Strong association between microsatellites and anHLA-B,DR haplotype (B18-DR3): implication for microsatellite evolution

TheHLA haplotypeB18-DR3 has a widespread geographical distribution, but has its greatest frequencies in Southern Europe, probably vestigial of the earliest populations of this region, particularly in the Pays Basque and Sardinia. This haplotype is of medical significance, being that most implicated as a factor of risk in insulin-dependent diabetes mellitus. In this study, the closely linked microsatellite markers (TNFa,b,c) in the region of the tumor necrosis factor (TNF) genes have been used in an attempt to subtype this haplotype in the two populations and/or in healthy and diabetic populations. A total of 79HLA-B18-DR3 haplotypes were analyzed: 54 in Basques (12 from healthy individuals and 42 from diabetics or their first-degree relatives) and 25 in Sardinians (13 from healthy and 12 from diabetic individuals). TheTNF haplotypea1-b5-c2 is completely associated withB18-DR3 in both populations. The homogeneity of theB18-DR3 haplotype in two ethnically pure populations implies stability in evolution, which suggests that the mutation rate of these microsatellite markers must be less than is usually assumed (i.e., ∼ 5×10⁻⁴ per site per generation). Such markers should be powerful tools for studying genetic drift and admixture of populations, but it remains to be established whether this stability is a rule for all microsatellites inHLA haplotypes or whether it is restricted to some microsatellites and/or someHLA haplotypes. The population genetics of those microsatellites associated withHLA B18-DR3 was also studied in a random sample of the Basque population.