A NEW POLYMORPHIC AND MULTICOPY MHC GENE FAMILY RELATED TO NONMAMMALIAN CLASS-I

We have used genomic analysis to characterize a region of the central major histocompatibility complex (MHC) spanning similar to 300 kilobas es (kb) between TNF and HLA-B. This region has been suggested to carry genetic factors relevant to the development of autoimmune diseases su ch as myasthenia gravis (MG) and insulin dependent diabetes mellitus ( IDDM). Genomic sequence was analyzed for coding potential, using two n eural network programs, GRAIL and GeneParser. A genomic probe, JAB, co ntaining putative coding sequences (PERB11) located 60 kb centromeric of HLA-B, was used for northern analysis of human tissues. Multiple tr anscripts were detected. Southern analysis of genomic DNA and overlapp ing YAC clones, covering the region from BAT1 to HLA-F, indicated that there are at least five copies of PERB11, four of which are located w ithin this region of the MHC. The partial cDNA sequence of PERB11 was obtained from poly-A RNA derived from skeletal muscle. The putative am ino acid sequence of PERB11 shares similar to 30% identity to MHC clas s I molecules from Various species, including reptiles, chickens, and frogs, as well as to other MHC class I-like molecules, such as the IgG FcR of the mouse and rat and the human Zn-alpha 2-glycoprotein. From direct comparison of amino acid sequences, it is concluded that PERB11 is a distinct molecule more closely related to nonmammalian than know n mammalian MHC class I molecules. Genomic sequence analysis of PERB11 from five MHC ancestral haplotypes (AH) indicated that the gene is po lymorphic at both DNA and protein level. The results suggest that we h ave identified a novel polymorphic gene family with multiple copies wi thin the MHC.