The MHC of wild chimpanzees: genetic variation, disease and reproductive success

描述(申请人提供)：主要组织相容性复合体(MHC)是一组对免疫反应至关重要的基因，因为它编码所有脊椎动物的抗原呈递蛋白。它保持着高度的多态，并与疾病、寄生虫抗性和繁殖成功有关。研究野生动物种群在其自然环境中的MHC对于了解MHC的功能、选择压力和进化史是必不可少的。长期目标是了解MHC如何影响人类的健康和生殖。这项建议的目的是在第一次对野生黑猩猩的研究中检查MHC的遗传变异和功能。对于人类来说，它们是一个有价值的模式系统，因为它们是我们最亲近的亲属，拥有超过98%的相同基因组和相似的社会模式，但社会经济混杂较少。这项研究将1)表征坦桑尼亚贡贝国家公园黑猩猩种群中MHC的遗传变异；2)检查MHC基因与健康指标的相关性，包括寄生虫载量和疾病易感性；3)调查MHC基因与繁殖成功的关系。黑猩猩将使用从粪便中非侵入性分离的DNA对MHC I类(A、B、C)和II类(DR、DQ、DP)经典基因座进行基因分型。黑猩猩的遗传变异将被表征，并将与可比的人类种群进行比较。健康和生殖成功的衡量标准将与特定等位基因的存在或不存在以及个体的杂合度相关。MHC匹配的交配对也将接受测试，以寻找与MHC匹配的配对相比生殖成功率降低的证据。MHC多态及其在自我和异体识别中的作用是导致组织移植排斥反应的关键因素，因此对MHC多态和功能的免疫遗传学研究是非常必要的。这项研究也将进一步加深对疾病抵抗力的理解，因为研究表明MHC等位基因的组成和多样性与免疫活性直接相关。此外，它还将有助于理解由于特定有害等位基因和个体杂合度而导致的不孕不育和失败妊娠，以及父母MHC匹配。 公共卫生相关性：研究免疫系统核心组成部分的编码基因对人类健康的几个方面至关重要。这些基因决定了人体对自我和非自我的认知，因此在组织移植排斥反应中起着关键作用。此外，这些基因的差异会影响身体抗击疾病的能力，以及个体和夫妇成功繁殖的能力。

DESCRIPTION (provided by applicant): The major histocompatibility complex (MHC) is a cluster of genes critical to the immune response since it codes for antigen-presenting proteins in all vertebrates. It maintains a high level of polymorphism and has been linked to disease and parasite resistance and reproductive success. Studies of the MHC in wild animal populations in their natural environment are essential to understanding MHC function, selective pressures and evolutionary history. The long-term goal is to understand how the MHC influences health and reproduction in humans. The objective of this proposal is to examine the genetic variation and function of the MHC in the first study of wild chimpanzees. They are a valuable model system for humans because they are our closest living relative and have over 98% identical genomes and similar social patterns but less socioeconomic confounds. The study will 1) Characterize the MHC genetic variation in the chimpanzee population (Pan troglodytes schweinfurthii) at Gombe National Park, Tanzania; 2) Examine the correlation between MHC genotype and health measures, including parasite load and disease susceptibility; 3) Investigate the relationship between MHC genotype and reproductive success. Chimpanzees will be genotyped at MHC class I (A, B, C) and class II (DR, DQ, DP) classical loci using DNA isolated non-invasively from feces. Genetic variation will be characterized within chimpanzees and will also be compared to that of comparable human populations. Measures of health and reproductive success will be correlated with the presence or absence of particular alleles as well as the degree of heterozygosity of individuals. MHC-matched mating pairs will also be tested for evidence of decreased reproductive success compared to MHC-unmatched pairs. Immunogenetic study of MHC polymorphism and function is essential because MHC polymorphism, and its role in self and non-self recognition, is a key factor causing tissue transplant rejection. This study will also further the understanding of disease resistance as studies suggest MHC allelic composition and diversity are directly related to immunocompetence. Furthermore, it will contribute to the understanding of infertility and failed pregnancy due to particular deleterious alleles and the degree of heterozygosity of individuals, as well as parental MHC matching. PUBLIC HEALTH RELEVANCE: Study of the genes that code for the core components of the immune system is essential to several aspects of human health. These genes determine the body's recognition of self versus non-self, and therefore play a key role in tissue transplant rejection. Additionally, differences in these genes affect the body's ability to fight disease as well as the ability of individuals and couples to successfully reproduce.