THE MAJOR HISTOCOMPATABILITY COMPLEX (MHC) CONTAINS CONSERVED POLYMORPHIC GENOMIC SEQUENCES THAT ARE SHUFFLED BY RECOMBINATION TO FORM ETHNIC-SPECIFIC HAPLOTYPES

The major histocompatibility complex (MHC) consists of polymorphic fro zen blocks (PFBs) that are linked to form megabase haplotypes. These b locks consist of polymorphic sequences and define regions where recomb ination appears to be inhibited. We have been able to show, using a hi ghly polymorphic sequence centromeric of HLA-B (within the beta block) , that PFBs are conserved and contain specific insertions/deletions an d substitutions that are the same for individuals with the same MHC ha plotype but that differ between at least most different haplotypes. A sequence comparison between ethnic-specific haplotypes shows that thes e sequences have remained stable and predate the formation of these ha plotypes. To determine whether the same conserved block has been invol ved in the generation of multiple haplotypes, we compared the block ty ping profiles of different ethnic specific haplotypes. Block typing pr ofiles have previously been shown to be identical in individuals with the same MHC haplotype but, generally, to differ between different hap lotypes. It was found that some PFBs are common to more than one haplo type, implying a common ancestry. Subsequently, haplotypes have been g enerated by the shuffling and exchange of these PFBs. The regions betw een these PFBs appear to permit the recombination sites and therefore could be expected to exhibit either low polymorphism or a localized '' hotspot.''