recombination based population genomics jaume bertranpetit marta melé francesc calafell asif javed...
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Recombination based population genomics
Jaume Bertranpetit
Marta Melé
Francesc Calafell
Asif Javed
Laxmi Parida
Recall: IRiS
Identification of Recombinations in SequencesIdentification of Recombinations in Sequences
IRiS is a computational method developed with
biological insight detects evidence of historical recombinations minimizes number of recombinations in
Ancestral Recombinational Graph (ARG)
Recotypes
recombinationedge
mutation edge
extantsequence
Two chromosomes Two chromosomes shareshare a recombination if a recombination if the junction is co-inherited.the junction is co-inherited.
RecotypesTwo chromosomes Two chromosomes shareshare a recombination if a recombination if the junction is co-inherited.the junction is co-inherited.
r1
a b
RecotypesTwo chromosomes Two chromosomes shareshare a recombination if a recombination if the junction is co-inherited.the junction is co-inherited.
r1
r2
a bc
RecotypesTwo chromosomes Two chromosomes shareshare a recombination if a recombination if the junction is co-inherited.the junction is co-inherited.
r1
r2
a bc
r1 r2 …
a 1 0
b 1 0
c 0 1
…
Validity of inferred recombinations
Comparison with sperm typing
Computer simulated recombinations
in vitroChr 1 near MS32 minisatellite
Jeffreys et al. 2005
80 UK semen donor of North European origin
- Sperm typing- LDhat and Phase (200 SNPs)
IRiS
LDhat Phase
spermtyping
HapMap 2 CEU populationsimilar SNP density
in silico
HapMap 3 X chromosome data
•Select 2 chromosomes at random.
•Pick a random breakpoint.
•Create a new chromosome.
•Check if it is unique, add to the dataset.
•Run IRiS on the dataset to see if the breakpoint is detected.
Chromosomes
in silico
HapMap 3 X chromosome data
•Select 2 chromosomes at random.
•Pick a random breakpoint.
•Create a new chromosome.
•Check if it is unique, add to the dataset.
•Run IRiS on the dataset to see if the breakpoint is detected.
Chromosomes
in silico
HapMap 3 X chromosome data
•Select 2 chromosomes at random.
•Pick a random breakpoint.
•Create a new chromosome.
•Check if it is unique, add to the dataset.
•Run IRiS on the dataset to see if the breakpoint is detected.
Chromosomes
in silico
HapMap 3 X chromosome data
•Select 2 chromosomes at random.
•Pick a random breakpoint.
•Create a new chromosome.
•Check if it is unique, add to the dataset.
•Run IRiS on the dataset to see if the breakpoint is detected.
Chromosomes
in silico
HapMap 3 X chromosome data
•Select 2 chromosomes at random.
•Pick a random breakpoint.
•Create a new chromosome.
•Check if it is unique, add to the dataset.
•Run IRiS on the dataset to see if the breakpoint is detected.
Chromosomes
in silico
HapMap 3 X chromosome data
•Select 2 chromosomes at random.
•Pick a random breakpoint.
•Create a new chromosome.
•Check if it is unique, add to the dataset.
•Run IRiS on the dataset to see if the breakpoint is detected.
Chromosomes
IRiS
recombination detected?
in silico
HapMap 3 X chromosome data
•Select 2 chromosomes at random.
•Pick a random breakpoint.
•Create a new chromosome.
•Check if it is unique, add to the dataset.
•Run IRiS on the dataset to see if the breakpoint is detected.
Chromosomes
IRiS
recombination detected?
69% recombinations detectedAll detected recombinations detect the correct sequenceNo false positives
Recombinomics
Strong population structure
Agreement with traditional methods FST vs. recombinational distance
More informative than SNPs STRUCTURE PCA
Regions18 regions selected from HapMap 3 X-chromosome in males
(to avoid phasing errors) 50 KB away from known CNV and SD
(to avoid genotyping errors) 50 KB away from genes
(to avoid selection) at least 80 SNPs
Chromosomes: LWK(4343), MKK (8888), YRI (8888), ASW (4242), GIH (4242), CHB (4040), CHD (2121), JPT(2525), MEX(2121), CEU (7474), TSI (4040)
Analysis
For each region IRiS inferred recotypes for each chromosome 5166 recombinations were inferred 3459 co-occurred in at least two chromosomes
r1 r2 r3 r4 r5 r6 … r3459
LK1 0 1 1 0 0 0 0
LK2 1 0 1 1 0 0 0
:
LK43 1 0 1 0 0 0
MK1 0 1 0 0 1 1 1
:
TI40 0 0 0 0 0 1 0
Chromosome
Recombination
Analysis
For each region IRiS inferred recotypes for each chromosome 5166 recombinations were inferred 3459 co-occurred in at least two chromosomes
r1 r2 r3 r4 r5 r6 … r3459
LK1 0 1 1 0 0 0 0
LK2 1 0 1 1 0 0 0
:
LK43 1 0 1 0 0 0
MK1 0 1 0 0 1 1 1
:
TI40 0 0 0 0 0 1 0
Chromosome
Recombination
Recotype
Agreement with LDhat
number of recombinations inferred by IRiS
reco
mbi
natio
n ra
te in
ferr
ed b
y LD
hat
Spearman correlation= 0.711pvalue <10-30
Each point represents a short haplotype segment Each point represents a short haplotype segment in HapMap CEU populationin HapMap CEU population
Agreement with LDhat
number of recombinations inferred by IRiS
reco
mbi
natio
n ra
te in
ferr
ed b
y LD
hat
Spearman correlation= 0.711pvalue <10-30
Each point represents a short haplotype segment Each point represents a short haplotype segment in HapMap CEU populationin HapMap CEU population
Correlation in hotspots
2 = 38.39
pvalue<6x10-10
Recombinational distance between populations
Two populations genetically closer will share a Two populations genetically closer will share a higher number of recombinationshigher number of recombinations
Recombinational distance
Correlation between FST distance and recombinational distance for the 18 region
[0.35 – 0.75 ] with pvalues < 0.025
=RA + RB -RAB
RABDAB
MDS All regions combined stress=6.1%
1 -
PCA of population data r1 r2 r3 r4 r5 r6 … r3459
LK1 0 1 1 0 0 0 0
LK2 1 0 1 1 0 0 0
:
LK43 1 0 1 0 0 0
MK1 0 1 0 0 1 1 1
:
TI40 0 0 0 0 0 1 0
Recall recotypes
PCA of population data r1 r2 r3 r4 r5 r6 … r3459
LK1 0 1 1 0 0 0 0
LK2 1 0 1 1 0 0 0
:
LK43 1 0 1 0 0 0
MK1 0 1 0 0 1 1 1
:
TI40 0 0 0 0 0 1 0
Recall recotypes
r1 r2 r3 r4 r5 r6 … r3459
LK 14 7 4 9 0 1 0
MK 1 4 7 0 5 7 24
:
TI 0 1 7 1 0 0 1
PCA of population data
r1 r2 r3 r4 r5 r6 … r3459
LK 14 7 4 9 0 1 0
MK 1 4 7 0 5 7 24
:
TI 0 1 7 1 0 0 1
The first two PCs capture 66.4% of the variance
PCA of recotypes
Recotypes vs. SNPs
Due to ascertainment bias gene diversity does Due to ascertainment bias gene diversity does not reflect population structurenot reflect population structure
Percentage of variance
SNPs Recotypes
Across groups 9% 6%
Within groups 4% 1%
Within populations
87% 93%
Normalized comparison linearly scaled to [0,1] using 21 samples per populationin agreement with Lewontin 72
results similar to Conrad 07
from SNPs to haplotypes to recotypes
(a STRUCTURE comparison)K=2
SNPs
haplotypes
recotypes
from SNPs to haplotypes to recotypes
(a STRUCTURE comparison)K=3
SNPs
haplotypes
recotypes
from SNPs to haplotypes to recotypes
(a STRUCTURE comparison)K=4
SNPs
haplotypes
recotypes
from SNPs to haplotypes to recotypes
(a STRUCTURE comparison)K=5
SNPs
haplotypes
recotypes
Africa within global genetic variation
Avg. Number of recombinations in 21 random chromsomes
Out of Africa hypothesisFounder’s effect
minority African specific component
Structure k=4
Genetic variation within Africa
Maasai specificminor component
Structure k=5
Subsaharan Maasai are distinct among Africans.
African-American exhibit stronger recombinational affinity with African populations than European populations. (Parra 98Parra 98)
Genetic variation outside Africa Structure k=5
Outside Africa, Gujarati and Japanese exhibit the highest and lowest number of recombinations respectively.
Gujarati Indians show intermediate position between Europeans and East Asians.
Avg. Number of recombinations in 21 random chromsomes
Venturing outside the X-chromosome Benefits
The bigger picture More regions and hence more information
Challenges Higher number of recombinations makes the
picture murkier Phasing errors
Regions
81 regions selected from HapMap 3
50 KB away from known CNV and SD(to avoid genotyping errors)
50 KB away from genes(to avoid selection)
at least 200 SNPs 25 samples per population
(each sample has twochromosomes)
Analysis For each region IRiS inferred recotypes for each
chromosome 34140 recombinations were inferred
For each sample the two recotypes were mergedmerged.
SNPs recotypes
PCA plots
Quantifying population structure PCA and by k nearest neighbors is used to
predict population of every sample
Africans Non- Africans
MKK
LKK
YRIASW
GIH E. Asian MEX European
CHB+CHD JPT CEU TSI(4,3)
(0,7)(3,13) (8,13)
Perfectly classified
classifiedwith errors
Misclassification by (recotypes, SNPs)
East Asian population
Recotypes are more informative of underlying Recotypes are more informative of underlying population structure.population structure.
SNPs recotypes
PCA plots
in conclusion …
Recotypes show strong agreement with in silico and
in vetro recombination rates estimates are highly informative of the underlying
population structure provide a novel approach to study the
recombinational dynamics
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