recombination based population genomics jaume bertranpetit marta melé francesc calafell asif javed...
TRANSCRIPT
![Page 1: Recombination based population genomics Jaume Bertranpetit Marta Melé Francesc Calafell Asif Javed Laxmi Parida](https://reader035.vdocuments.mx/reader035/viewer/2022062722/56649f315503460f94c4c65a/html5/thumbnails/1.jpg)
Recombination based population genomics
Jaume Bertranpetit
Marta Melé
Francesc Calafell
Asif Javed
Laxmi Parida
![Page 2: Recombination based population genomics Jaume Bertranpetit Marta Melé Francesc Calafell Asif Javed Laxmi Parida](https://reader035.vdocuments.mx/reader035/viewer/2022062722/56649f315503460f94c4c65a/html5/thumbnails/2.jpg)
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)
![Page 3: Recombination based population genomics Jaume Bertranpetit Marta Melé Francesc Calafell Asif Javed Laxmi Parida](https://reader035.vdocuments.mx/reader035/viewer/2022062722/56649f315503460f94c4c65a/html5/thumbnails/3.jpg)
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.
![Page 4: Recombination based population genomics Jaume Bertranpetit Marta Melé Francesc Calafell Asif Javed Laxmi Parida](https://reader035.vdocuments.mx/reader035/viewer/2022062722/56649f315503460f94c4c65a/html5/thumbnails/4.jpg)
RecotypesTwo chromosomes Two chromosomes shareshare a recombination if a recombination if the junction is co-inherited.the junction is co-inherited.
r1
a b
![Page 5: Recombination based population genomics Jaume Bertranpetit Marta Melé Francesc Calafell Asif Javed Laxmi Parida](https://reader035.vdocuments.mx/reader035/viewer/2022062722/56649f315503460f94c4c65a/html5/thumbnails/5.jpg)
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
![Page 6: Recombination based population genomics Jaume Bertranpetit Marta Melé Francesc Calafell Asif Javed Laxmi Parida](https://reader035.vdocuments.mx/reader035/viewer/2022062722/56649f315503460f94c4c65a/html5/thumbnails/6.jpg)
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
…
![Page 7: Recombination based population genomics Jaume Bertranpetit Marta Melé Francesc Calafell Asif Javed Laxmi Parida](https://reader035.vdocuments.mx/reader035/viewer/2022062722/56649f315503460f94c4c65a/html5/thumbnails/7.jpg)
Validity of inferred recombinations
Comparison with sperm typing
Computer simulated recombinations
![Page 8: Recombination based population genomics Jaume Bertranpetit Marta Melé Francesc Calafell Asif Javed Laxmi Parida](https://reader035.vdocuments.mx/reader035/viewer/2022062722/56649f315503460f94c4c65a/html5/thumbnails/8.jpg)
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
![Page 9: Recombination based population genomics Jaume Bertranpetit Marta Melé Francesc Calafell Asif Javed Laxmi Parida](https://reader035.vdocuments.mx/reader035/viewer/2022062722/56649f315503460f94c4c65a/html5/thumbnails/9.jpg)
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
![Page 10: Recombination based population genomics Jaume Bertranpetit Marta Melé Francesc Calafell Asif Javed Laxmi Parida](https://reader035.vdocuments.mx/reader035/viewer/2022062722/56649f315503460f94c4c65a/html5/thumbnails/10.jpg)
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
![Page 11: Recombination based population genomics Jaume Bertranpetit Marta Melé Francesc Calafell Asif Javed Laxmi Parida](https://reader035.vdocuments.mx/reader035/viewer/2022062722/56649f315503460f94c4c65a/html5/thumbnails/11.jpg)
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
![Page 12: Recombination based population genomics Jaume Bertranpetit Marta Melé Francesc Calafell Asif Javed Laxmi Parida](https://reader035.vdocuments.mx/reader035/viewer/2022062722/56649f315503460f94c4c65a/html5/thumbnails/12.jpg)
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
![Page 13: Recombination based population genomics Jaume Bertranpetit Marta Melé Francesc Calafell Asif Javed Laxmi Parida](https://reader035.vdocuments.mx/reader035/viewer/2022062722/56649f315503460f94c4c65a/html5/thumbnails/13.jpg)
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
![Page 14: Recombination based population genomics Jaume Bertranpetit Marta Melé Francesc Calafell Asif Javed Laxmi Parida](https://reader035.vdocuments.mx/reader035/viewer/2022062722/56649f315503460f94c4c65a/html5/thumbnails/14.jpg)
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?
![Page 15: Recombination based population genomics Jaume Bertranpetit Marta Melé Francesc Calafell Asif Javed Laxmi Parida](https://reader035.vdocuments.mx/reader035/viewer/2022062722/56649f315503460f94c4c65a/html5/thumbnails/15.jpg)
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
![Page 16: Recombination based population genomics Jaume Bertranpetit Marta Melé Francesc Calafell Asif Javed Laxmi Parida](https://reader035.vdocuments.mx/reader035/viewer/2022062722/56649f315503460f94c4c65a/html5/thumbnails/16.jpg)
Recombinomics
Strong population structure
Agreement with traditional methods FST vs. recombinational distance
More informative than SNPs STRUCTURE PCA
![Page 17: Recombination based population genomics Jaume Bertranpetit Marta Melé Francesc Calafell Asif Javed Laxmi Parida](https://reader035.vdocuments.mx/reader035/viewer/2022062722/56649f315503460f94c4c65a/html5/thumbnails/17.jpg)
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)
![Page 18: Recombination based population genomics Jaume Bertranpetit Marta Melé Francesc Calafell Asif Javed Laxmi Parida](https://reader035.vdocuments.mx/reader035/viewer/2022062722/56649f315503460f94c4c65a/html5/thumbnails/18.jpg)
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
![Page 19: Recombination based population genomics Jaume Bertranpetit Marta Melé Francesc Calafell Asif Javed Laxmi Parida](https://reader035.vdocuments.mx/reader035/viewer/2022062722/56649f315503460f94c4c65a/html5/thumbnails/19.jpg)
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
![Page 20: Recombination based population genomics Jaume Bertranpetit Marta Melé Francesc Calafell Asif Javed Laxmi Parida](https://reader035.vdocuments.mx/reader035/viewer/2022062722/56649f315503460f94c4c65a/html5/thumbnails/20.jpg)
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
![Page 21: Recombination based population genomics Jaume Bertranpetit Marta Melé Francesc Calafell Asif Javed Laxmi Parida](https://reader035.vdocuments.mx/reader035/viewer/2022062722/56649f315503460f94c4c65a/html5/thumbnails/21.jpg)
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
![Page 22: Recombination based population genomics Jaume Bertranpetit Marta Melé Francesc Calafell Asif Javed Laxmi Parida](https://reader035.vdocuments.mx/reader035/viewer/2022062722/56649f315503460f94c4c65a/html5/thumbnails/22.jpg)
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 -
![Page 23: Recombination based population genomics Jaume Bertranpetit Marta Melé Francesc Calafell Asif Javed Laxmi Parida](https://reader035.vdocuments.mx/reader035/viewer/2022062722/56649f315503460f94c4c65a/html5/thumbnails/23.jpg)
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
![Page 24: Recombination based population genomics Jaume Bertranpetit Marta Melé Francesc Calafell Asif Javed Laxmi Parida](https://reader035.vdocuments.mx/reader035/viewer/2022062722/56649f315503460f94c4c65a/html5/thumbnails/24.jpg)
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
![Page 25: Recombination based population genomics Jaume Bertranpetit Marta Melé Francesc Calafell Asif Javed Laxmi Parida](https://reader035.vdocuments.mx/reader035/viewer/2022062722/56649f315503460f94c4c65a/html5/thumbnails/25.jpg)
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
![Page 26: Recombination based population genomics Jaume Bertranpetit Marta Melé Francesc Calafell Asif Javed Laxmi Parida](https://reader035.vdocuments.mx/reader035/viewer/2022062722/56649f315503460f94c4c65a/html5/thumbnails/26.jpg)
PCA of recotypes
![Page 27: Recombination based population genomics Jaume Bertranpetit Marta Melé Francesc Calafell Asif Javed Laxmi Parida](https://reader035.vdocuments.mx/reader035/viewer/2022062722/56649f315503460f94c4c65a/html5/thumbnails/27.jpg)
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
![Page 28: Recombination based population genomics Jaume Bertranpetit Marta Melé Francesc Calafell Asif Javed Laxmi Parida](https://reader035.vdocuments.mx/reader035/viewer/2022062722/56649f315503460f94c4c65a/html5/thumbnails/28.jpg)
from SNPs to haplotypes to recotypes
(a STRUCTURE comparison)K=2
SNPs
haplotypes
recotypes
![Page 29: Recombination based population genomics Jaume Bertranpetit Marta Melé Francesc Calafell Asif Javed Laxmi Parida](https://reader035.vdocuments.mx/reader035/viewer/2022062722/56649f315503460f94c4c65a/html5/thumbnails/29.jpg)
from SNPs to haplotypes to recotypes
(a STRUCTURE comparison)K=3
SNPs
haplotypes
recotypes
![Page 30: Recombination based population genomics Jaume Bertranpetit Marta Melé Francesc Calafell Asif Javed Laxmi Parida](https://reader035.vdocuments.mx/reader035/viewer/2022062722/56649f315503460f94c4c65a/html5/thumbnails/30.jpg)
from SNPs to haplotypes to recotypes
(a STRUCTURE comparison)K=4
SNPs
haplotypes
recotypes
![Page 31: Recombination based population genomics Jaume Bertranpetit Marta Melé Francesc Calafell Asif Javed Laxmi Parida](https://reader035.vdocuments.mx/reader035/viewer/2022062722/56649f315503460f94c4c65a/html5/thumbnails/31.jpg)
from SNPs to haplotypes to recotypes
(a STRUCTURE comparison)K=5
SNPs
haplotypes
recotypes
![Page 32: Recombination based population genomics Jaume Bertranpetit Marta Melé Francesc Calafell Asif Javed Laxmi Parida](https://reader035.vdocuments.mx/reader035/viewer/2022062722/56649f315503460f94c4c65a/html5/thumbnails/32.jpg)
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
![Page 33: Recombination based population genomics Jaume Bertranpetit Marta Melé Francesc Calafell Asif Javed Laxmi Parida](https://reader035.vdocuments.mx/reader035/viewer/2022062722/56649f315503460f94c4c65a/html5/thumbnails/33.jpg)
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)
![Page 34: Recombination based population genomics Jaume Bertranpetit Marta Melé Francesc Calafell Asif Javed Laxmi Parida](https://reader035.vdocuments.mx/reader035/viewer/2022062722/56649f315503460f94c4c65a/html5/thumbnails/34.jpg)
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
![Page 35: Recombination based population genomics Jaume Bertranpetit Marta Melé Francesc Calafell Asif Javed Laxmi Parida](https://reader035.vdocuments.mx/reader035/viewer/2022062722/56649f315503460f94c4c65a/html5/thumbnails/35.jpg)
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
![Page 36: Recombination based population genomics Jaume Bertranpetit Marta Melé Francesc Calafell Asif Javed Laxmi Parida](https://reader035.vdocuments.mx/reader035/viewer/2022062722/56649f315503460f94c4c65a/html5/thumbnails/36.jpg)
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)
![Page 37: Recombination based population genomics Jaume Bertranpetit Marta Melé Francesc Calafell Asif Javed Laxmi Parida](https://reader035.vdocuments.mx/reader035/viewer/2022062722/56649f315503460f94c4c65a/html5/thumbnails/37.jpg)
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
![Page 38: Recombination based population genomics Jaume Bertranpetit Marta Melé Francesc Calafell Asif Javed Laxmi Parida](https://reader035.vdocuments.mx/reader035/viewer/2022062722/56649f315503460f94c4c65a/html5/thumbnails/38.jpg)
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)
![Page 39: Recombination based population genomics Jaume Bertranpetit Marta Melé Francesc Calafell Asif Javed Laxmi Parida](https://reader035.vdocuments.mx/reader035/viewer/2022062722/56649f315503460f94c4c65a/html5/thumbnails/39.jpg)
East Asian population
Recotypes are more informative of underlying Recotypes are more informative of underlying population structure.population structure.
SNPs recotypes
PCA plots
![Page 40: Recombination based population genomics Jaume Bertranpetit Marta Melé Francesc Calafell Asif Javed Laxmi Parida](https://reader035.vdocuments.mx/reader035/viewer/2022062722/56649f315503460f94c4c65a/html5/thumbnails/40.jpg)
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