Whole Individual Comprehensive KnowlEDge: Somatic Mosaicism across Human Tissues (WICKed SMaHT)

整体综合知识：人体组织的体细胞镶嵌（WICKed SMaHT）

• 批准号: 10662869
• 负责人: KRISTIN ARDLIE
• 金额: $ 92.14万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10662869
• 关键词: Affect; Aging; Agreement; Anatomy; Benchmarking; Biological Assay; Blood; Cardiovascular Diseases; Catalogs; Cell physiology; Cells; Chromosome Deletion; Chromosome Structures; Chromosome abnormality; Code; Collaborations; Communities; Computational Biology; DNA; DNA Damage; DNA sequencing; Data; Data Analyses; Data Set; Detection; Development; Disease; Dryness; Exposure to; Frequencies; Gene Expression; Generations; Genetic; Genome; Genomics; Genotype-Tissue Expression Project; Goals; Guidelines; Hematopoiesis; High Prevalence; Human; Human Biology; Human Development; Human Genetics; Human body; Individual; Joints; Knowledge; Life; Longevity; Malignant Neoplasms; Measures; Molecular; Mosaicism; Mutagenesis; Mutation; Normal tissue morphology; Nucleic Acid Regulatory Sequences; Organ; Outcome; Pathogenesis; Pattern; Phenotype; Phylogenetic Analysis; Process; Production; Proteins; Protocols documentation; Recording of previous events; Resolution; Resources; Role; Sampling; Science; Site; Somatic Mutation; Specimen; Standardization; Stretching; Technology; Tissue Banks; Tissue Procurements; Tissue Sample; Tissues; Trans-Omics for Precision Medicine; Trees; United States National Institutes of Health; Untranslated RNA; Variant; Work; age related; cohort; computer framework; data harmonization; data resource; data submission; design; exome sequencing; experience; fitness; genome sequencing; high throughput screening; human tissue; insight; life history; multidisciplinary; new technology; novel; preservation; programs; response; success; timeline; tissue processing; transcriptome sequencing

ABSTRACT: (max 30 lines) There is an enormous need to create a foundational dataset that will comprehensively catalog somatic mutations across a diverse range of human tissues, to understand their type, frequency, the cells, and anatomical compartments in which they are found, and their organizational, functional relationships and consequences. Somatic variants can occur widely throughout the genome and across the lifespan producing stochastic, clonal, and dynamic somatic mosaicism. A growing number of studies interrogating mutations in normal tissues have demonstrated causal roles for somatic variants in age-related processes and both oncologic and non-oncologic conditions, but these studies have generally been limited to few tissues or few individuals. The broader functional consequences of somatic variation remain largely unknown. Additionally, variants in non-coding, regulatory regions of the genome may affect gene expression in different cells or tissues within individuals, but their patterns also reflect a lifetime of exposures to certain mutational signatures, with likely differences between tissues and individuals. Recent advances in genomics provide an opportunity to build a somatic mutation catalog for human tissues and organs. A cross-tissue catalog of human somatic mutations at high cellular and genetic resolution will provide an extraordinary opportunity to discover the processes underlying normal tissue function, and leading to disease, but the development of such a catalog requires state-of-the-art, and novel, experimental and computational frameworks. As a Genome Characterization Center (GCC) for the Somatic Mosaicism across Human Tissues (SMaHT) program, our project will contribute to the characterization, and creation of a resource catalog of somatic variation across human tissues at scale. We will (1) work with the Tissue Procurement Centers and the network to share tissue sampling protocols; (2) collaborate with other GCCs to undertake benchmarking of samples across centers to compare production data and pipelines; (3) generate core assays (short and long-read DNA sequencing and RNA sequencing) across 750 samples, and an additional duplex sequencing assay across ~250 samples; (4) QC and analyze all data and submit to the Data Analysis Center; and (5) collaborate across the network broadly on benchmarking comparisons, the development of common analytical pipelines and QC metrics, and to perform joint data analysis. Our GCC brings together a team with expertise in human genetics/genomics, production science, computational biology, novel technologies, and the characterization and interpretation of somatic mutations. We will help create a somatic data resource for the scientific community that will catalyze studies to understand cellular and tissue changes during human development, aging, and disease variant interpretation.

摘要：（最多 30 行） 非常需要创建一个基础数据集来全面分类体细胞 跨多种人体组织的突变，以了解它们的类型、频率、细胞和 它们所在的解剖区室，以及它们的组织、功能关系和 结果。体细胞变异可以广泛发生在整个基因组和整个生命周期中 随机、克隆和动态体细胞镶嵌。越来越多的研究质疑基因突变 正常组织已证明体细胞变异在与年龄相关的过程中具有因果作用，并且 肿瘤和非肿瘤条件，但这些研究通常仅限于少数组织或少数组织 个人。体细胞变异的更广泛的功能后果在很大程度上仍然未知。此外， 基因组非编码调控区域的变异可能影响不同细胞或组织中的基因表达 个体内部，但它们的模式也反映了一生中暴露于某些突变特征的情况， 组织和个体之间可能存在差异。 基因组学的最新进展为建立人体组织和体细胞突变目录提供了机会。 器官。高细胞和遗传分辨率的人类体细胞突变的跨组织目录将提供 这是发现正常组织功能背后的过程的绝佳机会，并导致 疾病，但是这样一个目录的开发需要最先进的、新颖的、实验性的和 计算框架。作为体细胞嵌合体的基因组表征中心（GCC） 人体组织 (SMaHT) 计划，我们的项目将有助于资源的表征和创建 大规模人体组织体细胞变异目录。我们将 (1) 与组织采购部门合作 中心和网络共享组织采样协议； (2) 与其他海湾合作委员会合作开展 对各个中心的样品进行基准测试，以比较生产数据和管道； (3) 生成核心分析 （短读长和长读长 DNA 测序和 RNA 测序）涵盖 750 个样本，以及额外的双链体 约 250 个样本的测序分析； （4）对所有数据进行QC分析并提交数据分析中心； (5) 通过网络广泛合作进行基准比较、共同开发 分析流程和质量控制指标，并执行联合数据分析。我们的 GCC 汇集了一支团队 人类遗传学/基因组学、生产科学、计算生物学、新技术和 体细胞突变的表征和解释。我们将帮助创建体细胞数据资源 科学界将促进研究以了解人类过程中细胞和组织的变化 发育、衰老和疾病变异解释。