Analysis of Admixed Human Genomes: Methods and Challenges
Explore the methods and challenges involved in analyzing admixed human genomes, with a focus on the impact of gene flow on genetic diversity patterns. Learn about the underrepresentation of admixed populations in medical genetics and the goals of developing detailed quantitative models of human evolution. Discover how everyone is admixed to some extent, as evidenced by variance in ancestry across individuals.
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Methods and challenges in the analysis of admixed human genomes Simon Gravel Stanford University
An individual is admixed if its ancestors from G generations ago belong to distinct groups. Map from National Geographic
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
Goals Develop detailed quantitative models of human evolution Understand the impact of gene flow on genetic diversity patterns Empower medical association studies
Everyone is admixed Yoruba-European Gravel et al, PNAS108, 11983 (2011)
Global population structure Henn*, Gravel*, et al, Hum. Mol. Genet. 19, R221 (2010)
Variance in ancestry across individuals: simulations
Ancestry Varies Along The Genome Mexican-American Local ancestry inferred from phased HapMap3 SNPs 88% Native American, 11% European, and 1.5% African segments African European Native American Unassigned Assembly gap Kidd*, Gravel* et al (in Review)
Ancestry Varies Along The Genome ASW1 African-American MXL1 Mexican Kidd*, Gravel* et al (in Review)
Modeling ancestry tracts using a Markov model T1 Each recombination occurs independently, giving rise to a Poisson process. (Work in genetic units) Gravel S, Genetics 191, 607 (2012)
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)
Markov model vs simulation Gravel S, Genetics 191, 607 (2012)
Evidence for continuous gene flow African-Americans Mexican-Americans 18 GA 15 GA Gravel S, Genetics 191, 607 (2012) Kidd*, Gravel* et al (in Review)
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
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
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
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)
Modeling the admixture process Individuals Position (Mb) Kidd*, Gravel* et al (in Review)
Demography estimates using coalescent approach Effective population size (x104) 2000 Thousands of years ago Kidd*, Gravel* et al (in Review)
Analyzing admixed populations Native Americans Yorubans Mexicans African Americans (ASW) African-Americans West African Puerto Ricans Europeans 25 Kidd*, Gravel* et al (in Review)
Comparing with slave trade records Slave Trade [1500-1860] Hernan Cortes [1519] North America Spanish Central America
The simplest model of admixture T1 time
