Sporadic, Global Linkage Disequilibrium Between Unlinked Segregating Sites

Abstract

Demographic, genetic, or stochastic factors can lead to perfect linkage disequilibrium (LD) between alleles at two loci without respect to the extent of their physical distance, a phenomenon that Lawrence et al. (2005a) refer to as "genetic indistinguishability." This phenomenon can complicate genotype-phenotype association testing by hindering the ability to localize causal alleles, but has not been thoroughly explored from a theoretical perspective or using large, dense whole-genome polymorphism data sets. We derive a simple theoretical model of the prevalence of genetic indistinguishability between unlinked loci and verify its accuracy via simulation. We show that sample size and minor allele frequency are the major determinants of the prevalence of perfect LD between unlinked loci but that demographic factors, such as deviations from random mating, can produce significant effects as well. Finally, we quantify this phenomenon in three model organisms and find thousands of pairs of moderate-frequency ( . 5%) genetically indistinguishable variants in relatively large data sets. These results clarify a previously underexplored population genetic phenomenon with important implications for association studies and define conditions under which it is likely to manifest.KEYWORDS linkage disequilibrium; genome-wide association study; genetically indistinguishable A basic genomic property of sexually reproducing organisms is genetic disequilibrium, the nonrandom association between alleles at two or more loci. This quantity is often referred to as linkage disequilibrium (LD) to emphasize the important role of genetic linkage in generating and maintaining the association at physically proximal loci. The concept of LD as a property of two loci that are physically near each other is a natural viewpoint given the large body of theoretical and empirical work characterizing mechanisms by which demography and selection influence patterns of LD between physically proximal loci. The existence and extent of LD between linked loci is influenced by the demographic history of a population, reveals locus-specific selective forces, and is a critical parameter governing the resolution of marker-trait association studies (reviewed in Slatkin 2008). Nevertheless, it is well known that physically distant or even independently segregating loci can also exhibit nonrandom associations.Specifically, LD between alleles segregating at physically unlinked loci can be induced by a variety of forces such as selection, genetic drift, nonrandom mating, epistasis, pleiotropy, and nonrandom chromosome transmission (Michie 1953;Bennett and Binet 1956;Nei 1967;Crow and Kimura 1970;Lewontin 1988;Petkov et al. 2005;Platt et al. 2010;Rohlfs et al. 2010;Corbett-Detig et al. 2013;Long et al. 2013). In this article we examine nonrandom associations between alleles at pairs of physically unlinked loci. We use the term LD to describe these associations but stress that they are not a result of genetic linkage between the loci.For two main reasons, a co...

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