MECHANISMS OF SOMATIC MUTATION OF IMMUNOGLOBULIN GENES

免疫球蛋白基因体细胞突变机制

• 批准号: 2181008
• 负责人: Nancy Maizels
• 金额: $ 13.63万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-12-01 至 1994-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2181008
• 关键词: B cell receptor; B lymphocyte; cell transformation; gene conversion; gene mutation; immunogenetics; immunoglobulin genes; immunoregulation; laboratory mouse; lymph nodes; molecular cloning; molecular pathology; nucleic acid sequence; polymerase chain reaction; pseudogenes

Somatic hypermutation is the targetted process of mutagenesis which introduces single base changes into the rearranged variable regions encoding immunoglobulin heavy and light chains. Mutations are localized to the V regions of the rearranged heavy and light chain loci; promoter, leader, and constant regions do not display mutations, nor do unrearranged germ line V regions. The rate of mutation, 10-3 per base per generation, is about one million-fold higher that the typical rate of mutation in a mammalian cell. Somatic hypermutation results in the production of some B cell clones with increased affinity for antigen, thus enhancing the efficiency of the immune response. We have exciting recent results showing that gene conversion is the mechanism of somatic hypermutation of mammalian immunoglobulin genes. Our long-term goal is to understand in detail the molecular mechanism and regulation of the process of immunoglobulin gene hypermutation. Our specific experimental goals are (1) to expand the database demonstrating that gene conversion mediates somatic hypermutation: (2) to determine the molecular parameters of this process; and (3) to analyze the regulation of somatic hypermutation, asking in particular whether germinal centers are the site of hypermutation, and whether hypermutation and heavy chain class switch recombination are coordinately regulated. These experiments address the mechanism of a fundamental process in the immune response. Furthermore, since the somatic events that diversity the cellular genome during B lymphocyte development probably occur by directed use of mechanisms common to all cells, understanding the mechanism of somatic hypermutation at the immunoglobulin loci is likely to provide insight into analogous mutation events that are central to genomic evolution, genetic disease, and oncogenesis.

躯体过度突击是诱变的靶向过程， 将单个基础更改引入重新排列的变量区域 编码免疫球蛋白沉重和轻链。 突变本地化为 重新安排重链和轻链基因座的V区域；发起人， 领导者和恒定区域不显示突变，也没有透明 细菌线V区域。 突变速率，每一代每一代10-3， 与典型的突变发生率大约高约百万 哺乳动物细胞。 躯体过度突击导致一些B的产生 细胞克隆对抗原的亲和力增加，从而增强了 免疫反应的效率。 我们有令人兴奋的结果显示 该基因转化是哺乳动物体细胞超夸的机制 免疫球蛋白基因。 我们的长期目标是详细了解 免疫球蛋白基因过程的分子机制和调节 超名。 我们具体的实验目标是（1）扩展 数据库表明基因转化介导了体细胞超称： （2）确定该过程的分子参数； （3）到 分析躯体超臭的调节，特别是询问 生发中心是否是过度突击的位置，以及是否是 超名和重型链级开关重组是协调的 受监管。 这些实验解决了基本的机制 免疫反应中的过程。 此外，自从躯体事件以来 多样性B淋巴细胞发育过程中的细胞基因组可能 通过直接使用所有细胞共有的机制，了解 免疫球蛋白基因座的体细胞超数机理可能会达到 提供对基因组核心类似突变事件的见解 进化，遗传疾病和肿瘤发生。