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