Genetic Drift in Human Evolution (Part 2 of 2) 1 Ecology and Evolutionary Biology Center for Computational Molecular Biology Brown University Outline Introduction to genetic drift Modeling genetic drift (theory and simulation) The signature of genetic drift on human population genetic data Future directions for studying the role of genetic drift in human populations 2 Human demographic history is complex 3 and is characterized by bottlenecks, divergence and isolation, slavery and colonization, and super-exponential growth post-agriculture 1
One genomic signature in humans is quite distinct E[Heterozygosity] Africa Eurasia East Asia Oceania Americas Geographic distance to Addis Ababa, Ethiopia using waypoints [km] 4 Ramachandran et al. (2005) PNAS A model that predicts this signature is the serial founder effect model Population 1 Population 2 Population 3 De novo mutation rates are too small to counteract these events Number of microsatellite alleles averaged across loci # alleles 5 0 2 4 6 8 Ramachandran et al. (2005) PNAS Geographic distance to Addis Ababa, Ethiopia using waypoints [km] The serial founder effect model continues to be supported by additional samples Native American samples HGDP 6 Wang et al. (2007) PLoS Genet, Ramachandran and Rosenberg (2011) AJPA 2
Other predictions of the serial founder effect model: HGDP-CEPH diversity panel SNP-based studies 7 Jakobsson et al., 2008 Nature Within Africa, hunter-gatherers show very low LD, indicating very old genetic lineages 8 Henn et al. 2011 PNAS Recent methods allow the estimation of genetic drift along branches of a tree of populations ANI - Ancestral North Indians ASI - Ancestral South Indians 9 Reich et al. 2009 Nature 3
Genetic drift leaves a signature on the site frequency spectrum (SFS) SFS: the observed number of derived alleles at each frequency between (0,1) 10 Genetic drift leaves a signature on the site frequency spectrum (SFS) East Asians Model 2 = Two bottlenecks 11 Keinan et al. 2007 Nature Genetics What genomic signatures of genetic drift do we see in extant human populations today? A strong signature of our origin in Africa persists in extant human genomes based on multiple summary statistics Human expansion out of Africa and migrations since are characterized by bottlenecks, and little cross-continental back migration LD, which lies at the heart of identifying disease-causing mutations, differs dramatically by ancestral background Genetic drift also leads to differentiation among groups within geographic regions (Africa, South Asia, East Asia) 12 4
Outline Introduction to genetic drift Modeling genetic drift (theory and simulation) The signature of genetic drift on human population genetic data Future directions for studying the role of genetic drift in human populations 13 What were the relative roles of demographic history and natural selection in generating human genetic diversity? How is this small level of genetic differentiation among humans actually structured? Do the differences represent adaptations? Or are these more reflect history and genetic drift processes? 14 A classic challenge is distinguishing between genomic signatures of adaptation vs. bottlenecks KITLG Produces lighter skin pigmentation in non-africans 15 Coop et al., (2009) PLoS Genetics 5
A typical pipeline when scanning for loci under selection from genomic data Issues with this approach: Statistical significance is difficult to assess Single statistics do not carry much power Table 1 of paper 16 Can summary statistics distinguish between the exact site of an adaptive mutation and linked neutral sites? Neutral linked sites Adaptive mutations 17 Normalized distributions of scores Normalized distributions of scores From sequence data to estimating N(t) from whole genomes Sequentially Markov Coalescent 18 6
Example results using the Sequentially Markov Coalescent and the 1000 Genomes Years (g=25, = 2.5 x 10-8 ) 19 Li and Durbin (2011) Nature Human demographic history is complex 20 and is characterized by bottlenecks, divergence and isolation, slavery and colonization, and super-exponential growth post-agriculture 21 Summary: genetic drift Introduction to genetic drift: Loss of variation results from finite population size Modeling genetic drift: Deriving variance in allele frequency due to drift, observing that time to fixation is proportional to population size The signature of genetic drift on human population genetic data: Cross-continental human genetic diversity is well-modeled by sequential bottlenecks, and that drift can also leave strong signatures within continents Future directions for studying the role of genetic drift in human populations: Integrating modeling of bottlenecks and other demographic events into studies of selection is necessary; through whole-genome sequencing, we will learn more about the role drift has played in modern human evolution 7
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