Linkage disequilibrium--understanding the evolutionary past and mapping the medical future

Abstract

Linkage disequilibrium--the nonrandom association of alleles at different loci--is a sensitive indicator of the population genetic forces that structure a genome. Because of the explosive growth of methods for assessing genetic variation at a fine scale, evolutionary biologists and human geneticists are increasingly exploiting linkage disequilibrium in order to understand past evolutionary and demographic events, to map genes that are associated with quantitative characters and inherited diseases, and to understand the joint evolution of linked sets of genes. This article introduces linkage disequilibrium, reviews the population genetic processes that affect it and describes some of its uses. At present, linkage disequilibrium is used much more extensively in the study of humans than in non-humans, but that is changing as technological advances make extensive genomic studies feasible in other species.

Figure 1. Haplotype blocks

This graph provides some of the first evidence of haplotype blocks and their association with recombination hot spots. The figure shows the pattern of pairwise linkage disequilibrium (LD) in a 216 kb region of the class II region of the major histocompatibility complex in humans for all pairs of SNPs in the region for which the frequency (q) of the minor (that is, less common) allele exceeded 0.15. The region above the diagonal shows levels of L obtained when using D′ = 0 as the null hypothesis (L is the likelihood ratio from the test of linkage equilibrium). D′ is the ratio of D (a measure of LD) to its maximum possible absolute value, given the allele frequencies. This figure is reproduced, with permission, from Nature Genetics REF. 130 © (2001) Macmillan Publishers Ltd.