Sporadic, global linkage disequilibrium between unlinked segregating sites

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 indistin-guishability.” 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.