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

The intensely studied MHC has become the paradigm for understanding the arc hitectural evolution of vertebrate multigene families. The 4-Mb human MHC ( also known as the HLA complex) encodes genes critically involved in the imm une response, graft rejection, and disease susceptibility. Here we report t he continuous 1,796,938-bp genomic sequence of the HLA class I region, link ing genes between MICE and HLA-F. A total of 127 genes or potentially codin g sequences were recognized within the analyzed sequence, establishing a hi gh gene density of one per every 14.1 kb. The identification of 758 microsa tellite provides tools for high-resolution mapping of HLA class I-associate d disease genes. Most importantly, we establish that the repeated duplicati on and subsequent diversification of a minimal building block, MIC-HCCIX-3. 8-1-P5-HCGIV-HLA class I-HCGII, engendered the present-day MHC. That the cu rrently nonessential HLA-F and MICE genes have acted as progenitors to toda y's immune-competent HLA-ABC and MICA/B genes provides experimental evidenc e for evolution by "birth and death," which has general relevance to our un derstanding of the evolutionary forces driving vertebrate multigene familie s.