STRONG ASSOCIATION BETWEEN MICROSATELLITES AND AN HLA-B, DR HAPLOTYPE(B18-DR3) - IMPLICATION FOR MICROSATELLITE EVOLUTION

The HLA haplotype B18-DR3 has a widespread geographical distribution, but has its greatest frequencies in Southern Europe, probably vestigia l 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 diabete s 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 populatio ns and/or in healthy and diabetic populations. A total of 79 HLA-BI8-D R3 haplotypes were analyzed: 54 in Basques (12 from healthy individual s and 42 from diabetics or their first-degree relatives) and 25 in Sar dinians (13 from healthy and 12 from diabetic individuals). The TNF ha plotype al-b5-c2 is completely associated with B18-DR3 in both populat ions. The homogeneity of the B18-DR3 haplotype in two ethnically pure populations implies stability in evolution, which suggests that the mu tation rate of these microsatellite markers must be less than is usual ly assumed (i.e., similar to 5 x 10(-4) per site per generation). Such markers should be powerful tools for studying genetic drift and admix ture of populations, but it remains to be established whether this sta bility is a rule for all microsatellites in NW haplotypes or whether i t is restricted to some microsatellites and/or some HLA haplotypes. Th e population genetics of those microsatellites associated with HLA B18 -DR3 was also studied in a random sample of the Basque population.