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Analysis of the highly polymorphic beta1 domains of the HLA class II molecules encoded by the DRB1, DQB1, and DPB1 loci reveals contrasting levels of diversity at the allele and amino acid site levels. Statistics of allele frequency distributions, based on Watterson's homozygosity statistic F, reveal distinct evolutionary patterns for these loci in ethnically diverse samples (26 populations for DQB1 and DRB1 and 14 for DPB1). When examined over all populations, the DQB1 locus allelic variation exhibits striking balanced polymorphism (P < 10(-4)), DRB1 shows some evidence of balancing selection (P < 0.06), and while there is overall very little evidence for selection of DPB1 allele frequencies, there is a trend in the direction of balancing selection (P < 0.08). In contrast, at the amino acid level all three loci show strong evidence of balancing selection at some sites. Averaged over polymorphic amino acid sites, DQB1 and DPB1 show similar deviation from neutrality expectations, and both exhibit more balanced polymorphic amino acid sites than DRB1. Across ethnic groups, polymorphisms at many codons show evidence for balancing selection, yet data consistent with directional selection were observed at other codons. Both antigen-binding pocket- and non-pocket-forming amino acid sites show overall deviation from neutrality for all three loci. Only in the case of DRB1 was there a significant difference between pocket- and non-pocket-forming amino acid sites. Our findings indicate that balancing selection at the MHC occurs at the level of polymorphic amino acid residues, and that in many cases this selection is consistent across populations.

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.

We have developed a method, disequilibrium pattern analysis, for examining the disequilibrium distribution of the entire array of two locus multiallelic haplotypes in a population. It is shown that a selected haplotype will produce a distinct pattern of linkage disequilibrium values for all generations while the selection is acting. This pattern will also presumably be maintained for many generations after the selection event, until the disequilibrium pattern is eventually broken down by genetic drift and recombination. Related haplotypes, sharing an allele with a selected haplotype, assume a value of linkage disequilibrium proportional to the frequency of the unshared allele and have a single negative value of the normalized linkage disequilibrium. The analysis assumes zero linkage disequilibrium for all allelic combinations initially. The same basic results continue to apply if the selection involves a new mutant, the occurrence of which creates linkage disequilibrium for some haplotypes. The disequilibrium pattern predicted under selection is robust with respect to the influence of migration and random genetic drift. This method is applicable to population data having linked polymorphic loci including that determined from protein or DNA sequencing.

Disequilibrium pattern analysis, a general method for analyzing evolutionary events acting on pairs of tightly linked polymorphic loci, is applied to a large sample of Danish individuals typed for A and B loci of the HLA (human leukocyte antigen) system. Cases of selection on particular haplotypes are revealed from patterns of linkage disequilibrium among the HLA haplotypes. These patterns cannot be explained by either population admixture or random genetic drift. Six haplotypes out of the total array of 273 haplotypes have been identified which show in varying extents the patterns indicating selection.