Comparative MHC and KIR immunogenetics in the Great Apes

 描述（由申请人提供）：主要组织相容性复合体（MHC）编码的蛋白质和杀伤细胞免疫球蛋白样受体（KIR）在先天免疫、适应性免疫和生殖中发挥关键作用。HLA I类和KIR基因型的组合独特地使人类免疫系统多样化，并且与感染性、过敏性、自身免疫性和炎性疾病以及生殖成功密切相关。由于MHC和KIR基因进化迅速，与人类关系最密切的类人猿是迄今为止免疫遗传学和免疫基因组学比较的最佳模型系统。但这些研究仅限于少数圈养动物，这些动物不能很好地代表自然多样性和种群结构。在对野生黑猩猩贡贝种群的一项开创性研究中，我们发现了MHC-B等位基因跨物种谱系的深层进化根源，其中包括黑猩猩Patr-B*06和人类HLA-B*57，并可预防艾滋病毒/SIV疾病进展。这表明研究野生猿种群揭示了结构变异和功能之间的新联系和见解。我们建议在两个维度上扩展这种分析。首先，我们将深化分析以涵盖所有MHC和KIR基因。第二，我们将分析扩大到43个种群，代表9个非洲巨猿物种和亚种中的8个。目标1将开发新的方法快速获取序列数据和自动分析。目标2将产生一个完整的描述非洲大猿KIR和MHC基因及其等位基因的多样性在自然种群。对这些数据的分析将确定KIR受体及其MHC I类配体如何在非洲类人猿中共同进化，以及物种和亚种之间的差异。目标3将把免疫遗传多样性与非洲巨猿群体中SIV可变发生率相关的功能结果联系起来。来自两个经过充分研究的黑猩猩种群的纵向数据将用于确定与疾病、生存和繁殖成功相关的因素。总之，我们提出了一个全面的分析的免疫遗传学和免疫基因组学的自然种群的物种最密切相关的人类。这些结果将为人类免疫系统提供新的视角，并大大扩展我们对其优势和弱点的了解。

 DESCRIPTION (provided by applicant): Major histocompatibility complex (MHC) encoded proteins and Killer cell immunoglobulin-like receptors (KIR) serve critical functions in innate immunity, adaptive immunity and reproduction. The combination of HLA class I and KIR genotype uniquely diversifies human immune systems and is strongly associated with infectious, allergic, autoimmune and inflammatory diseases as well as reproductive success. Because MHC and KIR genes evolve rapidly, Great Apes, the species most closely related to humans, are by far best model systems for immunogenetic and immunogenomic comparisons. But such studies have been limited to small numbers of captive animals that poorly represent the natural diversity and population structure. In a pioneering study of the Gombe population of wild chimpanzees, we uncovered deep evolutionary roots of a trans-species lineage of MHC-B alleles, that includes chimpanzee Patr-B*06 and human HLA-B*57 and protects against HIV/SIV disease progression. This demonstrates how studying wild ape populations reveals novel linkage and insight between structural variation and function. We propose to expand this analysis in two dimensions. First, we will deepen the analysis to encompass all MHC and KIR genes. Second, we will broaden the analysis to 43 populations that represent eight of the nine African Great Ape species and subspecies. Aim 1 will develop new methods for rapid acquisition of sequence data and its automated analysis. Aim 2 will produce a complete description of the African Great Ape KIR and MHC genes and their allelic diversity in natural populations. Analysis of these data will determine how the KIR receptors and their MHC class I ligands have co-evolved in African Great Apes and how this differs between species and subspecies. Aim 3 will connect immunogenetic diversity with functional outcomes associated with the variable occurrence of SIV in the African Great Ape populations. Longitudinal data from two well-studied chimpanzee populations will be used to identify factors associated with disease, survival and reproductive success. In sum, we propose a comprehensive analysis of the immunogenetics and immunogenomics of natural populations of the species most closely related to humans. The results will give new perspectives on the human immune system and greatly expand our knowledge of its strengths and weaknesses.