EVOLUTION, SELECTION AND ORIGINS OF CLASS I MHC MOLECULE

I 类 MHC 分子的进化、选择和起源

• 批准号: 3146219
• 负责人: PETER R PARHAM
• 金额: $ 17.9万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-04-01 至 1996-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3146219
• 关键词: MHC class I antigen; MHC class II antigen; Pan; T lymphocyte; alleles; biochemical evolution; cellular immunity; complementary DNA; genetic library; histocompatibility antigens; human population genetics; immunogenetics; molecular cloning; nucleic acid sequence; polymerase chain reaction

DESCRIPTION (Adapted from the applicant's abstract): The immune system of higher vertebrates provides mechanisms of defense against a variety of antigens and rapidly evolving infectious agents. Almost all immune responses involve T-lymphocytes, cells clonally expressing a variable antigen receptor that interacts with processed peptide antigens bound to either class I or class II Major Histocompatibility Complex (MHC) molecules. Multiple, highly polymorphic MHC loci are expressed and they differ between species. It is hypothesized that this provides diversification in T cell responsiveness. Moreover, there is evidence that selection based upon the prevailing requirement for T cell immunity can act to introduce new alleles and inactivate old ones. The class I genes are particularly active in this regard. The best characterized MHCs, those of humans and mice, show such tremendous diversification that they provide little understanding of short range evolution. In this investigation class I MHC genes and polymorphism in ape species, closely related to humans, will be analyzed. This will allow the fate of genes and alleles over periods of 5 to 20 million years to be assessed, provide further understanding of mutational events and a perspective from which to assess HLA polymorphism and its relationship to disease. Methods will be developed for cloning class I HLA obtained from soft tissues of individuals, dated at 7500 years old and well-preserved in an acidic lake in Florida. The sequences of these alleles will be compared to those found in contemporary human, including Amerindian, populations. The phylogenetic origins and diversity of class I MHC heavy chains will be investigated. A polymerase chain-based method has been used to identify and obtain probes for class I genes in fish, reptiles and amphibians. The class I genes and polymorphism of selected species will be characterized and compared to their homologues in mammals and birds. This information will enable strategies for the examination of invertebrate species for class I genes to be designed.

描述(改编自申请者的摘要)： 高等脊椎动物提供了防御各种 抗原和快速进化的传染病病原体。几乎所有人都免疫 反应涉及T淋巴细胞，即克隆表达一种变量的细胞 与结合在一起的已加工多肽抗原相互作用的抗原受体 I类或II类主要组织相容性复合体(MHC) 分子。表达了多个高度多态的MHC基因座，它们 不同物种之间的差异。据推测，这提供了 T细胞反应性的多样化。此外，有证据表明， 基于对T细胞免疫的普遍需求的选择可以起作用 引入新的等位基因，使旧的等位基因失活。I类基因是 在这方面特别积极。最具特色的MHC，那些 人类和老鼠表现出如此巨大的多样性，它们提供了 对短期进化知之甚少。在这堂调查课上 与人类亲缘关系密切的猿类物种的MHC基因和多态性， 将会被分析。这将允许基因和等位基因的命运超过 有待评估的500万至2000万年的期间，进一步规定 对突变事件的理解和评估的视角 人类白细胞抗原基因多态性及其与疾病的关系。 将开发克隆从SOFTWARE获得的I类HLA的方法 个人的组织，日期在7500年前，保存完好 佛罗里达州的酸性湖。这些等位基因的序列将与 在包括美洲印第安人在内的当代人中发现的那些。这个 I类MHC重链的系统起源和多样性将是 调查过了。一种基于聚合酶链的方法被用来鉴定 并获得鱼类、爬行动物和两栖动物中I类基因的探针。这个 将描述选定物种的I类基因和多态。 并与它们在哺乳动物和鸟类中的同源物进行比较。此信息 将使研究无脊椎动物物种的战略成为可能 第一类基因将被设计。