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Methods and challenges in the analysis of admixed human genomes
Simon GravelStanford University
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Map from National Geographic
An individual is admixed if its ancestors from G generations ago belong to distinct groups.
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Admixed populations are underrepresented in medical genetics
96% of participants in genome-wide association studies are of European origin, because of • Geography/politics• Europeans are a model organism• “More statistically uniform”
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Goals
• Develop detailed quantitative models of human evolution
• Understand the impact of gene flow on genetic diversity patterns
• Empower medical association studies
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Everyone is admixed
Gravel et al, PNAS 108, 11983 (2011)
Yoruba-European
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Global population structure
Henn*, Gravel*, et al, Hum. Mol. Genet. 19, R221 (2010)
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Wright-Fisher Simulations
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Variance in ancestry across individuals:simulations
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Variance in ancestry across individuals:Models
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Variance in ancestry across individuals:Models
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Variance in ancestry across individuals:Models
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Variance in ancestry across individuals:Models
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Ancestry Varies Along The Genome
• Local ancestry inferred from phased HapMap3 SNPs
• 88% Native American, 11% European, and 1.5% African segments
Mexican-American
AfricanEuropeanNative AmericanUnassignedAssembly gap
Kidd*, Gravel* et al (in Review)
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Ancestry Varies Along The GenomeASW1 MXL1African-American Mexican
Kidd*, Gravel* et al (in Review)
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Modeling ancestry tracts using a Markov model
Each recombination occurs independently, giving rise to a Poisson process.(Work in genetic units)
T1
Gravel S, Genetics 191, 607 (2012)
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More complex demographic histories can be modeled via multiple-state Markov model
T1
T2
The entire demographic history contained in the transition matrix
Gravel S, Genetics 191, 607 (2012)
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Markov model vs simulation
Gravel S, Genetics 191, 607 (2012)
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Evidence for continuous gene flowAfrican-Americans Mexican-Americans
Kidd*, Gravel* et al (in Review)
18 GA 15 GA
Gravel S, Genetics 191, 607 (2012)
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Summary
• Proposed detailed models of linkage patterns in admixed populations
• Found evidence for continuous gene flow in many populations
• We can learn about recent admixture, and older demography of highly admixed populations
• Results are consistent with historical records
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Challenges
• Finer scale admixture:– Local ancestry assignment difficult/impossible– Large number of source populations
• Population genetics– Expand single-population, panmictic models to
models with population structure• Medical genetics – Facilitate inclusion of all individuals in medical
association studies
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Thanks to
• Stanford– Carlos Bustamante– Jake Byrnes– Brenna Henn– Jeff Kidd– Andres Moreno– Patricia Ortiz-Tello– Fouad Zakharia
• NHLBI exome sequencing project
• 1000 Genomes Project
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Ancestry statistics
• Global Ancestry• Tract Lengths• X-vs-Autosomes• Variance across individuals• Local ancestry fluctuations• Demography of source populations
Kidd*, Gravel* et al (in Review)
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Modeling the admixture process
Kidd*, Gravel* et al (in Review)
Individuals
Position (Mb)
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Demography estimates using coalescent approach
Kidd*, Gravel* et al (in Review)2000
Effective population size (x104)
Thousands of years ago
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25
West African
European
African Americans (ASW)
Analyzing admixed populations
Kidd*, Gravel* et al (in Review)
Europeans
Native Americans
Yorubans
African-Americans
Mexicans
Puerto Ricans
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Hernan Cortes [1519] North America
Slave Trade [1500-1860]
Spanish Central America
Comparing with slave trade records
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The simplest model of admixture
T1
time