Rates and Fitness Effects of Mutations

Adam Eyre-Walker

(University of Sussex)

Types of Mutation

• Deleterious

• Neutral

• Advantageous

0 +ve-ve

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

Protein Coding Sequences

CCC CTG GGTCCT CTG AGT

Synonymous Non-synonymous

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

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

Underestimation of U

• Excluded mutations in non-genic DNA

• Excluded indels

• Ignored AA adaptive substitution

• U > 2.2

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

U versus generation time

0.01

0.1

1

10

0.01 0.1 1 10 100

Generation time (Yrs)

U

• U ≥ 2.2

• Mutation Load = 89%

Each female must have 18 offspring

How have we survived?

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).”

Selection before birth

• Germ-line selection

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

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

Distribution of Fitness Effects

Random Genetic Drift

timefr

eque

ncy

Random Genetic Drift

timefr

eque

ncy

Prediction

Bigger populations have fewer deleterious mutations segregating than small

populations

Distribution of Effects

neutraldeleterious low high

The Model

f Ne-

Variation in (Effective) Population Size

• Autosomes > X > Y & mitochondria

• Natural selection

• Recombination

Dataset - humans

• Environmental genome project

• 275 human genes

• 90 individuals resequenced

• 549 non-synonymous polymorphisms

• 15746 intron polymorphisms

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

Results - human

Nes 01 110 10100 1001000 100010000

% 23 22 37 19 0.1

Shape = 0.28Nes = 240

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, )

Dataset - D.melanogaster

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

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

Results - drosophila

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

Adaptive Mutations

The Human Genome

Size = 3.4 x 109 nucleotides

1%

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

Random Genetic Drift

Last Names

Bush

Hussein

Chirac

Blair

Blair

Hussein

Chirac

Blair

Hussein

Hussein

Hussein

Hussein

1%

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

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

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

Dataset

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

Human Nuclear Genes

Poly Sub

Intron 17631 33223

Non 681 765

0.039 0.023

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

Human SNPs ≥ 10%

Poly Sub

Intron 4411 33223

Non 81 765

0.018 0.023

= 0.25 (0.05, 0.42)

Humans & Chimpanzees

1%290,000 amino acid differences

25% adaptive72,500 adaptive differences

1 every 165 years

D.simulans & D.yakuba

20%

36,000,000 differences

600,000 aa differences

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

D.simulans & D.yakuba

600,000 aa differences

33 % adaptive

200,000 adaptive

1 every 60 years

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

Thanks

Peter Keightley Nick Smith

Nicolas Bierne Gwenael Piganeau

Meg Woolfit