The%20Distribution%20of%20Fitness%20Effects%20of%20Mutations%20in%20Humans%20and%20Flies

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The Distribution of Fitness Effects of Mutations
in Humans and Flies

• Adam Eyre-Walker
• (University of Sussex)

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Types of Mutation

• Deleterious
• Neutral
• Advantageous

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Deleterious Mutations
Mutation accumulation and Mutagenesis expts
dn/ds in primates
lt30
lt10
1/100
1/10,000
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Distribution of Effects
neutral
deleterious
low
high
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Theory
Neutral sites (e.g. introns / synonymous)
Selected sites (e.g. non-synonymous) -assume all
mutations neutral or deleterious
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Simplication
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Theory
Neutral sites
Parameters n - known Ln - each gene Ls- each
gene ? - each gene ? - shared ? -
shared Estimation assume free recomb ?, ?,
? Bayesian estimation using MCMC
Selected sites
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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
Pn/Pi
?i
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Results - human
Nes 0?1 1?10 10?100 100?1000 1000?10000
23 22 37 19 0.1
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Results - human
0?1 1?10 10?100 100?1000 1000?10000
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
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Low Frequency Polymorphisms
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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
Shape 0.46 (0.15, 0.65)
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Adaptive Mutations
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Human1 CCC GCA GAG TTA CTA ATC GAA Human2 CCG GCA
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
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Model
Assume - synonymous mutations are neutral -
amino acid mutations are deleterious, neutral
or advantageous
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Estimation
Parameters n, Ln, Ls - known without error ? -
each gene ? - each gene ? - shared, beta
distributed or one per gene Estimation by ML
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Drosophila
35 genes with multiple alleles in D.simulans and
one allele in D.yakuba
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Result
? 0.26 (0.08, 0.41)
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Proportion Constant
Model n Log(L)
One ? 106 -327.5
Beta distributed 107 -327.5
One ? per gene 140 -302.9
Gene Amino Acid Div
Hsc70 0.0023
Adh 0.036
Est-6 0.20
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D.simulans D.yakuba
600,000 aa differences 26 adaptive 160,000
adaptive 1 every 75 years
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Human-Chimp

• Environmental Genome Project
• 232 human genes
• 90 individuals resequenced
• Non-synonymous versus intron
• Human sequence aligned against chimpanzee genome

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Human Nuclear Genes
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Low Frequency Polymorphisms
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Dealing With Deleterious Mutations

• Use estimate of distribution of fitness effects
  from SNP data
• Assume adaptive and slightly deleterious
  mutations governed by one distribution
• Ignore low frequency variants

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Excluding SNPs
Cutoff ML 95 CI
0 -0.62
5 0.09 (-0.11, 0.26)
10 0.26 (0.08, 0.41)
20 0.31 (0.11, 0.52)
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Humans Chimpanzees
1 290,000 amino acid differences 25
adaptive 72,500 adaptive differences 1 every 165
years
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Conclusions

• Distribution of fitness effects of
  slightly/moderately deleterious mutations is
  highly leptokurtic in humans and drosophila
• 25 of amino acid substitutions are driven by
  positive selection in humans and drosophila
• Proportion does not vary between genes

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Thanks
Gwenael Piganeau
Nick Smith
Meg Woolfit
Nicolas Bierne