Linkage to Gaucher mutations in the Ashkenazi population: effect of drift on decay of linkage disequilibrium and evidence for heterozygote selection.

The two most common Gaucher disease mutations in the Ashkenazi population, 1226A-->G and 84G-->GG in the glucocerebrosidase gene, are tightly linked to a marker in the nearby pyruvate kinase gene. This paper develops a simulation of the Ashkenazi population that considers the effects of selection and drift on the mutant allele frequency and the recombinant haplotype frequency over time. Although the fraction of mutants that are linked to the original marker decays exponentially on average, this expected value is not very likely to occur. Instead, due to random loss of the recombinant haplotype, a mutation has a significant probability of retaining complete linkage disequilibrium long after its origin, so there may be large errors in estimating the age of a mutation based on linkage data. The simulations show that the 1226G mutation probably originated between 40 and 1000 generations ago (1000 to 25,000 years ago), and the 84GG mutation probably originated between 50 and 4800 generations ago (1300 to 120,000 years ago). The recent origin of the 1226G mutation and its high current allele frequency provide strong evidence for heterozygote selection. New techniques and results developed in this paper have general applicability toward analyzing linkage disequilibrium near other mutations. For example, they potentially explain the unexpected pattern of linkage disequilibrium seen around the DeltaF508 mutation of the cystic fibrosis transmembrane conductance regulator gene.