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 100Generation time (Yrs)
U
• U ≥ 2.2• Mutation Load = 89%
Each female must have 18 offspring
How have we survived?
Evolution does not occurhttp://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
timefre
quen
cy
Random Genetic Drift
timefre
quen
cy
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 D s≈2ut
Non Pn≈4Neu f D n≈2ut 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 highfrequency
proportion
synnon-syn
Human SNPs ≥ 10%
Poly Sub
Intron 4411 33223
Non 81 765
0.018 0.023
a = 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 a = 33%
a 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