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

• 批准号: 10663162
• 负责人: Paul John Norman
• 金额: $ 76.7万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 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/10663162
• 关键词: Address; Admixture; Affect; Algorithms; Alleles; Asia; Autoimmune Diseases; Autoimmunity; Bioinformatics; CRISPR/Cas technology; Cell physiology; Cells; Characteristics; Chronic; Chronic Disease; Communicable Diseases; Complex; Country; Data; Development; Disease; Disease susceptibility; Disparity; Donor person; Environment; Evolution; Experimental Designs; 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; Severities; Shapes; Signal Transduction; Southeastern Asia; Specificity; Syndrome; Testing; Tissues; Training; Treatment Efficacy; Underrepresented Populations; Variant; Work; analytical tool; bioinformatics pipeline; cancer risk; combinatorial; experimental study; fetal; genetic variant; immunoregulation; 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

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 人白细胞抗原（HLA）和杀伤细胞免疫球蛋白样受体（KIR）是关键方面 人类免疫系统。由天然杀伤细胞（NK细胞）表达的KIR的相互作用与HLA I类 用大多数组织细胞表达，调节免疫细胞功能。高度多态KIR和 HLA基因与NK细胞功能直接相关，并对人类健康产生深远影响，包括 与自身免疫和神经疾病，传染病的严重程度，怀孕的关联 综合征和癌症的风险。我们解决免疫介导疾病机制的能力，发展 个性化药物，包括免疫疗法，并将器官捐赠者与收件人相匹配，依靠我们 能够准确表征KIR和HLA I类多样性的能力。尽管重要的重要性，但缺乏 关于KIR和HLA I类多样性的知识。这种赤字包括 东半球涵盖了世界一半的人口，多人代表人数不足 在美国。在此项目中，我们将通过确定这些知识来填补这些空白 整个东部的KIR和HLA I类多样性的特征和功能后果 半球。 我们将检查15,612名代表51个离散人群的人，包括土著人口 来自东亚，南亚，多个太平洋群岛和大洋洲。为了克服分析这些困难 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 以及高通量和分辨率的HLA I类基因。为了分析另外22,905个人，我们将 开发一种归合算法来确定全基因组SNP数据的高分辨率KIR等位基因。我们 将专门为这些在以前被忽略的人群建造插补小组 分析。通过生成的广泛培训数据，将实现这一目标。然后我们会 表征KIR和HLA单倍型在东半球的分布。 我们将研究KIR和HLA多样性的地理模式如何通过自然选择来塑造 并研究专门针对KIR和HLA基因座的自适应渗入和混合物的影响 在我们的研究人群中。我们将确定我们已确定为那些变体的功能属性 以自然选择为目标。我们将追求这些目标，以实施创新的实验室和分析 工具。这些发展包括CRISPR/CAS9对长阅读测序的靶向检查KIR结构 多样性和方法都可以识别受自然选择的等位基因，以及选择的选择方式 他们。这项工作的预期结果是HLA和KIR的遗传和功能表征 多个人类人群，以及对这种变化在地理上如何的全面理解 通过自然选择分布和塑造。这项工作将使对免疫介导的调查和 传染病以及为美国和美国个人建立个性化治疗 全世界。

项目成果

Adaptive Admixture of HLA Class I Allotypes Enhanced Genetically Determined Strength of Natural Killer Cells in East Asians.

• DOI: 10.1093/molbev/msab053
• 发表时间: 2021-05-19
• 期刊: Molecular biology and evolution
• 影响因子: 10.7
• 作者: Deng Z;Zhen J;Harrison GF;Zhang G;Chen R;Sun G;Yu Q;Nemat-Gorgani N;Guethlein LA;He L;Tang M;Gao X;Cai S;Palmer WH;Shortt JA;Gignoux CR;Carrington M;Zou H;Parham P;Hong W;Norman PJ
• 通讯作者: Norman PJ