Download Deleterious Mutations

The Distribution of Fitness
Effects of Mutations in
Humans and Flies
Adam Eyre-Walker
(University of Sussex)
Types of Mutation
• Deleterious
• Neutral
• Advantageous
-ve
0
+ve
Deleterious Mutations
Mutation
accumulation
and
Mutagenesis expts
dn/ds
in
primates
<30%
<10%
1/100
1/10,000
Distribution of Effects
deleterious
neutral
low
high
Theory
Neutral sites (e.g. introns / synonymous)
n- 1
Ps = L s i
1
i
i=1
!
Selected sites (e.g. non-synonymous)
-assume all mutations neutral or deleterious
(1 - e - S (1 - x) )
n
n
Pn = L n i # # D(S)
- S (1 - x - (1 - x) ) 2S2x
x (1 - x) (1 - e )
Simplication
1
f +
b
Ne
Theory
Neutral sites
n- 1
Ps = L s i
1
!i = 1 i
Selected sites
Parameters
n - known
Ln - each gene
Ls- each gene
 - each gene
 - shared
 - shared
n- 1
1
1
Pn . L n i ! i a b
i
i=1
Estimation
assume free recomb
, , 
Bayesian estimation
using MCMC
Dataset - humans
•
•
•
•
•
Environmental genome project
275 human genes
90 individuals resequenced
549 non-synonymous polymorphisms
15746 intron polymorphisms
Pn/Pi versus i
Human
2.5
2.0
Pn/Pi
1.5
1.0
0.5
0.0
-0.5
-0.002
0.002
0.006
0.01
i
0.014
Results - human
Shape = 0.28
Nes = 240
N es
01
110
10100
1001000
100010000
%
23
22
37
19
0.1
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
0
0
0.62
0.23
0.22
0.37
0.19
0.001
0.17
0.33
0.47
0.03
0.000
Low Frequency
Polymorphisms
0.7
0.6
syn
non-syn
proportion
0.5
0.4
0.3
0.2
0.1
0
low
medium
frequency
high
Dataset - D.melanogaster




44 genes
5-55 alleles sequenced
141 non-synonymous polymorphisms
346 synonymous polymorphisms
Pn/Ps versus s
D.melanogaster
3.0
2.5
2.0
1.5
1.0
0.5
0.0
-0.5
-0.01
0
0.01
0.02
0.03
0.04
0.05
Shape = 0.46 (0.15, 0.65)
Adaptive Mutations
Human1
Human2
Human3
Human4
CCC
CCG
CCC
CCC
GCA
GCA
GCA
GCA
GAG
GAG
AAG
AAG
TTA
TTA
TTA
TTA
CTA
CTA
CTA
CTA
Chimp
CCC GCC GAG TTA GTA ATT GAA
Poly
Sub
Syn
1
2
Non
1
1
ATC
ATC
ATC
ATC
GAA
GAA
GAA
GAA
Model
Assume - synonymous mutations are neutral
- amino acid mutations are deleterious, neutral
or advantageous
Poly
Sub
Syn
Ps4Neu
Ds2ut
Non
Pn4Neu f
Dn2ut f + a
P
a = D n - D s Pn
s
D
s Pn
a =1- D P
n
s
Estimation
Parameters
n, Ln, Ls - known without error
 - each gene
 - each gene
 - shared, beta distributed or one per gene
Estimation by ML
Drosophila
35 genes with multiple alleles in D.simulans and
one allele in D.yakuba
Poly
Sub
Syn
707
2489
Non
153
1054
0.22
0.42
Result
 = 0.26 (0.08, 0.41)
Proportion Constant
Model
One 
Beta distributed
One  per gene
Gene
Hsc70
Adh
Est-6
n
106
107
140
Log(L)
-327.5
-327.5
-302.9
Amino Acid Div
0.0023
0.036
0.20
D.simulans & D.yakuba
600,000 aa differences
26 % adaptive
160,000 adaptive
1 every 75 years
Human-Chimp
•
•
•
•
•
Environmental Genome Project
232 human genes
90 individuals resequenced
Non-synonymous versus intron
Human sequence aligned against
chimpanzee genome
Human Nuclear Genes
Poly
Sub
Intron
17631
33223
Non
681
765
0.039
0.023
Low Frequency
Polymorphisms
0.7
0.6
syn
non-syn
proportion
0.5
0.4
0.3
0.2
0.1
0
low
medium
frequency
high
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
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)
Humans & Chimpanzees
1%
290,000 amino acid differences
25% adaptive
72,500 adaptive differences
1 every 165 years
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
Thanks
Gwenael Piganeau
Nick Smith
Meg Woolfit
Nicolas Bierne