MHC CLASS I AND KIR GENE EVOLUTION IN HIGHER PRIMATES

高等灵长类动物 MHC I 类和 KIR 基因的进化

• 批准号: 7349828
• 负责人: PETER R PARHAM
• 金额: $ 0.63万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7349828
• 关键词: MHC; CLASS; KIR; GENE; EVOLUTION

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.

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。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构适用于该中心，这不一定是调查员的机构。通过多样化和快速发展的病原体的选择使MHC I类和KIR成为多样化，快速发展的基因家族，这些基因家族控制了先天和适应性免疫中的杀手型淋巴细胞。由于人和小鼠MHC I类基因是如此不同，而KIR基因是灵长类动物特异性的，因此将在大猿中研究这些基因家族，并将其与它们的人类对应物进行比较。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，并欣赏它们对免疫反应和人类健康的后果。四个具体目标包括建立在免疫遗传专业知识的综合攻击，并建立在过去五年中获得的大量新信息基础上。目标1和2将研究新发现的MHC I类基因，该基因为研究MHC I类基因的出生，分化和死亡提供了理想的系统。 AIM 1将检验以下假设：该Al基因已沿着非常不同的进化轨迹进化，成为橙色的高度多态性的“经典” I类I基因，它是黑猩猩中的非多态性的“非经典” I类I基因，并且是人类中的A Defunct corsic Gene。在黑猩猩中，Al蛋白具有暗示适应性和先天免疫功能的特性。 AIM 2的研究将检查Al的功能性能，并搜索结合该配体的细胞表面受体。它将揭示人类免疫系统通过漂移或选择损失的功能。 AIM 3专注于B 7301，这是一个保留祖先（猿）特征并抗拒重组的异常发散的人类HLA-B等位基因。可以解释这些异常特性的三个替代模型：将通过对B 7301侧面的区域的基因组分析来测试和区分种群。 AIM 4专注于猩猩MHC I类和KIR及其在NK细胞调节中的相互作用。这将检验以下假设：猩猩是一种在人类中占主导地位的HLA-C介导的NK细胞调节的物种，正处于发育的中间阶段。