Lower-than-expected linkage disequilibrium between tightly linked markers in humans suggests a role for gene conversion

Abstract

Understanding the pattern of linkage disequilibrium (LD) in the human genome is important both for successful implementation of disease-gene mapping approaches and for inferences about human demographic histories. Previous studies have examined LD between loci within single genes or confined genomic regions, which may not be representative of the genome; between loci separated by large distances, where little LD is seen; or in population groups that differ from one study to the next. We measured LD in a large set of locus pairs distributed throughout the genome, with loci within each pair separated by short distances (average 124 bp). Given current models of the history of the human population, nearly all pairs of loci at such short distances would be expected to show complete LD as a consequence of lack of recombination in the short interval. Contrary to this expectation, a significant fraction of pairs showed incomplete LD. A standard model of recombination applied to these data leads to an estimate of effective human population size of 110,000. This estimate is an order of magnitude higher than most estimates based on nucleotide diversity. The most likely explanation of this discrepancy is that gene conversion increases the apparent rate of recombination between nearby loci.

Figure 1

Expected number of obligate recombination events (R_M) as a function of population recombination parameter 4Nr. Dashed line indicates the observed value of R_M=7. Each blackened circle is an average over 1,000 simulated replicates of the data. Vertical bars show the values that fall at 2.5%–97.5% of the simulated distribution.