POPULATION GENETICS OF THE HLA REGION

HLA 区域的群体遗传学

• 批准号: 3287886
• 负责人: GLENYS J THOMSON
• 金额: $ 18.46万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-04-01 至 1994-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3287886
• 关键词: alleles; biological polymorphism; ethnic group; evolution; gene conversion; genetic disorder; genetic mapping; genetic markers; genetic models; genome; haploidy; histocompatibility gene; human genetic material tag; human population genetics; immune response genes; immunogenetics; linkage mapping; major histocompatibility complex; mathematical model; nucleic acid sequence; restriction fragment length polymorphism; restriction mapping

The human histocompatibility (HLA) system contains a number of closely linked genes whose products control a variety of functions concerned with the regulation of immune responses. The great variety and complexity of molecular, genetic and physiological phenomena present in the HLA region make it an extraordinary resource and testing ground for examining evolutionary processes. To understand the mechanisms by which disease predisposing genes become common in populations, it is essential that we be familiar with the population genetics features and multilocus interaction of specific genetic regions of the human genome in both general and patient population data. This particularly applied to the HLA region which has been shown to influence disease susceptibility to over 40 diseases. The specific aim of our research is investigation of theoretical and empirical population genetic data of multilocus systems with particular emphasis on the investigation of models to elucidate the evolutionary history of the HLA region. Our research approach will be based on mathematical modelling and development of methods to analyze a number of large population data sets available to us. Our studies will include identification of HLA haplotypes subject to recent selection events, investigation of the relationship of linkage disequilibrium to map distance, ethnic comparison of evolutionary events, establishment of the relative importance of point mutation, gene conversion and intragenic recombination in the evolution of HLA alleles and of a phylogenetic tree incorporating these events, analysis of the apparently different evolutionary histories of genes in the HLA regions, analysis of 11 non-HLA genetic markers from a large French study as well as of restriction fragment length polymorphism (RFLP) data that is accumulating for the human genome; and modelling of life history selection in the HLA region and the effect of finite and variable population size in the context of HLA variation. The methods developed to study the HLA region are in most cases directly applicable to other regions of the human genome. Over 500 RFLP sites have been mapped in the human genome and the number of expected to increase tremendously in the next few years. The rest of our study will contribute to inferences that can be made on the forces acting in natural populations, and how these contribute to the origin, maintenance and evolution of genetic variation, as well as the delineation of possible mechanisms by which disease predisposing genes become common in population.

人类组织相容性（HLA）系统包含许多 紧密相连的基因，其产物控制多种功能 与免疫反应的调节有关。 伟大的 分子、遗传和生理学的多样性和复杂性 HLA 区域中存在的现象使其成为非凡的 检查进化过程的资源和试验场。 了解疾病诱发基因的机制 在人群中变得普遍，我们必须熟悉 具有群体遗传学特征和多位点相互作用 人类基因组的特定遗传区域 和患者群体数据。 这尤其适用于 HLA 已被证明影响疾病易感性的区域 超过40种疾病。 我们研究的具体目标是理论调查 和多位点系统的经验群体遗传数据 特别强调模型研究以阐明 HLA 区域的进化史。 我们的研究方法将 基于数学建模和方法开发 分析我们可用的大量人口数据集。 我们的研究将包括 HLA 单倍型的鉴定 到最近的选择事件，调查关系 连锁不平衡与地图距离、种族比较 进化事件，建立相对重要性 点突变、基因转换和基因内重组 HLA 等位基因的进化和系统发育树的进化 这些事件，对明显不同的进化的分析 HLA 区域基因的历史，11 个非 HLA 的分析 来自法国一项大型研究的遗传标记以及限制 正在积累的片段长度多态性 (RFLP) 数据 人类基因组；以及生活史选择的建模 HLA 区域和有限且可变的群体规模的影响 在 HLA 变异的背景下。 在大多数情况下，研究 HLA 区域的方法是 直接适用于人类基因组的其他区域。 超过500 RFLP 位点已在人类基因组中绘制，并且数量 预计未来几年将大幅增长。 其余的部分 我们的研究将有助于做出推论 作用于自然群体的力量，以及这些力量如何促进 遗传变异的起源、维持和进化，以及 作为疾病发生的可能机制的描述 诱发基因在人群中变得普遍。