Evolution and Function of Immunogenetic Diversity across the Eastern Hemisphere

东半球免疫遗传多样性的演变和功能

基本信息

批准号：
10365232
负责人：
Paul John Norman
金额：
$ 79.45万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-11 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10365232
关键词：
Address Admixture Affect Algorithms Alleles Asia Autoimmunity Bioinformatics CRISPR/Cas technology Cell physiology Cells Characteristics Chronic Chronic Disease Communicable Diseases Complex Country Data Development Disease Disease susceptibility Donor person Environment Evolution Far East Genes Genetic Genetic Polymorphism Genetic Variation Genome Genomic Segment Genotype Geographic Distribution Geographic Locations Geography Goals HLA Antigens Haplotypes Health High-Throughput Nucleotide Sequencing Histocompatibility Antigens Class I Human Human Genome Immune Immune response Immune system Immunity Immunogenetics Immunoglobulins Immunotherapy Individual Indonesia Infection Inflammation Investigation Killer Cells Knowledge Laboratories Life Ligands Link MHC Class I Genes Malignant Neoplasms Maps Mediating Methods Modeling Morbidity - disease rate Native-Born Natural Killer Cells Natural Selections Nature Oceania Organ Donor Outcome Pacific Islands Pattern Phenotype Population Predisposition Pregnancy Property Registries Research Resolution Role Severity of illness Shapes Signal Transduction Southeastern Asia Specificity Syndrome Testing Tissues Training Treatment Efficacy Underrepresented Populations Variant Work analytical tool bioinformatics pipeline cancer risk combinatorial design experimental study fetal genetic variant implantation innovation mortality multi-ethnic neglect nervous system disorder novel novel strategies pathogen pathogen exposure personalized medicine pressure receptor reproductive response study population targeted sequencing trait tumor whole genome

项目摘要

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.

抽象的人类白细胞抗原 (HLA) 和杀伤细胞免疫球蛋白样受体 (KIR) 是免疫系统的重要组成部分。人体免疫系统。由自然杀伤细胞（NK 细胞）表达的 KIR 与 I 类 HLA 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，对人类健康产生深远影响，包括与自身免疫和神经系统疾病、传染病严重程度、怀孕的关系综合症和癌症风险。我们有能力解决免疫介导疾病的机制，开发个性化药物，包括免疫疗法，以及将器官捐献者与接受者相匹配依赖于我们的能够准确表征 KIR 和 HLA I 类多样性。尽管这一点至关重要，但仍缺乏关于全球 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拥有世界一半的人口，并且有多个代表性不足的国家美国的团体。在这个项目中，我们将通过确定整个东部地区 KIR 和 HLA I 类多样性的特征和功能后果半球。我们将检查代表 51 个离散人群（包括土著人群）的 15,612 名个体来自东亚、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，具有高通量和分辨率。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。我们将专门为这些在以前被忽视的人群建立插补小组分析。通过生成的大量培训数据可以实现这一目标。我们随后将描述了 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 多样性的地理模式并研究专门针对 KIR 和 HLA 基因座的适应性基因渗入和混合的影响在我们的研究人群中。我们将确定我们已识别的那些变体的功能特性自然选择的目标。我们将通过实施创新实验室和分析来实现这些目标工具。这些进展包括 CRISPR/cas9 靶向长读长测序以检查 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，以及选择作用的模式他们。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，并全面了解这种差异在地理上的分布通过自然选择分布和塑造。这项工作将有利于免疫介导和免疫介导的研究传染病以及为美国和美国的个人建立个性化治疗全世界。