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

摘要：（最多30行） 非常需要创建一个能够全面编目体细胞的基础数据集 突变在不同的人体组织，以了解他们的类型，频率，细胞， 它们所处的解剖区室，以及它们的组织、功能关系和 后果体细胞变异可以广泛地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， 正常组织已经证明了体细胞变异在年龄相关过程中的因果作用， 肿瘤学和非肿瘤学条件，但这些研究通常仅限于少数组织或少数组织 个体体细胞变异的更广泛的功能性后果在很大程度上仍然未知。此外，本发明还 基因组的非编码调控区的变异可能影响不同细胞或组织中的基因表达 但它们的模式也反映了一生中对某些突变特征的暴露， 组织和个体之间可能存在的差异。 基因组学的最新进展为建立人体组织的体细胞突变目录提供了机会， 机关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 这是一个非凡的机会，可以发现正常组织功能背后的过程，并导致 疾病，但这样一个目录的发展需要最先进的，新颖的，实验性的， 计算框架。作为一个基因组表征中心（GCC）的体细胞镶嵌， 人类组织（SMaHT）计划，我们的项目将有助于表征，并创建一个资源 大规模的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GCC合作， 对各中心的样本进行基准测试，以比较生产数据和管道;（3）生成岩心分析 （短和长读段DNA测序和RNA测序），以及额外的双链体 对约250个样本进行测序分析;（4）对所有数据进行QC和分析，并提交给数据分析中心; 和（5）在整个网络中广泛合作，进行基准比较，制定共同的 分析管道和质量控制指标，并执行联合数据分析。我们的GCC汇集了一个团队， 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。我们将帮助创建一个躯体数据资源， 科学界，将促进研究，以了解细胞和组织的变化，在人类 发育、衰老和疾病变异解释。

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.