Molecular dynamics of MHC genesis unraveled by sequence analysis of the 1,796,938-bp HLA class I region

Abstract

The intensely studied MHC has become the paradigm for understanding the architectural evolution of vertebrate multigene families. The 4-Mb human MHC (also known as the HLA complex) encodes genes critically involved in the immune response, graft rejection, and disease susceptibility. Here we report the continuous 1,796,938-bp genomic sequence of the HLA class I region, linking genes between MICB and HLA-F. A total of 127 genes or potentially coding sequences were recognized within the analyzed sequence, establishing a high gene density of one per every 14.1 kb. The identification of 758 microsatellite provides tools for high-resolution mapping of HLA class I-associated disease genes. Most importantly, we establish that the repeated duplication and subsequent diversification of a minimal building block, MIC-HCGIX-3.8 -1-P5-HCGIV-HLA class I-HCGII, engendered the present-day MHC. That the currently nonessential HLA-F and MICE genes have acted as progenitors to today's immune-competent HLA-ABC and MICA͞B genes provides experimental evidence for evolution by ''birth and death,'' which has general relevance to our understanding of the evolutionary forces driving vertebrate multigene families.

Genomic evolution of MHC class I region in primates

“…14. A number of genes have been shown to possess their duplicated counterparts in the yeast genome (15,16), the human genome (17)(18)(19), and other genomes (20). Actually, in the case of the yeast genome, the duplicated genes are considered to be products of genome fragments duplication (GFD), rather than those of gene duplication (15,16).…”

Natural killer cell receptors: new biology and insights into the graft-versus-leukemia effect

“…Bahram 91 and Shiina et al 92 have demonstrated that MIC transcripts are not expressed in the spleen and cells of the lymphohematopoietic lineage, although they are expressed in fibroblast and epithelial cell lines as well as almost all tissues harboring these cell types. The expression of MICA and MICB are under the control of promoter elements similar to those of the heat shock protein gene PSP70.…”

“…91 There are 7 MIC loci, A to G, but only the MICA and MICB genes are transcribed; MIC-C, -D, -E, -F and -G are pseudogenes. [91][92][93] The MIC glycoproteins contain 3 MHC-like ␣-domains but, in contrast to MHC class I molecules, do not require ␤ 2 -microglobulin or peptide for stable surface expression. 95 MICA and MICB have been shown to be specific ligands for human NKG2D.…”

“…In the human, these recently defined ligands belong to 2 distinct families, the MHC class I chain-related (MIC) antigens, and the UL16 binding proteins (ULBPs). [91][92][93][94] The MIC antigens are encoded by a distinct family of genes stationed along the entire MHC class I region on human chromosome 6. They have a low degree of homology to other MHCencoded class I genes, distinct transcriptional control elements, and a peculiar pattern of polymorphism.…”

How selection shapes variation of the human major histocompatibility complex: a review

“…The location of large numbers of polymorphic markers (e.g. over 700 microsatellite loci in the class I region alone, Shiina et al 1999) will be useful in efforts to estimate recombination rates among loci and refine observations of hotspots of recombination in the HLA region (Thomsen et al 1997).…”