Evolutionary relationship between human major histocompatibility complex HLA-DR haplotypes

Abstract

HLA-DR haplotypes of the human major histocompatibility complex are organized in five different groups. They can be identified based on the serological specificity expressed by the polymorphic DRB1 locus and by the presence of a characteristic set of DRB genes. The nucleotide sequences of introns 4 and 5 of the two DRB genes (DRB1(*)01 and DRB6(*)01 ) from a DR1 haplotype and the three DRB genes (DRB1(*)15, DRB6(*)15 , and DRB5(*)15 ), from a DR51 haplotype were determined. This study identified endogenous retroviral long terminal repeat elements (ERV9 LTR) located at identical positions in intron 5 of the DRB1 genes in both the DR1 and DR51 haplotypes. Phylogenetic analyses revealed a close evolutionary relationship between these two haplotypes. The DRB5 gene, unique for the DR51 haplotype, may have been lost by a recent gene deletion event creating the DR1 haplotype. A model for the evolution of the human DR haplotypes involving separate duplication and contraction events is presented.

Impact of Endogenous Intronic Retroviruses on Major Histocompatibility Complex Class II Diversity and Stability

“…This particular chimpanzee region configuration also contains the DRB2 and DRB6 genes (13). It is well known that HERV structures may promote recombination and sequence-transduction processes, and their possible role in contraction and expansion of the DR region has been discussed in the past (1,2,5,62,63,66). In general, HERVs and solitary LTRs of most retroviral families are less common in introns or in closer proximity to genes than to intergenic regions.…”

Contributions of vitamin D response elements and HLA promoters to multiple sclerosis risk

“…Conversely, those DRB1 alleles that lack a vitamin D-responsive VDRE motif (DRB1*04, DRB1*07, and DRB1*09) are also characterized by promoter sequence variation within X-box and Y-box domains that confer low constitutive gene expression and nonresponsiveness to cytokine stimuli. 18,22 In light of these observations, it is interesting that risk of MS in a large case-control study involving Caucasian participants from Western Australia could be effectively stratified according to groups of HLA-DRB1 alleles that reflect these promoter haplotypes in part, but which are also defined by their evolutionary ancestry, 19,21 antigen-binding preferences, 20 and linkage disequilibrium with additional HLA-DRB loci (i.e., HLA-DRB3/4/5). 23 In this respect it is also notable that the serologic HLA-DR groups originally defined before the advent of high-resolution sequence-based typing methods appear to provide a very useful classification system for assessing MS risk in this study.…”

“…Investigating the promoter region more generally (table 1), we identified sequence identity throughout the entire promoter region between HLA-DRB1*15:01 and the closely related DRB1*15:02 and DRB1*16:01 alleles that make up the DR51 haplotype group, 18 as well as HLA-DRB1*01 alleles (4 DRB1*01:01, 1 DRB1*01:02, and 3 DRB1*01:03-positive samples) that share a distant ancestral history with HLA-DRB1*15:01 19 but which display only limited sequence similarity and epitope binding preferences. 20,21 It is also notable that the HLA-DRB1*15:01, DRB1*15:02, and DRB1*16:01 alleles within the HLA-DR51 haplotype group share an association with HLA-DRB5, while loss of this additional HLA-DRB locus has been identified as a feature of the evolutionary divergence of HLA-DRB1*01 from the ancestral HLA-DR51 group.…”

“…20,21 It is also notable that the HLA-DRB1*15:01, DRB1*15:02, and DRB1*16:01 alleles within the HLA-DR51 haplotype group share an association with HLA-DRB5, while loss of this additional HLA-DRB locus has been identified as a feature of the evolutionary divergence of HLA-DRB1*01 from the ancestral HLA-DR51 group. 19 All 53 HLA-DRB1*15:01-positive samples showed sequence identity across the promoter region (figure 1).…”

The Noncoding Regions of HLA-DRB Uncover Interlineage Recombinations as a Mechanism of HLA Diversification

“…The analyses of multiple nucleotide sequences of different DR regions allowed the proposition of a model for HLA-DR haplotype evolution (3). In this model, the human haplotypes DR53 as well as DR52 represent very ancient DR haplotypes created by several gene duplication events that happened very early during mammalian evolution (4 -5).…”