1. The Distribution of Fitness Effects of Mutations in Humans and Flies
Adam Eyre-Walker
(University of Sussex)

2. Types of Mutation
Deleterious
Neutral
Advantageous
+ve
-ve

3. Deleterious Mutations
accumulation
and
Mutagenesis expts
dn/ds in
primates
<30%
<10%
1/100
1/10,000

4. Distribution of Effects
deleterious
neutral
low
high

5. Neutral sites (e.g. introns / synonymous)
Theory
Neutral sites (e.g. introns / synonymous)
Selected sites (e.g. non-synonymous)
-assume all mutations neutral or deleterious

6. Simplication

7. Theory Neutral sites Parameters n - known Ln - each gene Ls- each gene
 - shared
 - shared
Estimation
assume free recomb
, , 
Bayesian estimation
using MCMC
Selected sites

8. Dataset - humans Environmental genome project 275 human genes
90 individuals resequenced
549 non-synonymous polymorphisms
15746 intron polymorphisms

9. Pn/Pi versus i
Human
Pn/Pi i

10. Results - human Shape = 0.28 Nes = 240 Nes 01 110 10100 1001000
100010000 % 23 22 37 19
0.1

11. Results - human Shape = 0.28 (0.03, 0.48) Nes = 240 (90, ) 01 110
10100
1001000
100010000
0.38
0.62
0.23
0.22
0.37
0.19
0.001
0.17
0.33
0.47
0.03
0.000

12. Low Frequency Polymorphisms
Cargill snps

13. Dataset - D.melanogaster
44 genes
5-55 alleles sequenced
141 non-synonymous polymorphisms
346 synonymous polymorphisms

14. Pn/Ps versus s
D.melanogaster
Shape = 0.46 (0.15, 0.65)

15. Adaptive Mutations

16. 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

17. Model Assume - synonymous mutations are neutral
- amino acid mutations are deleterious, neutral
or advantageous

18. Estimation Parameters n, Ln, Ls - known without error  - each gene
 - shared, beta distributed or one per gene
Estimation by ML

19. Drosophila
35 genes with multiple alleles in D.simulans and one allele in D.yakuba

20. Result
 = 0.26 (0.08, 0.41)

21. Proportion Constant Model n Log(L) One  106 -327.5 Beta distributed
107
One  per gene
140
-302.9
Amino acid divergence in terms of aa subs per codon
Gene
Amino Acid Div
Hsc70
0.0023
Adh
0.036
Est-6
0.20

22. D.simulans & D.yakuba 600,000 aa differences 26 % adaptive
1 every 75 years

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

24. Human Nuclear Genes

25. Low Frequency Polymorphisms
Cargill snps

26. 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

27. Excluding SNPs Cutoff ML 95% CI 0% -0.62 5% 0.09 (-0.11, 0.26) 10%
(0.08, 0.41)
20%
0.31
(0.11, 0.52)

28. 290,000 amino acid differences
Humans & Chimpanzees 1%
290,000 amino acid differences
25% adaptive
72,500 adaptive differences
1 every 165 years

29. 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

30. Thanks
Gwenael Piganeau
Nick Smith
Meg Woolfit
Nicolas Bierne