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

The genomic region encompassing the Major Histocompatibility Complex (MHC) contains polymorphic frozen blocks which have developed by local imperfect sequential duplication associated with inser tion and deletion (indels). In the alpha block surrounding HLA-A, there are ten duplication units or bead s on the 62.1 ancestral haplotype. Each bead contains or contained sequence s representing Class I, PERB11 (MHC Class I chain related (MIC)) and human endogenous retrovirus (HERV) 16. Here we consider explanations for co-occur rence of genomic polymorphism, duplication and HERVs and we ask how these f eatures encode susceptibility to numerous and very diverse diseases. Ancest ral 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. Populati on-specific integration of retroviral sequences could explain rapid diversi fication through duplication and differential disease susceptibility. If HE RV sequences can be protective, there are exciting prospects for manipulati on. In the meanwhile, it will be necessary to understand the function of MH C genes such as PERB11 (MIC) and many others discovered by genomic sequenci ng.