rates and fitness effects of mutations
DESCRIPTION
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 PresentationTRANSCRIPT
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Rates and Fitness Effects of Mutations
Adam Eyre-Walker
(University of Sussex)
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Types of Mutation
• Deleterious
• Neutral
• Advantageous
0 +ve-ve
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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
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Protein Coding Sequences
CCC CTG GGTCCT CTG AGT
Synonymous Non-synonymous
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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
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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
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Underestimation of U
• Excluded mutations in non-genic DNA
• Excluded indels
• Ignored AA adaptive substitution
• U > 2.2
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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
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U versus generation time
0.01
0.1
1
10
0.01 0.1 1 10 100
Generation time (Yrs)
U
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• U ≥ 2.2
• Mutation Load = 89%
Each female must have 18 offspring
How have we survived?
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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).”
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Selection before birth
• Germ-line selection
• Selection before birth– Rate of spontaneous abortion > 50%
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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
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Distribution of Fitness Effects
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Random Genetic Drift
timefr
eque
ncy
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Random Genetic Drift
timefr
eque
ncy
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Prediction
Bigger populations have fewer deleterious mutations segregating than small
populations
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Distribution of Effects
neutraldeleterious low high
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The Model
f Ne-
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Variation in (Effective) Population Size
• Autosomes > X > Y & mitochondria
• Natural selection
• Recombination
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Dataset - humans
• Environmental genome project
• 275 human genes
• 90 individuals resequenced
• 549 non-synonymous polymorphisms
• 15746 intron polymorphisms
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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
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Results - human
Nes 01 110 10100 1001000 100010000
% 23 22 37 19 0.1
Shape = 0.28Nes = 240
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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, )
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Dataset - D.melanogaster
44 genes 5-55 alleles sequenced 141 non-synonymous polymorphisms 346 synonymous polymorphisms
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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
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Results - drosophila
Shape = 0.46 (0.15, 0.65)Nes = 1000 (400,107)
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Adaptive Mutations
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The Human Genome
Size = 3.4 x 109 nucleotides
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1%
34,000,000 nucleotide differences290,000 amino acid differences
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Random Genetic Drift
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Last Names
Bush
Hussein
Chirac
Blair
Blair
Hussein
Chirac
Blair
Hussein
Hussein
Hussein
Hussein
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1%
34,000,000 nucleotide differences290,000 amino acid differences
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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
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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
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Dataset
• Environmental Genome Project• 232 human genes• 90 individuals resequenced• Non-synonymous versus intron
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Human Nuclear Genes
Poly Sub
Intron 17631 33223
Non 681 765
0.039 0.023
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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
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Human SNPs ≥ 10%
Poly Sub
Intron 4411 33223
Non 81 765
0.018 0.023
= 0.25 (0.05, 0.42)
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Humans & Chimpanzees
1%290,000 amino acid differences
25% adaptive72,500 adaptive differences
1 every 165 years
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D.simulans & D.yakuba
20%
36,000,000 differences
600,000 aa differences
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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
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D.simulans & D.yakuba
600,000 aa differences
33 % adaptive
200,000 adaptive
1 every 60 years
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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
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Thanks
Peter Keightley Nick Smith
Nicolas Bierne Gwenael Piganeau
Meg Woolfit