MOLECULAR GENETICS OF THE HUMAN MHC CLASS III REGION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 在相邻的人类补体C4和类固醇21-羟基酶(CyP21)基因的两侧是新的基因RP和基因X。在主要组织相容性复合体(MHC)中，RP-C4-CyP21-基因X形成了一个称为RCCX的模块结构。在种群中，RCCX模块的数量和结构存在差异。RCCX中功能基因的缺陷可能导致遗传和/或自身免疫缺陷。我们在RCCX模块中发现了三组可移动的遗传元件：介导C4基因大小变异的内源性逆转录病毒HERV-K(C4)，8个Alu元件，以及在RP1基因中形成一个离散遗传单位的一组新的复合重复Dn，即SVA元件。通过绘制疾病标志物和突变图谱来分析跨越十多个人类基因的180kb DNA序列，从而全面描述RCCX在人群中的模块化结构。这项研究将扩展到HERV-K(C4)的38个成员，以及人类基因组中的复合SVA。共同的主题是阐明导致MHC遗传不稳定性的机制。DNA序列的确定、多序列比对的序列分析和数据库搜索是本研究最重要的组成部分。PSC的设备和软件使我们能够有效地分析RCCX的复杂结构和大量的序列信息。作者：曲晓东，杨扬，沈振中，L，张世贤，AW，Redman KL，Hughes J，Wu LC，Yu Cy：人类HLADEVH-box蛋白Ski2w与多聚体和核糖体相关。《核酸研究》26：4068-4077；1998。4个普遍表达的基因RD(D6S45)-SKI2W(SKIV2L)-DOM3Z-RP1(D6S60E)存在于人类白细胞抗原Ⅲ类补体基因因子B和C4之间。《基因组学》53：338-347；1998。余承勇：人类MHC补体基因簇的分子遗传学。实验克莱恩。免疫原网。15：213-230；1998。成果-在人和鼠的主要组织相容性复合体中发现了新的基因DOM3Z；表明人DEVH box蛋白位于核仁中，并与核糖体相关；阐明了高加索人群补体C4a和C4b缺乏的分子基础。Blanchong，C.A.，周，B.，Rupert，K.L.，Chung，K.T.，Jones，K.N.，Sotos，J.F.，Zipf，W.B.，Rennebohm，R.M.，and Yu，C.Y.人类补体成分C4a和C4b的缺陷以及高加索人Rp-C4-CyP21-Tnx(RCCX)模块长度变异的杂合性：RCCX遗传多样性对MHC相关疾病的负载。《实验医学杂志》191：2183-2196：2000。本文确定了高加索人群中人类补体C4基因和RCCX模块的1-2-3位点现象。2.Yu，C.Y.，Yang，Z.，Blanchong，C.A.，Miller，W.人类和小鼠MHC III类区域：着丝粒片段的21个基因组成的序列。《今日免疫学》(出版，2000年7月)。本文比较了21对人和小鼠MHC III类基因的基因结构的分子结构，并将序列保守性与生理功能联系起来。这些基因从第三类区域NOTCH4的前哨开始到补体基因簇C2的末端。对这些基因的分子遗传学研究将为MHC相关疾病的基础提供重要的见解，因为一些疾病可能与该区域新基因的突变有关。文章还介绍了具有相关功能的基因的聚集性，并对RCCX组分之间的模块变异和遗传重组进行了综述。3.人和小鼠MHC补体基因簇的组织结构和基因复制。实验克莱恩。免疫原网。17：1-17：2000。[附杂志封面插图]本文描述了小鼠RP、C4、CYP21和TNX基因的复制，并比较了人和小鼠MHC补体基因簇的组织结构。还报道了小鼠RP1和DOM3Z cDNAs的克隆和鉴定。成就--三份非常重要的出版物(见下文)

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)