MOLECULAR GENETICS OF THE HUMAN MHC CLASS III REGION

人类 MHC III 类区域的分子遗传学

• 批准号: 7601294
• 负责人: CHACK Y YU
• 金额: $ 0.03万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7601294
• 关键词: Achievement; Alu Elements; Autoimmune Process; Boxing; CYP21A2 gene; Caucasians; Caucasoid Race; Cell Nucleolus; Class; Cloning; Complement; Complement 4b; Complement Component Gene; Complement Factor B; Complement component C4a; Complex; Computer Retrieval of Information on Scientific Projects Database; Computer software; DNA Sequence; DNA Sequence Analysis; Databases; Defect; Disease; Disease Marker; Endogenous Retroviruses; Funding; Gene Cluster; Gene Duplication; Gene Structure; Genes; Genetic; Genetic Variation; Genomics; Grant; HERVs; Human; Human Gene Mapping; Human Genetics; Human Genome; Immunology; Indium; Institution; Journals; Lead; Length; Major Histocompatibility Complex; Mediating; Medicine; Mobile Genetic Elements; Molecular; Molecular Genetics; Mus; Mutation; NOTCH4 gene; Nucleic Acids; Numbers; Physiological; Polyribosomes; Population; Proteins; Publications; Reporting; Research; Research Personnel; Resources; Ribosomes; Sequence Alignment; Source; Steroid 21-Monooxygenase; Structure; Today; United States National Institutes of Health; Variant; Yang; base; human CYP21A2 protein; insight; journal article; member; novel; size

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)

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 相邻的人补体C4和类固醇21-羟化酶（CYP 21）基因的侧翼是新基因RP和基因X。RP-C4-CYP 21-Gene X在主要组织相容性复合体（MHC）中形成称为RCCX的模块结构。种群中RCCX模块的数量和结构存在变化。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模块中发现了三组移动的遗传元件：一个调节C4基因大小变异的内源性逆转录病毒HERV-K（C4），八个Alu元件，以及一组新的复合重复DN，在RP 1基因中形成一个离散的遗传单元--SVA元件。本文提出全面表征人群中的RCCX模块结构，通过绘制疾病标志物和突变来分析跨越十多个人类基因的180 Kb DNA序列。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序列测定、多重序列比对分析和数据库检索是本研究的重要组成部分。PSC的硬件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。出版物- 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 polysome and ribosomes. Nucleic Acids Res. 26：4068-4077;1998. Yang Z、Shen L、Dangel AW、Wu LC和Yu CY：在HLA III类区域的补体成分基因因子B和C4之间存在四个普遍表达的基因RD（D 6S 45）-SKI 2 W（SKIV 2L）-DOM 3 Z-RP 1（D 6S 60 E）。Genomics 53：338-347;1998.于春艳：人类MHC补体基因簇的分子遗传学。Exp.临床免疫学15：213-230;1998.成果-在人类和小鼠的主要组织相容性复合体中发现了新基因DOM 3 Z;表明人类DEVH盒蛋白位于核仁中并与核糖体相关;阐明了高加索人群中补体C4 A和C4 B缺乏的分子基础。 出版物- 1. Blanchong，CA，Zhou，B.，鲁珀特，K.L.，Chung，K.T.，Jones，K.N.，索托斯，J.F.，Zipf，W.B.，Rennebohm，R.M.，和Yu，C.Y.高加索人补体成分C4 A和C4 B缺陷以及RP-C4-CYP 21-TNX（RCCX）模块长度变体的杂合性：RCCX遗传多样性对MHC相关疾病的影响实验医学杂志191：2183-2196：2000。本文明确了高加索人群中人补体C4基因和RCCX模块的1-2-3位点现象。2. Yu，C.Y.，杨志，Blanchong，C.A.和米勒，W.人类和小鼠MHC III类区域：着丝粒段的21个基因的游行。《今日免疫学》（2000年7月出版）。本文比较了21对人类和小鼠MHC III类基因的分子结构，并将其序列保守性与生理功能联系起来。这些基因开始于III类区域的前哨，NOTCH 4到补体基因簇C2的末端。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，因为一些疾病与该区域新基因的突变有关。本文还介绍了具有相关功能的基因的聚类，并回顾了RCCX模块的变化和RCCX组分之间的遗传重组。3.杨，Z.和Yu，C.Y.人类和小鼠MHC补体基因簇的组织和基因复制。Exp.临床免疫学17：1-17：2000。[with本文描述了小鼠RP、C4、CYP 21和TNX基因的重复，并比较了人和小鼠MHC补体基因簇的组织。本文还报道了小鼠RP 1和DOM 3 Z cDNA的克隆和鉴定。 成就-三份非常重要的出版物（见下文）