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.

摘要 该项目的总体目标是绘制一幅全面的层序和结构变异图， NK（自然杀伤）细胞受体在不同祖先人群中的分布。两个基因组区域编码 NK细胞受体，白细胞受体复合物（LRC）和自然杀伤复合物（NKC），容纳超过90 在NK细胞对感染细胞和癌细胞的细胞毒性中具有重要作用的基因。复杂的结构 这些区域内基因之间的变异和高度序列同一性已经成为 对以前的全基因组关联和测序研究进行了全面分析。凭借我们的专业知识和 在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 以及人类群体中LRC和NKC的结构变异。在具体目标1中，我们将进行高- 通量研究需要这两个复合物的完整测序，使用我们的新的和验证的下一个- 世代排序法来自18个种群的2150个样本的DNA样本，包括原住民 美国人和来自南美洲、非洲人、欧洲裔美国人和非洲裔美国人的混合人群 美国人序列数据将通过我们定制设计的生物信息学管道进行分析。我们将重点 不仅在具有已知拷贝数结构变异的基因家族上，例如KIR（嗜热细胞）， 免疫球蛋白样受体）和LILR（白细胞免疫球蛋白样受体），但将分析所有常见的 所有90个NKC和LRC基因的变异，以表征其变异的全部范围。与此协同 方法，在具体目标2，我们将执行一个强大的单细胞表达数量性状位点（eQTL） 通过对来自外周血的NK细胞的单细胞转录组测序来定位LRC和NKC 40个健康个体的单核细胞。我们将确定与差异表达水平相关的变异 在NK细胞中用于对新兴功能假说的初步评估。我们将确定任何常见的变体 在LRC和NKC中，与eQTL效应相关，导致对EQTL效应的最全面的研究。 迄今为止，人群中的NK受体组遗传变异。这一探索性项目将为进一步开展 这可能有助于NK细胞功能研究，并最终发现NK细胞免疫疗法的新靶点。