Population Genetics of the HLA Region

HLA 区域的群体遗传学

• 批准号: 6635929
• 负责人: GLENYS J THOMSON
• 金额: $ 26.56万
• 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 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6635929
• 关键词: MHC class I antigen; MHC class II antigen; alleles; biochemical evolution; computer simulation; ethnic group; family genetics; gene conversion; genetic disorder; genetic mapping; genetic markers; genetic models; genetic susceptibility; histocompatibility typing; human genetic material tag; human population genetics; immune response genes; immunogenetics; linkage disequilibriums; linkage mapping; major histocompatibility complex; mathematical model; nucleic acid sequence; polymerase chain reaction; restriction fragment length polymorphism; restriction mapping

Our research includes human, population, and evolutionary genetics, with particular emphasis on study of the HLA region, the major histocompatibility complex (MHC) of humans. The genes of the HLA region control several different functions involved inthe immune response. They also influence susceptibility to over 200 diseases, including autoimmune diseases, cancers, and infectious diseases. A number of functional and population features implicate selection as an important factor maintaining the extensive HLA variation. Although the precise nature of this selection is not known, response to a wide variety of pathogens is believed to be a major evolutionary pressure. Recent advances in genomics, combined with increasing knowledge of structure-function of MHC molecules, provides new tools for exploring HLA polmorphism and an opportunity to address fundamental questions about HLA sequence variation, immunity, and disease. Such detailed information has not previously been available and is critical for a complete understanding of the immune system, autoimmune and infectious diseases, transplantation, and development of T-cell therapies and vaccines. Our major goal is to advance knowledge of the evolutionary factors maintaining the genetic diversity of the HLA classical genes, particularly the selective forces acting, and specifically to identify amino acid sites, and combinations of sites, critically involved in HLA regulated immune responses and in disease predisposition/protection. Our research methodology involved theoretical modeling, computer simulation, molecular biology, and hypothesis testing of genetic data. Theoretical and statistical methods developed in our study of HLA variation have applicability to any polymorphic marker system in humans and other species. Our research will also include genome-wide analyses, given that access to such data will increasingly be available. Characterization of genetic variation across the human genome, including comparison with HLA region data, is essential for mapping complex disease genes, identifying genomic regions that have undergone recent selection, and understanding the origin, maintenance, and evolution of genetic variation in human populations, including variation involved in disease processes.

我们的研究包括人类、群体和进化遗传学，特别侧重于人类白细胞抗原 (HLA) 区域的研究，这是人类的主要组织相容性复合体 (MHC)。 HLA 区域的基因控制着免疫反应中涉及的几种不同功能。 它们还会影响 200 多种疾病的易感性，包括自身免疫性疾病、癌症和传染病。 许多功能和群体特征表明选择是维持广泛的 HLA 变异的重要因素。 尽管这种选择的确切性质尚不清楚，但对多种病原体的反应被认为是主要的进化压力。基因组学的最新进展，加上对 MHC 分子结构功能的了解不断增加，为探索 HLA 多态性提供了新工具，并为解决有关 HLA 序列变异、免疫和疾病的基本问题提供了机会。 此类详细信息以前从未获得过，对于全面了解免疫系统、自身免疫和传染病、移植以及 T 细胞疗法和疫苗的开发至关重要。我们的主要目标是增进对维持 HLA 经典基因遗传多样性的进化因素的了解，特别是选择力的作用，特别是识别与 HLA 调节的免疫反应和疾病密切相关的氨基酸位点和位点组合。倾向/保护。我们的研究方法涉及理论建模、计算机模拟、分子生物学和遗传数据的假设检验。我们在 HLA 变异研究中开发的理论和统计方法适用于人类和其他物种的任何多态性标记系统。 鉴于对此类数据的访问将越来越容易，我们的研究还将包括全基因组分析。人类基因组遗传变异的表征，包括与 HLA 区域数据的比较，对于绘制复杂的疾病基因、识别最近经历选择的基因组区域以及了解人类遗传变异的起源、维持和进化至关重要，包括疾病过程中涉及的变异。