Constrained Disequilibrium Values and Hitchhiking in a Three-Locus System

Positive selection on a new mutant allele can increase the frequencies of closely linked alleles (through hitchhiking), as well as create linkage disequilibrium between them. Because this disequilibrium is induced by the selected allele, one may be able to identify loci under selection by measuring the influence of a candidate locus on pairwise disequilibrium values at nearby loci. The constrained disequilibrium values (CDV) method approaches this problem by examining differences in pairwise disequilibrium values, which have been normalized for two- and three-locus systems, respectively. We have investigated in detail the reliability of inferences based on CDV, using simulation and analytical methods. Our main results are (i) in some circumstances, CDV may not distinguish well between a selected locus and a neighboring neutral locus, but (ii) CDV seldom indicates “selection” in neutral haplotypes with moderate to large 4Nc. We conclude that, although the CDV method does not appear to precisely locate selected alleles, it can be used to screen for regions in which hitchhiking is a plausible hypothesis. We present a microsatellite data set from human chromosome 6, in which constrained disequilibrium values suggest the action of selection in a region containing the human leukocyte antigen (HLA)-A and myelin oligodendrocyte glycoprotein (MOG) loci. The connection between hitchhiking and disequilibrium has received relatively little attention, so our investigation presents opportunities to address more general issues.