page 31: Rates and Fitness Effects of Mutations

The Human Genome

Size = 3.4 x 109 nucleotides

Page 32: Rates and Fitness Effects of Mutations

1%

34,000,000 nucleotide differences290,000 amino acid differences

Page 33: Rates and Fitness Effects of Mutations

Random Genetic Drift

Page 34: Rates and Fitness Effects of Mutations

Last Names

Bush

Hussein

Chirac

Blair

Blair

Hussein

Chirac

Blair

Hussein

Hussein

Hussein

Hussein

Page 35: Rates and Fitness Effects of Mutations

1%

34,000,000 nucleotide differences290,000 amino acid differences

Page 36: Rates and Fitness Effects of Mutations

Human1 CCC GCA GAG TTA CTA ATC GAAHuman2 CCG GCA GAG TTA CTA ATC GAAHuman3 CCC GCA AAG TTA CTA ATC GAAHuman4 CCC GCA AAG TTA CTA ATC GAA

Chimp CCC GCC GAG TTA GTA ATT GAA

Poly Sub

Syn 1 2

Non 1 1

Page 37: Rates and Fitness Effects of Mutations

Expectations

Poly Sub

Syn Ps≈4Neu Ds≈2ut

Non Pn≈4Ne u f Dn≈2 ut f + a

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

a=Dn - Ds Ps

Pn

a =1- DnPs

DsPn

Page 38: Rates and Fitness Effects of Mutations

Dataset

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

Page 39: Rates and Fitness Effects of Mutations

Human Nuclear Genes

Poly Sub

Intron 17631 33223

Non 681 765

0.039 0.023

Page 40: Rates and Fitness Effects of Mutations

Low Frequency Polymorphisms

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

low medium high

frequency

proportion

synnon-syn

Page 41: Rates and Fitness Effects of Mutations

Human SNPs ≥ 10%

Poly Sub

Intron 4411 33223

Non 81 765

0.018 0.023

= 0.25 (0.05, 0.42)

Page 42: Rates and Fitness Effects of Mutations

Humans & Chimpanzees

1%290,000 amino acid differences

25% adaptive72,500 adaptive differences

1 every 165 years

Page 43: Rates and Fitness Effects of Mutations

D.simulans & D.yakuba

20%

36,000,000 differences

600,000 aa differences

Page 44: Rates and Fitness Effects of Mutations

Adaptive Evolution in Drosophila

Poly Sub

Syn 707 2489

Non 153 1054 = 33%

constant across genes

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

Page 45: Rates and Fitness Effects of Mutations

D.simulans & D.yakuba

600,000 aa differences

33 % adaptive

200,000 adaptive

1 every 60 years

Page 46: Rates and Fitness Effects of Mutations

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

Page 47: Rates and Fitness Effects of Mutations

Thanks

Peter Keightley Nick Smith

Nicolas Bierne Gwenael Piganeau

Meg Woolfit


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