Evolution and Function of Immunogenetic Diversity across the Eastern Hemisphere

摘要 人类白细胞抗原(人类白细胞抗原)和杀伤细胞免疫球蛋白样受体(KIR)是 人类的免疫系统。自然杀伤细胞(NK细胞)表达的KIR与人类白细胞抗原I类分子的相互作用 由大多数组织细胞表达，调节免疫细胞功能。高度多态的KIR和 人类白细胞抗原基因与自然杀伤细胞功能直接相关，并对人类健康有深远影响，包括 自身免疫与神经系统疾病、传染病严重程度、妊娠的关系 症状和癌症风险。我们解决免疫介导性疾病的机制的能力 个性化药物，包括免疫疗法，以及将器官捐赠者与接受者配对依赖于我们的 能够准确表征KIR和HLAI类多样性。尽管这一点至关重要，但它缺乏 关于全世界KIR和HLAI类多样性的范围和性质的知识。这一赤字包括 包括世界一半人口的东半球，以及多个代表性不足的地区 在美国的团体。在这个项目中，我们将通过确定 整个东部地区KIR和HLAI类多样性的特征和功能后果 半球。 我们将检查代表51个离散人口的15,612个个体，包括土著人口 来自东亚、南亚、多个太平洋岛屿和大洋洲。克服分析这些问题的困难 对于复杂的基因组区域，我们开发了一种有针对性的测序和生物信息学方法来分析KIR 和高通量、高分辨率的人类白细胞抗原I类基因。为了分析另外22,905个人，我们将 开发一种用于从全基因组SNP数据中确定高分辨率KIR等位基因的填充算法。我们 将专门为这些在过去被忽视的人群建立归责小组 分析。这一目标将通过生成的大量培训数据来实现。到时候我们会的 描述KIR和人类白细胞抗原单倍型在东半球的分布。 我们将研究KIR和人类白细胞抗原多样性的地理模式是如何由自然选择塑造的 并研究了适应性渗入和混合对KIR和HL A基因座的影响 在我们研究的人群中。我们将确定我们已经确定的那些变体的功能属性 自然选择的目标。我们将实现这些目标，实施创新的实验室和分析 工具。这些进展包括CRISPR/CAS9靶向长读测序以检查KIR结构 多样性，以及识别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人类白细胞抗原和KIR的基因和功能特征 多个人类种群，并全面了解这种变异是如何在地理上发生的 由自然选择分配和塑造的。这项工作将有助于研究免疫介导的和 传染病和为个人建立个性化治疗，在美国和 全世界。

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.