The major histocompatability complex (MHC) contains conserved polymorphic genomic sequences that are shuffled by recombination to form ethnic-specific haplotypes

Abstract

The major histocompatibility complex (MHC) consists of polymorphic frozen blocks (PFBs) that are linked to form megabase haplotypes. These blocks consist of polymorphic sequences and define regions where recombination appears to be inhibited. We have been able to show, using a highly polymorphic sequence centromeric of HLA-B (within the beta block), that PFBs are conserved and contain specific insertions/deletions and substitutions that are the same for individuals with the same MHC haplotype but that differ between at least most different haplotypes. A sequence comparison between ethnic-specific haplotypes shows that these sequences have remained stable and predate the formation of these haplotypes. To determine whether the same conserved block has been involved in the generation of multiple haplotypes, we compared the block typing profiles of different ethnic specific haplotypes. Block typing profiles have previously been shown to be identical in individuals with the same MHC haplotype but, generally, to differ between different haplotypes. It was found that some PFBs are common to more than one haplotype, implying a common ancestry. Subsequently, haplotypes have been generated by the shuffling and exchange of these PFBs. The regions between these PFBs appear to permit the recombination sites and therefore could be expected to exhibit either low polymorphism or a localized "hotspot."

Linkage disequilibrium and haplotype blocks in the MHC vary in an HLA haplotype specific manner assessed mainly by DRB1*03 and DRB1*04 haplotypes

“…It has been suggested that the HLA haplotype specific differences seen for 'frozen blocks' predates the separation of ethnic groups. 37 Our finding of different LD patterns and haplotype blocks defined on different HLA background coincide with the previous observation that the recombination rate varies in an HLA haplotypedependent manner. [38][39][40] Recombination hot spots seem to play a more pronounced role in shaping the LD landscape than population history, 15 and in the MHC class II region meiotic crossover hot spots have been shown to strongly correlate with break down of LD.…”

The evolution and diversity of TNF block haplotypes in European, Asian and Australian Aboriginal populations

“…This has been proposed using a highly polymorphic intragenic sequence in the central MHC typed in small numbers of cell lines from European, Japanese and Chinese donors and is confirmed here using biologically relevant loci and population-based samples. 6 Consistent with the underlying haplotype structure, pairs of SNPs occurring together in a single or in a few haplotypes were in significant linkage disequilibrium. Four pairs of SNPs (rs1129640-rs2516393, rs2239528-rs2523504, rs3130059-rs2071591 and rs7738380-rs2516312) were in complete linkage disequilibrium.…”

Microsatellite typing for DRB1 alleles: application to the analysis of HLA associations with rheumatoid arthritis

“…This commonality of haplotypes across the major ancestral groups is consistent with the ancient origin of these haplotype families. [15][16][17] We also observed that certain microsatellites exhibited multiple repeat differences within a haplotype group. For example, multiple alleles of the D6S2446 microsatellite are found on DR*07 haploytpes, involving GT repeats between 13 and 16, giving rise to multiple three-marker haplotypes in this group (e.g.…”