MOLECULAR GENETICS OF THE HUMAN MHC CLASS III REGION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The neighboring human complement C4 and steroid 21-hydroxylase(CYP21) genes are flanked by novel genes RP and Gene X. RP-C4-CYP21-Gene X form a modular structure termed RCCX in the major histocompatability complex(MHC). There is a variation in the number and structure of RCCX modules in the population. Deficiencies of the functional genes in RCCX may lead to genetic and/or autoimmune defects. Three groups of mobile genetic elements have been found by us at the RCCX modules: an endogenous retrovirus HERV-K(C4) which mediates the size variation of C4 genes, eight Alu elements, and a novel group of composite repetitive DN forming a discrete genetic unit, the SVA element, in the RP1 gene. It is proposed here to fully characterize the RCCX modular structures in the population, to analyze the 180 Kb DNA sequence spanning more than ten human genes by mapping the disease markers and mutations. This research will be extended to the 38 members of HERV-K(C4), and the composite SVA in the human genome. The common theme is to elucidate the mechanisms leading to genetic instabilities of the MHC. Determination of DNA sequences, analysis of sequences through multiple sequence alignments and database searching are the most important component of this research. The facilities and software of PSC enable us to analyze the complex structures of RCCX and large amounts of sequence information effectively. Publications - Qu XD, Yang, Z. Shen L, Zhang SX, Dangel AW, Redman KL, Hughes J, Wu LC and Yu CY: The human HLA DEVH-box protein Ski2w is associated with polysomes and ribosomes. Nucleic Acids Res. 26:4068-4077;1998. Yang Z, Shen L, Dangel AW, Wu LC and Yu CY: Four ubiquitously expressed genes, RD(D6S45)-SKI2W (SKIV2L)-DOM3Z-RP1(D6S60E), are present between complement component genes factor B and C4 in the class III region of the HLA. Genomics 53:338-347;1998. Yu CY: Molecular genetics of the human MHC complement gene cluster. Exp. Clin. Immunogenet. 15:213-230;1998. Achievements - Discovered novel gene DOM3Z in the major histocompatibility complex of human and mouse; showed that human DEVH box protein is located in the nucleolus and is associated with ribosomes; elucidated the molecular basis of complement C4A and C4B deficiency in the Caucasian population. Publications - 1. Blanchong, C.A., Zhou, B., Rupert, K.L., Chung, K.T., Jones, K.N., Sotos, J.F., Zipf, W.B., Rennebohm, R.M., and Yu, C.Y. Deficiencies of human complement component C4A and C4B and heterozygosities in length variants of RP-C4-CYP21-TNX (RCCX) modules in Caucasians: the load of RCCX genetic diversity on MHC-associated disease. Journal of Experimental Medicine 191: 2183-2196:2000. This article firmly establishes the 1-2-3 loci phenomenon of the human complement C4 genes and RCCX modules in the Caucasian population. 2. Yu, C.Y., Yang, Z., Blanchong, C.A. and Miller, W. The human and mouse MHC class III region: a parade of 21 genes at the centromeric segment. Immunology Today (in press; July, 2000). This article compares the molecular organizations of the gene structures and correlates sequence conservation with physiological functions between 21 pairs of human and mouse MHC class III genes. These genes start at the outpost of the class III region, NOTCH4 to the end of the complement gene cluster, C2. Molecular genetic studies of these genes would provide important insight for the basis of MHC-associated diseases, as some of the diseases would be related to mutations of the novel genes in this region. The article also describes the clustering of genes with related functions, and reviews the RCCX modular variations and genetic recombinations between the RCCX constituents. 3. Yang, Z. and Yu, C.Y. Organizations and gene duplications of the human and mouse MHC complement gene clusters. Exp. Clin. Immunogenet. 17:1-17:2000. [with cover illustration of the journal] This article describes duplications of the mouse RP, C4, CYP21 and TNX genes and compares the organizations of human and mouse MHC complement gene clusters. It also reports the cloning and characterization of mouse RP1 and DOM3Z cDNAs. Achievements - Three very important publications (see below)