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Haplotypes and imputed genotypes in diverse human
populationsNoah RosenbergApril 29, 2009
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Human Genome Diversity Cell Line Panel525,910 single-nucleotide
polymorphisms in 29 populationsM Jakobsson et al. (2008) Nature
451:998-1003
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How do we measure and compare haplotype diversity across
populations?Imputation in diverse populationsOverview
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Which populations and genomic sites have more haplotype
diversity?Population 1Population 2
X0XX0X000X00X000000000000
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0X0X0XX000000XXX000XXX0XX
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Which populations and genomic sites have more haplotype
diversity?Population 1Population 2
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Which populations and genomic sites have more haplotype
diversity?Population 1Population 2P Scheet, M Stephens (2006) AJHG
78:629-644
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Which populations and genomic sites have more haplotype
diversity?Population 1Blue
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Which populations and genomic sites have more haplotype
diversity?Population 1BlueGreen
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Which populations and genomic sites have more haplotype
diversity?Population 1BlueGreenOrange
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Which populations and genomic sites have more haplotype
diversity?Population 1BlueGreenOrangePink
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Which populations and genomic sites have more haplotype
diversity?Population 1BlueGreenOrangePinkYellow
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Which populations and genomic sites have more haplotype
diversity?
Chart2
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Population 1
Population 2
Site number
Heterozygosity
Sheet1
10.70.72
Blue111256666666666666666333320.70.7
Green333200000000000000000000030.70.7
Orange000000000000000000000666640.720.76
Pink444432222222222222222111150.620.72
Yellow222222222222222222222000060.560.72
1010101010101010101010101010101010101010101010101070.560.72
0.70.70.70.720.620.560.560.560.560.560.560.560.560.560.560.560.560.560.560.560.560.540.540.540.5480.560.72
90.560.72
Blue2333111111111111111111111100.560.72
Green4443000000000000000003333110.560.72
Orange0001333333333333333333333120.560.72
Pink2111333333333333333332222130.560.72
Yellow2222333333333333333331111140.560.72
10101010101010101010101010101010101010101010101010150.560.72
0.720.70.70.760.720.720.720.720.720.720.720.720.720.720.720.720.720.720.720.720.720.760.760.760.76160.560.72
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Sheet1
Population 1
Population 2
Site number
Heterozygosity
Sheet2
Sheet3
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Which populations and genomic sites have more haplotype
diversity?Population 1
Less diversityPopulation 2
More diversity
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Haplotype cluster frequencies for a typical genomic regionM
Jakobsson et al. (2008) Nature 451:998-1003
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More haplotype diversity in
AfricaAfricaEuropeMiddleEastEastAsiaOceaniaAmericaC AsiaM Jakobsson
et al. (2008) Nature 451:998-1003
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Less haplotype homozygosity and more haplotype diversity in
AfricaM Jakobsson et al. (2008) Nature 451:998-1003
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Genetic diversity declines with distance from
AfricaHaplotypeheterozygosity
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Haplotype clusters recover population structureAfricaMiddle
EastEuropeCentral/South AsiaOceaniaAmericaEast AsiaM Jakobsson et
al. (2008) Nature 451:998-1003
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Haplotype clusters recover population structureM Jakobsson et
al. (2008) Nature 451:998-1003
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Low haplotype diversity in the lactase region in
EuropeAfricaEuropeMiddleEastEastAsiaOceaniaAmericaC AsiaM Jakobsson
et al. (2008) Nature 451:998-1003
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Haplotype cluster homozygosity as a test for selectionRandom
regionM Jakobsson et al. (2008) Nature 451:998-1003
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Haplotype clusters can be used to encode haplotypes pointwise
for measurement of diversityHaplotype cluster diversity is greatest
in AfricaLow haplotype cluster diversity can potentially be used to
detect selectionHaplotype diversity summary
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Measuring haplotype diversity using haplotype clustersImputation
in diverse populationsOverview
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StudysampleGenotyped positionsImputed genotypes can be tested
for disease associationGenotypes can be imputed using a reference
panel but imperfectly
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443 individuals in 29 populations from the Human Genome
Diversity Panel Genotypes at >500,000 SNPs (Jakobsson et al.
Nature 451:998-1003, 2008)420 HapMap reference haplotypes of
~2,000,000 SNPs, omitting offspring in triosRandomly hide 15%
genotypes in HGDP individuals and impute with MACHMeasure the
proportion of alleles imputed correctlyEvaluating imputation
accuracy in worldwide populations
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Imputation accuracy is predicted by haplotype
diversityImputation accuracyL Huang et al. (2008) AJHG
84:235-250
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Imputation accuracy is greatest with a close reference panelL
Huang et al. (2008) AJHG 84:235-250
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Highest-accuracy reference panels match geographic
locationsAfricaEurope/W AsiaE Asia/Oceania/AmericasL Huang et al.
(2008) AJHG 84:235-250
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Instead of imputing based on separate HapMap panels, impute from
mixturesChoose mixtures to have optimal size given specified
ratiosImputation accuracy can be increased using HapMap mixturesL
Huang et al. (2008) AJHG 84:235-250
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Imputation accuracy can be increased using HapMap mixturesL
Huang et al. (2008) AJHG 84:235-250
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Strategies to improve imputation studies
-Increased sample size
-Improved imputation algorithms
-Improved use of reference panels
-Development of additional reference panels
-Improved haplotyping
-Use of additional data from relativesSummary imputation
accuracy
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Imputation error and sample size inflation are greatest in
AfricaImputation summarySeveral strategies may be available for
improving imputation, including use of mixtures
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Rosenberg labJames DegnanMike DeGiorgioLucy HuangMattias
JakobssonTrevor PembertonPaul ScheetZach SzpiechJenna
VanLiereChaolong WangCollaboratorsGoncalo Abecasis (Michigan)Raph
Gibbs (NIA)John Hardy (UCL)Yun Li (Michigan)Sonja Scholz (NIA)Andy
Singleton (NIA)FundingAlfred P. Sloan FoundationBurroughs Wellcome
Fund National Institutes of HealthU of M Rackham Graduate School [M
DeGiorgio]U of M Center for Genetics in Health and Medicine [M
Jakobsson]
