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. 2013 Apr;193(4):1233-54.
doi: 10.1534/genetics.112.147330. Epub 2013 Feb 14.

Inferring admixture histories of human populations using linkage disequilibrium

Po-Ru Loh  1 , Mark Lipson, Nick Patterson, Priya Moorjani, Joseph K Pickrell, David Reich, Bonnie Berger
Affiliations

Inferring admixture histories of human populations using linkage disequilibrium

Po-Ru Loh et al. Genetics. 2013 Apr.

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 LD-based 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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Figures

Figure 1
Figure 1
Notational diagram of phylogeny containing admixed population and references. Population C′ is descended from an admixture between A and B to form C; populations A′ and B′ are present-day references. In practice, we assume that postadmixture drift is negligible; i.e., the C–C′ branch is extremely short and C′ and C have identical allele frequencies. The branch points of A′ and B′ from the A–B lineage are marked A″ and B″; note that in a rooted phylogeny, these need not be most recent common ancestors (as in panel B; compare to panel A).
Figure 2
Figure 2
Dependence of date estimates and weighted LD amplitudes on fitting start point. Rows correspond to three test scenarios: simulated 75% YRI/25% CEU mixture 50 generations ago with Yoruba–French weights (A–C); Uygur with Han–French weights (D–F); HapMap Maasai with Yoruba–French weights (G–I). (A, D, and G) The weighted LD curve a^(d) (blue) with best-fit exponential decay curve (red), fit starting from d0 = 0.5 cM. The middle and right columns show the date estimate (B, E, H) and amplitude (C, F, I) as a function of d0. (We note that our date estimates for Uygur are somewhat more recent than those in Patterson et al. 2012, most likely because of our direct estimate of the affine term in the weighted LD curve.)
Figure 3
Figure 3
Weighted LD curves for Mbuti using San and Yoruba as reference populations (A) and using Mbuti itself as one reference and several different second references (B), and analogous curves for Biaka (C and D). Genetic distances are discretized into bins at 0.05 cM resolution. Data for each curve are plotted and fit starting from the corresponding ALDER-computed LD correlation thresholds. Different amplitudes of one-reference curves (B and D) imply different phylogenetic positions of the references relative to the true mixing populations (i.e., different split points Xi″), suggesting a sketch of a putative admixture graph (E). Relative branch lengths are qualitative, and the true root is not necessarily as depicted.
Figure 4
Figure 4
Weighted LD curves for HGDP Sardinian using Italian–Yoruba weights (A) and HapMap Japanese (JPT) using JPT itself as one reference and HapMap Han Chinese in Beijing (CHB) as the second reference (B). The exponential fits are performed starting at 1 cM and 1.2 cM, respectively, as selected by ALDER based on detected correlated LD.
Figure 5
Figure 5
Weighted LD curves for Onge using Onge itself as one reference and several different second references.
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