The implications of intergenic polymorphism for major histocompatibility complex evolution

A systematic survey of six intergenic regions flanking the human HLA-B locu s in eight haplotypes reveals the regions to be up to 20 times more polymor phic than the reported average degree of human neutral polymorphism. Furthe rmore, the extent of polymorphism is directly related to the proximity to t he HLA-B locus. Apparently linkage to HLA-B locus alleles, which are under balancing selection, maintains the neutral polymorphism of adjacent regions . For these linked polymorphisms to persist, recombination in the 200-kb in terval from HLA-B to TNF must occur at a low frequency. The high degree of polymorphism found distal to HLA-B suggests that recombination is uncommon on both sides of the HLA-B locus. The least-squares estimate is 0.15% per m egabase with an estimated range from 0.02 to 0.54%. These findings place st rong restrictions on possible recombinational mechanisms for the generation of diversity at the HLA-B.