Analyse comparative des génomes de primates: mais où est donc passée la sélection naturelle ?
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Analyse comparative des génomes de primates: mais où est donc passée la sélection naturelle ?
Laurent Duret, Nicolas Galtier, Peter Arndt
ACI-IMPBIO 4-5 octobre 2007
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What’s in our genome ?
• 3.1 109 bp• Repeated sequences: ~50%
• 20,000-25,000 protein-coding genes• Protein-coding regions : 1.2%
• Other functional elements in non-coding regions: 4-10%
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How to identify functional elements ?
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What make chimps different from us ?
• What are the functional elements responsible for adaptative evolution ?
30 106 point substitutions + indels + duplications (copy number variations)
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Genome annotation by comparative genomics
• Basic principle :– Functional element <=> constrained by natural
selection– Detecting the hallmarks of selection in genomic
sequences• Negative selection (conservation)
• Positive selection (adaptation)
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Evolution : mutation, selection, drift
Base modification,replication error, deletion,
insertion, ... = premutation
Mutation
DNA repair
germline
transmission to the offspring(polymorphism) Loss of the allele
Individual
Population (N)
Fixation
Su
bst
itu
tion
no transmission to the offspring
soma
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Evolution : mutation, selection, drift
Probability of fixation:
p = f(s, Ne)
s : relative impact on fitness s = 0 : neutral mutation (random genetic drift) s < 0 : disadvantageous mutation = negative (purifying) selection s > 0 : advantageous mutation = positive(directional) selection
Ne : effective population size: stochastic effects of gamete sampling are stronger in small populations
|Nes| < 1 : effectively neutral mutation
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Demonstrate the action of selection = reject the predictions of the neutral model
Base modification,replication error,
deletion, insertion, etc.
Mutation
Polymorphism
Individual
Population (Ne)Fixation
Su
bst
itu
tion
Substitution rate =
f(mutation rate, fixation probability)
|Nes| < 1 : substitution rate = mutation rate
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Tracking natural selection ...
• Mutation rate: u
• Substitution rate: K
• Negative selection => K < u
• Neutral evolution => K = u
• Positive selection => K > u
How to estimate u ? => Use of neutral markers
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Tracking natural selection ...• Synonymous substitution rate: Ks• Non-synonymous substitution rate: Ka
• Hypothesis: synonymous sites evolve (nearly) neutraly Ks ~ u
• Negative selection => Ka < Ks • Neutral evolution => Ka = Ks • Positive selection => Ka > Ks
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Tracking natural selection ... is not so easy
• Patterns of neutral substitution vary along chromosomes
– Impact of molecular processes (replication, DNA-repair, transcription, recombination, …)
– Genomic environment (susceptibility to mutagens)
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Mammalian genomic landscapes
• Large scale variations of base composition along chromosomes (isochores)
30
40
50
60
GC
%
0 200 400 600 800 1000kb
100 kb
Sliding windows : 20 kb, step = 2 kb
chromosome 19
chromosome 21
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GC content variations affect both coding and non-coding regions
10%30%50%70%90%30%40%50%60%G+C% 3rd codon positionN=3661 genes
R2 = 0.43
DNA fragment G+C content
3661 human genes from 1652 large genomic sequences (> 50 kb; average = 134 kb). Total = 221 Mb (98% non-coding)
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What is the evolutionary process responsible for these large-scale
variations in base composition ?
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Variation in mutation patterns ?
• Analysis of polymorphism data: in GC-rich regions, AT->GC mutations have a higher probability of fixation than GC->AT mutations (Eyre-Walker 1999; Duret et al. 2002; Spencer et al. 2006)
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Selection ?
• What could be the selective advantage confered by a single AT->GC mutations in a Mb-long genomic region ???
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Biased Gene Conversion ?
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Biased Gene Conversion (BGC)
If DNA mismatch repair is biased (i.e. probability of repair is not 50% in favor of each base) => BGC
Non-crossover Crossover
Molecular events of meiotic recombination
Heteroduplex DNA
T
G DNA mismatch repair
T
A
C
G
(G->A) (T->C)
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BGC: a neutral process that looks like selection
• The dynamics of the fixation process for one locus under BGC is identical to that under directional selection (Nagylaki 1983)
• BGC intensity depends on:– Recombination rate– Bias in the repair of DNA mismatches– Effective population size
• GC-alleles have a higher probability of fixation than AT-alleles (Eyre-Walker 1999, Duret et al. 2002, Lercher et al. 2002, Spencer et al. 2006)
• This fixation bias in favor of GC-alleles increases with recombination rate (Spencer 2006)
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Does BGC affect substitution patterns ?
• BGC should affect the relative rates of AT->GC vs GC->AT substitutions in regions of high recombination
• Relationship between neutral substitution patterns and recombinaion rate ?
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Substitution patterns in the hominidae lineage
• Human, chimp, macaca whole genome alignments:– Genomicro: database of whole genome alignments– 2700 Mb (introns and intergenic regions)
• Substitutions infered by maximum likelihood approach (collaboration with Peter Arndt, Berlin)
• Substitution rates:– 4 transversion rates: A->T; C->G; A->C; C->A– 2 transition rates: A->G; G->A– transitions at CpG sites: G->A
• Cross-over rate: HAPMAP
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GC-content expected at equilibrium (GC*)
• Equilibrium GC-content : the GC content that sequences would reach if the pattern of substitution remains constant over time = the future of GC-content
• Ratio of ATGC over GCAT substitution rates (taking into account CpG hypermutability)
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GC-content expected at equilibrium and recombination
30%
40%
50%
60%
0 1 2 3 4 5 6 7 8 9
R2 = 36%p < 0.0001
Cross-Over Rate (cM/Mb)
EquilibriumGC-contentGC*
N = 2707 non-overlapping windows (1 Mb), from autosomes
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GC-content and Recombination
• Strong correlation: suggests direct causal relationship
• GC-rich sequences promote recombination ? – Gerton et al. (2000), Petes & Merker (2002), Spencer et al. (2006)
• Recombination promotes ATGC substitutions ?
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GC-content and recombination
N = 2707R2 = 14%p < 0.001
Cross-Over Rate (cM/Mb)
Present GC- content
40%
50%
60%
70%
0 1 2 3 4 5 6 7 8 9
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GC-content expected at equilibrium and recombination
30%
40%
50%
60%
0 1 2 3 4 5 6 7 8 9
R2 = 36%p < 0.0001
Cross-Over Rate (cM/Mb)
EquilibriumGC-contentGC*
N = 2707 non-overlapping windows (1 Mb), from autosomes
QuickTime™ et undécompresseur TIFF (LZW)
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Recombination and GC-content
• Recombination events: crossover + non-crossover
• Genetic maps: crossover
Non-crossover Crossover
Molecular events of meiotic recombination
=> The correlation between GC* and crossover rate might underestimate the real correlation between GC* and recombination
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Evolution of GC-content: distance to telomeres
0.30
0.40
0.50
0.60
0.1 1 10 100
Distance to Telomere (Mb)
N = 2707R2 = 41%p < 0.0001
EquilibriumGC-contentGC*
GC* vs. crossover rate + distance telomeres: R2 = 53%
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BGC: a realistic model ?
• Recombination occurs predominantly in hotspots that cover only 3% of the genome (Myers et al 2005)
• Recombination hotspots evolve rapidly (their location is not conserved between human and chimp) (Ptak et al. 2005, Winkler et al. 2005)
Can BGC affect the evolution of Mb-long isochores ?
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BGC: a realistic model ?
• Probability of fixation of a AT-allele
• Probability of fixation of a GC-allele
• Effective population size N ~ 10,000• s : BGC coefficient
– Recombination hotspots: s = 1.3 10-4 (Spencer et al. 2006)
– No BGC outside hotspots: s = 0
• Hotspots density: 3% (in average), variations along chromosomes (0.05% to 10.7% )
• Pattern of mutation: constant across chromosomes
€
p =1− e−2s
1− e−4Ns
€
q =1− e2s
1− e4Ns
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BGC: a realistic model ?
Crossover rate (cM/Mb)
EquilibriumGC-contentGC*
Observations Predictions of the BGC model
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Summary (1)• Recombination :
– Strong impact on patterns of substitutions– drives the evolution of GC-content
• Most probably an consequence of BGC– Mutation: ! fixation bias favoring GC alleles !– Selection: ! correlation with recombination rate !– BGC: all observations fit the predictions of the
model
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BGC can affect functional regions
• Fxy gene : translocated in the pseudoautosomal region (PAR) of the X chromosome in Mus musculus
X specific PAR
Recombination rate normal extreme
GC synonymous sites normal very high (55%) (90%)
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Amino-acid substitutions in Fxy
Homo Rattus M. spretus M. musculus
Y
X
PAR
Y
X
PAR
0
20
80
40
60
Tim
e (M
yrs) 5’ part of Fxy : 4
2 1
0 1 0 28
3’ part of Fxy : 5
1 0
3 1
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Amino-acid substitutions in Fxy
Homo Rattus M. spretus M. musculus
0
20
80
40
60
Tim
e (M
yrs) 5’ part of Fxy : 4
2 1
0 1 0 28
3’ part of Fxy : 5
1 0
3 1
28 non-synonymous substitutions, all ATGCNB: strong negative selection (Ka/Ks < 0.1)
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Amino-acid substitutions in Fxy
BGC can drive the fixation of deleterious mutations
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BGC: a neutral process that looks like selection
• BGC can confound selection tests
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HARs: human-accelerated regions
• Pollard et al. (Nature, Plos Genet. 2006) : searching for positive selection in non-coding regulatory elements
• Identify regulatory elements that have significantly accelerated in the human lineage = HARs
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Positive selection in the human lineage ?
• 49 significant HARs• HAR1: 120 bp
– Rate of evolution >> neutral rate (18 fixed substitutions in the human lineage, vs. 0.7 expected)
– Part of a non-coding RNA gene– Expressed in the brain– Involved in the evolution of human-specific brain
features ?
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Positive selection ?
• GC-biased substitution pattern in HARs– HAR1: the 18 substitutions are all ATGC changes
– Known functional elements (coding or non-coding) are not GC-rich
• HAR1-5: no evidence of selective sweep (Pollard et al. 2006)
• HAR1: the accelerated region covers >1 kb, i.e. is not restricted to the functional element
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Positive selection or BGC ?
• HARs are located in regions of high recombination
• Recombination occurs in hotspots (<2 kb)
• Given known parameters (population size, fixation bias), the BGC model predicts substitution hotspots within recombination hotspots
HARs = substitution hotspots caused by BGC in recombination hotspots
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Conclusion (1)
GC-rich isochores = result of BGC in highly recombining parts of the genome
Recombination drives the evolution of GC-content in mammals
Probably a universal process: correlation GC / recombination in many
taxa (yeast, drosophila, nematode, paramecia, …)
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Conclusion (2)
Recombination hotspots = the Achilles’ heel of our genome
BGC => substitution hotspots in recombination hotspots
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Conclusion (3)Probability of fixation depends on:
- selection- drift (population size)- BGC
Extending the null hypothesis of neutral evolution: mutation + BGC
Galtier & Duret (2007) Trends Genet
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Thanks
• Vincent Lombard (Génomicro)• Nicolas Galtier (Montpellier)• Peter Arndt (Berlin)
• Katherine Pollard (UC Davis)
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Sex-specific effects
• Correlation GC* / crossover rate (deCODE genetic map):– male: R2 = 31% – female: R2 = 15%
• The rate of cross-over is a poor predictor of the total recombination rate in female: more variability in the ratio non-crossover / crossover along chromosomes ?
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Chromosome length (Mb) Crossover rate (cM/Mb)
GC
*
Crossover rate (cM/Mb)
R2=0.84 R2=0.66
Cro
ssov
er r
ate
(cM
/Mb)
R2=0.82 R2=0.81
Human Human
Chicken Chicken
Cro
ssov
er r
ate
(cM
/Mb)
Cur
rent
GC
Chromosome length (Mb)
Chromosome size, recombination and GC-content
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Recombination and GC-content: a universal relationship ?
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G+C content vs. chromosome length: yeast
R2= 61%
Bradnam et al. (1999) Mol Biol Evol
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G+C content vs. chromosome length: Paramecium
GC-content
Chromosome size (kb)
R2= 67%
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Evolution of GC-content
• Equilibrium GC-content correlates with ...– Cross-over rate (HAPMAP): R2 = 36% – Distance to telomere: R2 = 41%
– Cross-over rate + distance telomeres: R2 = 53%
• Recombination pattern: ratio non-crossover / crossover higher near telomeres ?
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Frequency distribution of GC and AT alleles
<5% 5%-15% 15%-50% >50%0
0.2
0.4
0.6
allele frequency
proportionof SNPs
GC ATGC
Distribution expected in absence of fixation bias
NB: the shape of the distribution may vary according
to population history, but should be identical for GC and AT alleles
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Frequency distribution of AT and GC alleles at
silent sites• 410 SNPs with allele
frequency (Cargill et al 1999)
• Chimpanzee as an outgroup to orientate mutations
• GC alleles segregate at significantly higher frequencies than AT alleles in GC-median and GC-rich genes
<5%5%-15%15%-50%>50%00.20.40.6<5%5%-15%15%-50%>50%00.20.40.6<5%5%-15%15%-50%>50%00.20.4GC-poor genesGC-median genesGC-rich genes allele frequencyproportion of SNP's GC→ AT→ GC
Duret et al. 2002
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Frequency distribution of GC and AT alleles
• Spencer (2006): analysis of HAPMAP data (SNPs from 60 unrelated individuals)
• The fixation bias in favor of GC increases near recombination hotspots
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Frequency distribution of GC and AT alleles
Spencer (2006)
Average Derived Frequency
Allele AT->GC
Allele GC->AT
Allele GC->GC
Allele AT->AT