MHC CLASS I AND KIR GENE EVOLUTION IN HIGHER PRIMATES

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。通过多样和快速进化的病原体的选择，已经驱动MHC I类和KIR成为控制先天和适应性免疫中的杀伤淋巴细胞的多样和快速进化的基因家族。由于人类和小鼠的MHC I类基因是如此不同，KIR基因是灵长类动物特异性的，这些基因家族将在类人猿中进行研究，并与人类进行比较。这种方法将了解这些基因家族多样化和共同进化的遗传原理，并了解它们对免疫反应和人类健康的影响。四个具体目标包括一个综合和独特的攻击基础上免疫遗传学的专业知识和建立在大量的新信息在过去五年中获得。目的1和2将研究一个新发现的MHC I类基因，为研究MHC I类基因的出生、分化和死亡提供一个理想的系统。目的1将检验这一假设，即AL基因已经沿着沿着非常不同的进化轨迹进化成猩猩中的高度多态性“经典”I类基因、黑猩猩中的非多态性“非经典”I类基因和人类中的不存在的遗迹基因。在黑猩猩中，AL蛋白具有暗示在适应性免疫和先天免疫中的功能的特性。目的2的研究将检查AL的功能特性，并寻找结合这种配体的细胞表面受体。它将揭示人类免疫系统已经失去的功能，无论是通过漂移还是选择。目标3集中于B 7301，这是一种异常不同的人类HLA-B等位基因，保留了祖先（类人猿）的特征，并抵抗重组。可以解释这些不寻常特性的三种替代模型：选择、染色体重排和群体分离，将通过对B 7301侧翼区域的基因组分析进行测试和区分。猩猩是最接近人类的物种，其中表达的MHC I类基因的内容是显着不同的。目的4研究红毛猩猩MHC I类分子和KIR在NK细胞调节中的相互作用。这将检验红毛猩猩是一种HLA-C介导的NK细胞调节（在人类中占主导地位）处于中间发育阶段的物种的假设。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Selection by diverse and rapidly evolving pathogens has driven MHC class I and KIR to become diverse and fast evolving gene families that control killer lymphocytes in innate and adaptive immunity. Because human and mouse MHC class I genes are so different and KIR genes are primate-specific, these gene families will be studied in the great apes and compared to their human counterparts. This approach will achieve understanding of genetic principles underlying diversification and co-evolution of these gene families, and appreciation of their consequences for immune response and human health. Four specific aims comprise an integrated and unique attack founded on immunogenetic expertise and built upon substantial new information acquired during the last five years. Aims 1 and 2 will study a newly discovered MHC class I gene that provides an ideal system for studying the birth, differentiation and death of MHC class I genes. Aim 1 will test the hypothesis that this AL gene has evolved along very different evolutionary trajectories to become a highly polymorphic 'classical' class I gene in orangutan, a non- polymorphic 'non-classical' class I gene in chimpanzee, and a defunct relic gene in human. In chimpanzee the AL protein has properties suggestive of functions in both adaptive and innate immunity. The investigation of Aim 2 will examine functional properties of AL and search for cell-surface receptors that bind this ligand. It will reveal functions that the human immune system has lost, either through drift or selection. Aim 3 focuses on B 7301, an exceptionally divergent human HLA-B allele that retains ancestral (ape-like) features and has resisted recombination. Three alternative models that can explain these unusual properties: selection, chromosomal rearrangement, and population isolation, will be tested and distinguished by genomic analysis of the regions flanking B 7301. The orangutan is the species closest to humans in which the content of expressed MHC class I genes is markedly different. Aim 4 focuses on orangutan MHC class I and KIR and their interaction in NK cell regulation. This will test the hypothesis that orangutan is a species in which the HLA-C-mediated regulation of NK cells, which is dominant in humans, is at an intermediate stage of development.