Rates%20and%20Fitness%20Effects%20of%20Mutations

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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

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DNA Sequence Data
Assume all mutations are neutral or deleterious
Selected (exon)
Neutral (intron)
?
? f
X
X
X
X
X
X
X
X
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Protein Coding Sequences
CCC CTG GGT CCT 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 gt 2.2

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Estimates of U
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U versus generation time
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How have we survived?

• U 2.2
• Mutation Load 89
• ? Each female must have 18 offspring

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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 gt 50

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Dominance Epistasis

• Synergistic epistasis
• One mutation reduces fitness by 5
• Two mutations reduce fitness by
• 10 with multiplicative selection
• gt10 with synergistic epistasis
• Inbreeding and recessive mutations
• Sexual selection

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Distribution of Fitness Effects
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Random Genetic Drift
frequency
time
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Random Genetic Drift
frequency
time
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Prediction

• Bigger populations have fewer deleterious
  mutations segregating than small populations

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Distribution of Effects
neutral
deleterious
low
high
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The Model
f ? Ne-?
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Variation in (Effective) Population Size

• Autosomes gt X gt 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
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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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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
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Results - drosophila
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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 differences 290,000
amino acid differences
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Random Genetic Drift
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Last Names
Hussein
Bush
Blair
Hussein
Hussein
Blair
Blair
Hussein
Hussein
Hussein
Chirac
Chirac
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1 34,000,000 nucleotide differences 290,000
amino acid differences
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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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Expectations
Assume - synonymous mutations are neutral -
amino acid mutations are deleterious, neutral
or advantageous
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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
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Low Frequency Polymorphisms
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Human SNPs 10
? 0.25 (0.05, 0.42)
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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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D.simulans D.yakuba
20 36,000,000 differences 600,000 aa
differences
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Adaptive Evolution in Drosophila
35 genes with multiple alleles in D.simulans and
one allele in D.yakuba

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• constant across genes

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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 gt 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
Meg Woolfit
Nicolas Bierne
Gwenael Piganeau