Genomics of the major histocompatibility complex: haplotypes, duplication, retroviruses and disease

Abstract

The genomic region encompassing the Major Histocompatibility Complex (MHC) contains polymorphic frozen blocks which have developed by local imperfect sequential duplication associated with insertion and deletion (indels). In the alpha block surrounding HLA-A, there are ten duplication units or beads on the 62.1 ancestral haplotype. Each bead contains or contained sequences representing Class I, PERB11 (MHC Class I chain related (MIC) and human endogenous retrovirus (HERV) 16. Here we consider explanations for co-occurrence of genomic polymorphism, duplication and HERVs and we ask how these features encode susceptibility to numerous and very diverse diseases. Ancestral haplotypes differ in their copy number and indels in addition to their coding regions. Disease susceptibility could be a function of all of these differences. We propose a model of the evolution of the human MHC. Population-specific integration of retroviral sequences could explain rapid diversification through duplication and differential disease susceptibility. If HERV sequences can be protective, there are exciting prospects for manipulation. In the meanwhile, it will be necessary to understand the function of MHC genes such as PERB11 (MIC) and many others discovered by genomic sequencing.

MHC Susceptibility Genes to IgA Deficiency Are Located in Different Regions on Different HLA Haplotypes

“…This is especially so in the region extending from HLA-B to HLA-DR, where haplotypes seem to have been conserved from remote ancestors and have been called conserved, extended, or ancestral haplotypes. It has been estimated that ϳ70% of the human haplotypes are conserved, extended haplotypes or recombinants of no more than two of them (17,32,33). It is generally accepted that a small number of these MHC conserved haplotypes are found in the majority of IgAD patients (5,7,8,10,11,13,19) and that these haplotypes share a susceptibility locus designated IGAD1.…”

“…Some early studies already signaled that the association was with particular combinations of MHC alleles rather than with individual alleles per se (5,7) and that these combinations reflected extended, conserved, or "ancestral" haplotypes A1-B8-DR3, A28-B14-DR1, and B44-DR7 (7,8,11,15). The conservation of these haplotypes, which appear derived from a common remote ancestor (16,17), has rendered difficult the identification of the individual genes responsible for IgAD.…”

Association between the MHC class I gene HFE polymorphisms and longevity: a study in Sicilian population

“…[13][14][15][16][17][18][19][20][21][22][23][24] Besides, it usually occurs on the ancestral haplotype 7.1. 4,12,20,25 Thus, it has been suggested that an estimated 60 to 70 generations ago, this mutation occurred in the HFE gene of a Celtic individual who is the ancestor of more than 5% of white subjects now carrying the allele. 4,26 In contrast, the H63D substitution is not restricted to European populations, being found at allele frequencies of more than 5% in countries bordering the Mediterranean, in the Middle East, and in the Indian subcontinent, suggesting that the H63D substitution must have occurred earlier than the C282Y substitution.…”

Genetic control of autoantibody expression in autoimmune myasthenia gravis: role of the self-antigen and of HLA-linked loci

“…12,13 As is the case for most autoimmune diseases, MG has a complex genetic control. 14 The extended HLA-A1-B8-DR3 haloptype, also called the 8.1 ancestral haplotype, 15 has long been associated with the form of MG with thymus hyperplasia, 16 defining the MYAS1 locus. 17 Association with HLA, however, explains the genetic component of MG only partly.…”