Selection, Hitchhiking and Disequilibrium Analysis at Three Linked Loci with
Application to HLA Data
W.P. Robinson , A. Cambon-Thomsen , N. Borot , W. Klitz , G. Thomson
Department of Integrative Biology, University of California, Berkeley 94720.
Genetics ,
129(3), 931-948 (1991)
Abstract
The HLA system has been extensively studied from an evolutionary
perspective. Although it is clear that selection has acted on the genes in the HLA
complex, the nature of this selection has yet to be fully clarified. A study of constrained
disequilibrium values is presented that is applicable to HLA and other less polymorphic
systems with three or more linked loci, with the purpose of identifying selection events.
The method uses the fact that three locus systems impose additional constraints on the
range of possible disequilibrium values for any pair of loci. We have thus examined the
behavior of the normalized pairwise disequilibrium measures using two locus (D'), and
also three locus (D"), constraints on pairwise disequilibria in a three locus system when
one of the three loci is under positive selection. The difference between these measures,
delta = magnitude of D' - magnitude of D", has a distribution for the two unselected loci
differing from that for the selected locus with either of the unselected loci (the hallmark is
a high positive value of delta for the two unselected loci). An examination of genetic drift
indicates that positive delta values are unlikely to be found in human populations in the
absence of selection when recombination is greater than about 0.1%. This measure can
thus provide insight into which allele of several linked loci might have been subject to
selection. Application of this method to HLA haplotypes from a large French population
study (Provinces Francaise) identifies selected alleles on particular haplotypes.
Application of a complementary method, disequilibrium pattern analysis also confirms the
action of selection on these haplotypes.
Association Studies