Discovering and Analyzing Development and Age-Associated CNAs in the All of Us Cohort

发现并分析我们所有人队列中的发育和与年龄相关的 CNA

• 批准号: 10797689
• 负责人: ALEXEJ ABYZOV
• 金额: $ 16.14万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10797689
• 关键词: Age; Alzheimer' s disease risk; Blood; Blood specimen; Brain; Cardiovascular Diseases; Cell division; Cells; Collection; Copy Number Polymorphism; Data; Detection; Development; Disease; Documentation; Enrollment; Etiology; Frequencies; Future; Genes; Genome; Genomics; Gilles de la Tourette syndrome; Hematopoiesis; Hematopoietic; Hematopoietic Neoplasms; Individual; Inherited; Length; Manuals; Methodology; Methods; Mosaicism; Mutagenesis; Mutation; Outcome; Phenotype; Point Mutation; Predisposition; Process; Research; Research Personnel; Resources; Risk; Role; SNP array; Schizophrenia; Signal Transduction; Somatic Cell; Somatic Mutation; Stratification; Testing; Variant; Visualization; Work; Y Chromosome; age related; autism spectrum disorder; cohort; driver mutation; genetic variant; genome sequencing; insight; mortality; neuropsychiatric disorder; sample collection; sex; tool; transmission process; whole genome

Abstract Genomic variants in an individual may be either inherited (i.e., transmitted through the germline) or generated by mutagenesis in post-zygotic cells, which results in no two cells in any individual having the same genome. Clonal hematopoiesis is the phenomenon of age-related outgrowth of somatic clones in the blood. Such an outgrowth has been associated with increased all-cause mortality, risk of blood cancer and cardiovascular diseases but reduced risks of Alzheimer’s disease. In the proposed project we will discover and analyze somatic CNVs using whole genome sequencing (WGS) data in the All of Us cohort. We will apply CNVpytor to all All of Us WGS data to discover somatic CNVs and provide discovered CNVs as a resource to researchers in the All of Us Researcher Workbench. The resource will include a tiered list of CNVs, processed and small sized files for instant manual inspection of CNVs, and documentation and video tutorial with examples how to access, inspect, analyze and visualize the discovered CNVs in IGV. Additionally, we will include stratification of CNV types (i.e., deletions, duplications, LOHs) by age, defining their likely age of occurrence, determining their precise breakpoints, and analyzing sequences at the breakpoints to reveal their likely origin. Completing the described project will result in a large-scale assessment of somatic CNVs in the blood of individuals in the All of Us cohort and will provide a new insight into the etiology of such somatic CNVs. The developed methodologies can be applied to data generated in the future, as All of Us expands the collection of samples. 1

摘要 个体中的基因组变体可以是遗传的（即，通过生殖系传播）或 通过在合子后细胞中诱变产生，这导致任何个体中没有两个细胞具有相同的 基因组克隆性造血是血液中体细胞克隆与年龄相关的生长现象。等 一种副产物与全因死亡率、血癌和心血管疾病风险的增加有关。 但降低了患阿尔茨海默病的风险。在拟议的项目中，我们将发现和分析体细胞 在All of Us队列中使用全基因组测序（WGS）数据的CNV。我们将把CNVpytor应用到所有的 美国WGS数据发现体细胞CNVs，并将发现的CNVs作为资源提供给全世界的研究人员 我们的研究员。该资源将包括一个分层列表的CNV，处理和小型文件 对于CNV的即时手动检查，以及文档和视频教程，其中包含如何访问的示例， 检查、分析和可视化IGV中发现的CNV。此外，我们将纳入CNV的分层 类型（即，缺失、重复、LOH），定义其可能发生的年龄，确定其精确的 断点，并分析断点处的序列以揭示其可能的起源。完成所描述的 一个项目将导致对“我们所有人”队列中个体血液中的体细胞CNV进行大规模评估 并将提供一个新的见解，这种体细胞CNVs的病因。开发的方法可以是 应用于未来生成的数据，因为All of Us扩展了样本集合。 1