Evolution and Function of Immunogenetic Diversity across the Eastern Hemisphere

摘要 人类白细胞抗原（HLA）和杀伤细胞免疫球蛋白样受体（KIR）是免疫球蛋白的重要方面。 人体免疫系统由自然杀伤细胞（NK细胞）表达的KIR与HLA I类的相互作用， 由大多数组织细胞表达，调节免疫细胞功能。高度多态性的KIR和 HLA基因与NK细胞功能直接相关，对人类健康有深远影响，包括 与自身免疫和神经系统疾病、感染性疾病严重程度、妊娠相关 综合症和癌症风险。我们解决免疫介导疾病机制的能力， 个性化的药物，包括免疫疗法，并匹配器官捐赠者与受体依赖于我们的 准确表征KIR和HLA I类多样性的能力。尽管这一点至关重要，但缺乏 关于KIR和HLA I类多样性的程度和性质的知识。这一赤字包括 东半球占世界人口的一半， 在美国的团体。在本项目中，我们将通过确定 整个东部地区KIR和HLA I类多样性的特征和功能后果 半球 我们将研究代表51个离散种群的15，612个个体，包括土著种群 来自东亚、南亚、多个太平洋岛屿和大洋洲。为了克服分析这些问题的困难， 复杂的基因组区域，我们开发了一种靶向测序和生物信息学方法来分析KIR 和HLA-I类基因。为了分析另外22，905人，我们将 开发一种插补算法，从全基因组SNP数据中确定高分辨率KIR等位基因。我们 我将专门为这些在以前的研究中被忽视的人群构建插补小组。 分析。这一目标将通过生成的大量培训数据得以实现。然后我们将 描述KIR和HLA单倍型在东半球的分布。 我们将研究自然选择如何塑造KIR和HLA多样性的地理模式 研究适应性基因渗入和混合对KIR和HLA基因座的影响 in our study研究populations人群.我们将确定我们已确定为 是自然选择的目标我们将努力实现这些目标， 工具.这些进展包括CRISPR/cas9靶向长读序测序，以检查KIR结构， 多样性，以及鉴定受自然选择影响的等位基因的方法，以及选择作用于 他们这项工作的预期结果是HLA和KIR的遗传和功能特征， 多个人群，并全面了解这种变化是如何在地理上 由自然选择分布和塑造。这项工作将有利于免疫介导的研究， 传染病和建立个性化治疗的个人都在美国和 国际吧

ABSTRACT Human leukocyte antigens (HLA) and killer cell immunoglobulin-like receptors (KIR) are critical facets of the human immune system. Interactions of KIR, expressed by natural killer cells (NK cells), with HLA class I, expressed by most tissue cells, modulate immune cell functions. Variations in the highly polymorphic KIR and HLA genes are linked directly to NK cell functions and have profound impact on human health, including associations with autoimmunity and neurological disease, severity of infectious disease, pregnancy syndromes, and risk of cancer. Our ability to resolve the mechanisms of immune-mediated disease, to develop personalized medicines, including immunotherapies, and to match organ donors with recipients relies on our ability to accurately characterize KIR and HLA class I diversity. Despite this crucial importance, there is a lack of knowledge concerning the extent and nature of KIR and HLA class I diversity worldwide. This deficit includes the Eastern Hemisphere, which encompasses half the world's population, and multiple underrepresented groups in the USA. During this project we will fill these gaps in this knowledge through determining the characteristics and functional consequences of KIR and HLA class I diversity across the entire Eastern Hemisphere. We will examine 15,612 individuals representing 51 discrete populations, including indigenous populations from East Asia, South Asia, multiple Pacific Islands and Oceania. To overcome difficulties in analyzing these complex genomic regions, we developed a targeted sequencing and bioinformatics approach to analyze KIR and HLA class I genes at high throughput and resolution. To analyze an additional 22,905 individuals, we will develop an imputation algorithm to determine high-resolution KIR alleles from whole-genome SNP data. We will construct imputation panels specifically for these populations who have been neglected in previous analyses. This goal will be made possible through the extensive training data generated. We will then characterize the distribution of KIR and HLA haplotypes across the Eastern Hemisphere. We will examine how the geographic patterns of KIR and HLA diversity have been shaped by natural selection and investigate the impact of adaptive introgression and admixture specifically focused to the KIR and HLA loci in our study populations. We will determine the functional properties of those variants we have identified as targeted by natural selection. We will pursue these aims implementing innovative laboratory and analytical tools. These developments include CRISPR/cas9 targeting of long-read sequencing to examine KIR structural diversity, and methods both to identify alleles subject to natural selection, and the mode of selection acting on them. The expected outcome of this work is the genetic and functional characterization of HLA and KIR across multiple human populations, and a comprehensive understanding of how this variation is geographically distributed and shaped by natural selection. This work will benefit investigations of immune-mediated and infectious disease and in establishment of personalized treatments for individuals both in the USA and worldwide.