Academic journal article Genetics

Inferring Admixture Histories of Human Populations Using Linkage Disequilibrium

Academic journal article Genetics

Inferring Admixture Histories of Human Populations Using Linkage Disequilibrium

Article excerpt

ABSTRACT Long-range migrations and the resulting admixtures between populations have been important forces shaping human genetic diversity. Most existing methods for detecting and reconstructing historical admixture events are based on allele frequency divergences or patterns of ancestry segments in chromosomes of admixed individuals. An emerging new approach harnesses the exponential decay of admixture-induced linkage disequilibrium (LD) as a function of genetic distance. Here, we comprehensively develop LD-based inference into a versatile tool for investigating admixture. We present a new weighted LD statistic that can be used to infer mixture proportions as well as dates with fewer constraints on reference populations than previous methods. We define an LDbased three-population test for admixture and identify scenarios in which it can detect admixture events that previous formal tests cannot. We further show that we can uncover phylogenetic relationships among populations by comparing weighted LD curves obtained using a suite of references. Finally, we describe several improvements to the computation and fitting of weighted LD curves that greatly increase the robustness and speed of the calculations. We implement all of these advances in a software package, ALDER, which we validate in simulations and apply to test for admixture among all populations from the Human Genome Diversity Project (HGDP), highlighting insights into the admixture history of Central African Pygmies, Sardinians, and Japanese.

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ADMIXTURE between previously diverged populations has been a common feature throughout the evolution of modern humans and has leftsignificant genetic traces in contemporary populations (Li et al. 2008; Wall et al. 2009; Reich et al. 2009; Green et al. 2010; Gravel et al. 2011; Pugach et al. 2011; Patterson et al. 2012). Resulting patterns of variation can provide information about migrations, demographic histories, and natural selection and can also be a valuable tool for association mapping of disease genes in admixed populations (Patterson et al. 2004).

Recently, a variety of methods have been developed to harness large-scale genotype data to infer admixture events in the history of sampled populations, as well as to estimate a range of gene flow parameters, including ages, proportions, and sources. Some of the most popular approaches, such as STRUCTURE (Pritchard et al. 2000) and principal component analysis (PCA) (Patterson et al. 2006), use clustering algorithms to identify admixed populations as intermediates in relation to surrogate ancestral populations. In a somewhat similar vein, local ancestry inference methods (Tang et al. 2006; Sankararaman et al. 2008; Price et al. 2009; Lawson et al. 2012) analyze chromosomes of admixed individuals with the goal of recovering continuous blocks inherited directly from each ancestral population. Because recombination breaks down ancestry tracts through successive generations, the time of admixture can be inferred from the tract length distribution (Pool and Nielsen 2009; Pugach et al. 2011; Gravel 2012), with the caveat that accurate local ancestry inference becomes difficult when tracts are short or the reference populations used are highly diverged from the true mixing populations.

A third class of methods makes use of allele frequency differentiation among populations to deduce the presence of admixture and estimate parameters, either with likelihoodbased models (Chikhi et al. 2001; Wang 2003; Sousa et al. 2009; Wall et al. 2009; Laval et al. 2010; Gravel et al. 2011) or with phylogenetic trees built by taking moments of the site-frequency spectrum over large sets of SNPs (Reich et al. 2009; Green et al. 2010; Patterson et al. 2012; Pickrell and Pritchard 2012; Lipson et al. 2012). For example, f-statisticbased three- and four-population tests for admixture (Reich et al. 2009; Green et al. 2010; Patterson et al. 2012) are highly sensitive in the proper parameter regimes and when the set of sampled populations sufficiently represents the phylogeny. …

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