Defining Variation in the Natural Killer Cell Receptome in Human Populations

定义人类自然杀伤细胞受体组的变异

• 批准号: 10430920
• 负责人: Danillo G Augusto
• 金额: $ 20.67万
• 依托单位: UNIVERSITY OF NORTH CAROLINA CHARLOTTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-18 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10430920
• 关键词: 19q13; Address; African; African American population; Alleles; American; Amerindian; Bioinformatics; Bolivia; C Type Lectin Receptors; Cells; Characteristics; Chromosome 19; Code; Complex; Comprehension; Copy Number Polymorphism; Custom; DNA; Data; Disease; Elements; European; Exhibits; Future; Gene Cluster; Gene Expression Regulation; Gene Family; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Genetic Variation; Genomic Segment; Genotype; Germ Cells; Goals; Homologous Gene; Human; Immune response; Immunoglobulins; Immunotherapy; Individual; Infection; Killer Cells; Lead; Leukocytes; Linkage Disequilibrium; Malignant Neoplasms; Maps; Medical; Mononuclear; Native Americans; Natural Immunity; Natural Killer Cells; Natural Selections; Paraguay; Pattern; Peripheral; Peripheral Blood Mononuclear Cell; Peru; Population; Population Genetics; Quantitative Trait Loci; Receptor Cell; Role; Sampling; South Africa; South America; South Asian; Translating; Validation; Variant; Work; bioinformatics pipeline; cancer cell; cytotoxicity; design; differential expression; experience; genetic association; genome wide association study; genomic variation; innovation; next generation sequencing; novel; receptor; single cell analysis; single cell sequencing; single-cell RNA sequencing; transcriptome; transcriptome sequencing; tumor

ABSTRACT The overall goal of this project is to develop a comprehensive map of sequence and structural variation of the NK (natural killer) cell receptome in ancestrally diverse human populations. The two genomic regions encoding NK cell receptors, leukocyte receptor complex (LRC) and natural killer complex (NKC), house more than 90 genes with an essential role in NK cell cytotoxicity against infected and cancer cells. The complex structural variation and the high degree of sequence identity among genes within these regions have served as barriers to a comprehensive analysis in former genome-wide association and sequencing studies. With our expertise and experience in studying complex genomic variation, we will develop the most comprehensive map of sequence and structural variation of the LRC and NKC in human populations. In Specific Aim 1, we will conduct a high- throughput study entailing the complete sequencing of these two complexes using our novel and validated next- generation sequencing approach. DNA samples from 2150 samples from 18 populations, including Native Americans and admixed populations from South America, Africans, European Americans, and African Americans. Sequence data will be analyzed with our custom-designed bioinformatics pipelines. We will focus not only on gene families with a known structural variation of copy number, such as KIR (killer-cell immunoglobulin-like receptor) and LILR (leukocyte immunoglobulin-like receptors) but will analyze all common variants in all 90 NKC and LRC genes to characterize the full extent of their variation. Synergized with this approach, in Specific Aim 2, we will perform a powerful single-cell expression quantitative trait loci (eQTL) mapping of LRC and NKC by sequencing the single-cell transcriptomes of NK cells from peripheral blood mononuclear cells of 40 healthy individuals. We will identify variants associated with differential expression levels in NK cells for the initial assessment of emerging functional hypotheses. We will identify any common variants within the LRC and NKC that are associated with eQTL effects, resulting in the most comprehensive study of the NK receptome genetic variation in populations to date. This exploratory project will lay the basis for further functional studies and may ultimately lead to discovering new targets for NK cell immunotherapies.

抽象的 该项目的总体目标是制定序列和结构变化的综合图 NK（天然杀手）细胞在祖先多样化的人群中。编码两个基因组区域 NK细胞受体，白细胞受体复合物（LRC）和天然杀手型复合物（NKC），容纳90多个 对感染和癌细胞的NK细胞细胞毒性具有至关重要的基因。复杂的结构 这些区域内基因之间的变异和高度序列身份已成为 对以前全基因组关联和测序研究的全面分析。有了我们的专业知识和 研究复杂的基因组变异的经验，我们将开发最全面的序列图 LRC和NKC的结构变化在人群中。在特定的目标1中，我们将进行高 吞吐量研究需要使用我们的小说进行完整测序这两个复合物，并进行了验证 生成测序方法。来自18个人群的2150个样本的DNA样品，包括本地 美国人和来自南美，非洲人，欧洲美国人和非洲的人口 美国人。序列数据将通过我们的自定义设计的生物信息学管道进行分析。我们将集中精力 不仅在具有已知拷贝数的已知结构变化的基因家族上，例如KIR（杀手细胞 免疫球蛋白样受体）和LILR（白细胞免疫球蛋白样受体），但将分析所有常见 所有90个NKC和LRC基因中的变体以表征它们的全部变化程度。与此协同作用 方法，在特定的目标2中，我们将执行强大的单细胞表达定量特质基因座（EQTL） 通过对外周血NK细胞的单细胞转录组进行测序，对LRC和NKC的映射 40个健康个体的单核细胞。我们将确定与差分表达水平相关的变体 在NK细胞中，以初步评估新兴的功能假设。我们将确定任何常见变体 在LRC和NKC中与EQTL效应相关，从而最全面地研究了 迄今为止，NK受体遗传变异。这个探索性项目将为进一步的基础 功能研究，最终可能导致发现NK细胞免疫疗法的新靶标。