Large-scale recombination rate patterns are conserved among human populations David Serre

Large-scale recombination rate patterns are conserved among human populations

David SerreMcGill University and Genome Quebec Innovation Center

UQAMJanuary 2006

- Recombination?

- Why is recombination important?

- How do we measure recombination rates?

- Large scale recombination rate differences among human populations

Recombination rate patterns in Humans

(for gene conversion see Padhukasahasram AJHG 2004)

Why Studying Recombination ?

Recombination separates history of two loci located on same chromosome.

n+1 generation

Recombination and disease mapping

n


n-1


n-1


n-2


n-20


today


today


Neutral locus Locus under selection

Hitchhiking effect Low recombination rateIndependent evolution High recombination rate

Sabeti et al, 2002

Recombination and natural selection

Recombination

Direct Indirect

Genetic map

Sperm typing

Linkage Disequilibrium

Population history

Understanding Recombination…

How often do we observe a recombination event between two markers ?

Divide recombination fraction by physical distance (bp)

recombination rate

- Marshfield map Yu et al., 2001

- DeCode mapKong et al., 2002Kong et al., 2004

Genetic maps

ba

BA

How often do we observe a recombinant spermatozoid ?

Divide recombination fraction by physical distance (bp)

recombination rate

Papers from Alec Jeffreysand Norm Arnheim

Sperm typing

“non-random association of alleles”

A a

B p(A)p(B) (1-p(A))p(B)

b p(A)(1-p(B)) (1-p(A))(1-p(B))

IfPr(AB) ≠ P(A)*P(B)

Then markers are in LD

Random-association no linkage linkage “equilibrium”Non-random association linkage linkage disequilibrium

Linkage Disequilibrium (LD)

If Pr(AB) ≠ P(A)*P(B) then markers are in LD

|D’|:D’= p(AB) – p(A)p(B)influenced by allele frequency

R2:R2=(p(AB) – p(A)p(B))2 / (p(A)p(B)p(a)p(b))normalizedchi-squared distributed

Measures of LD

Dawson et al, 2002

Polymorphism data

Measure LD

(Given a model of population history)

Estimate recombination: ρ=4Nec

Inferring Recombination from LD

Pritchard and Przeworski, 2001

neutral growth structure

LD reflects the number/location of historical recombination events.

For a given population size, A given population history,

What is the most likely recombination rate that would produce the observed LD pattern?

Hudson 2001, McVean 2004

From LD to Recombination rates

From LD to Recombination rates

LD between Likelihood | ρ=0.001 Likelihood | ρ=0.002 … Likelihood | ρ=1.000

SNP1-SNP2

SNP1-SNP3

SNP1-SNP4

SNP1-SNP5

SNP2-SNP3

SNP2-SNP4

SNP2-SNP5

SNP3-SNP4

…

Total

- Fine-scale variations (<100kb)

- Individual variation in hotspot intensity (sperm typing)(Jeffreys 1998, 2002, 2005)

- Inter-species variation in hotspot intensity and/or location (LD)(Wall 2003, Ptak 2004, 2005, Winckler 2005)

- Population differences in hotspot location and/or intensity ?(Crawford 2004)

Recombination variations in Humans











- Large-scale variations (>1Mb)

- Individual variation in number of recombination events per meiosis(Yu 1996, Broman 1998, Kong 2002, 2004)

- Inter-species variation in genetic map length(Rogers 2000)






“The total centimorgan distances among homologous markers are 28.0% longer in the human genome than in the baboon, suggesting that rates of recombination may be higher in humans.” (Rogers et al. 2000)
















Are large-scale recombination patterns conserved among human populations ?


Used genome-wide polymorphism data from Perlegen Sciences (Hinds 2005)

re-sequencing followed by genotyping

>1,500,000 SNPs (average: one SNP per 1.8kb)

23 individuals from 3 populations- European-Americans (Utah residents with ancestry from northern and western Europe),- African-Americans,

- and Han Chinese (from the Los Angeles area).

Materiel & Methods

For each population,split genome in 1Mb-windowfor each window,

if more than 100 SNPs, calculated ρcl=4Nec using Hudson 2001

I considered only window for which I obtained ρcl in each population:

2,613 non-overlapping windows of 1Mbcovering the 22 autosomal chromosomes

Materiel & Methods

Is ρ more strongly correlated with genetic map estimate in Eur.-Am.?

Kong (2002) estimated recombination rates using 146 Icelandic families.

If the recombination rate patterns differ between human populations, the DeCode estimates should predict better the population recombination rates in populations of European ancestry than they do in populations of non-European ancestry.

N.B. the slope of the correlation is proportional to Ne and will therefore differ for different populations but the strength of the correlation (i.e. Pearson’s r) will allow detecting differences in the recombination patterns.

Performed a linear regression analysis between:the recombination rates estimated from polymorphism data

(ρ) and those obtained in the DeCode map (cmap)

for 2,609 non-overlapping 1Mb windows.

0

0.0005

0.001

0.0015

0.002

0.0025

0.003

0 1 2 3 4 5 6 7

c_map (DeCode)

Po

p.

Rec

om

bin

atio

n R

ate

Pearson’s r

r2 99% CI

European-Americans 0.5087 [0.4733-0.5431]

Han Chinese 0.4986 [0.4624-0.5329]

African-Americans 0.4964 [0.4610-0.5314]

Is ρ more strongly correlated with genetic map estimate in Eur.-Am.?

Is the ratio ρ/ρ constant along the chromosomes?

Population recombination rate: ρ=4Nec

If c is identical in different populations,

ρ(pop1)/ρ(pop2) = Ne(pop1)/Ne(pop2) = constant

Thus, if the patterns of recombination rates are conserved, the ratios of the population recombination rate estimates should be constant along the chromosomes.

(this is true if the variations of Ne along the chromosomes are negligible at the scale considered)

0 50 100 150 200 250

chromosomal position (in Mb)

Lo

g R

atio

Rh

o

Is the ratio ρ/ρ constant along the chromosomes?

Looking at the most extreme ρ/ρ ratios…

Looked at the 2.5% highest-2.5% lowest ratios of each comparison

- no significant deviation from a uniform distribution across chromosomes

- distribution in centromeric, telomeric and rest of the genome is marginally significant.

Looking at the most extreme ρ/ρ ratios…

Is there any biological outliers?

Selected regions with 2+ extreme windows within 3Mb (and in the same direction)

The region with the most extreme ratios corresponds to a well-describedpolymorphic inversion on chromosome 8p (Giglio 2001)

African-American/HanChinese

European-American/HanChinese

African-American/European-American

6

671

2

0

0.2

0.4

0.6

0.8

1

1.2

1.4

0 5 10 15 20 25 30 35 40 45

chromosomal position (in Mb)

log

Rat

io R

ho

Polymorphic inversion on chromosome 8p

Conclusion:

Overall conservation of large-scale recombination rate patterns among human populations.

- Genetic maps established in European populations can be directly used for linkage analyses in other populations.

- Local recombination rate differences can be used to investigate population differences: chromosomal rearrangements or selection.

- There is a discrepancy between the variability of hotspots and the conservation of the recombination rates on a larger scale.It is possible that the position and intensity of recombination hotspots can vary among humans but that the overall frequency of hotspots over a larger scale has to be maintained.

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Large-scale recombination rate patterns are conserved among human populations David Serre

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