Program Director/Principal Investigator (Bell, Thomas, J.): Project Summary: The Somatic Mosaicism across Human Tissues (SMaHT) network project will establish the first comprehensive public resource correlating genetic variation due to somatic mosaicism in human tissues from all development layers in the human body. The SMaHT Network will have multiple centers to support the advancement of three primary initiatives: 1) somatic variant discovery, 2) data analysis and network organization, and 3) technology and tool development. The data from the SMaHT network project will provide an unparalleled research resource for investigators to gain new insights on genetic variation due to somatic mosaicism processes in healthy human tissues. In addition to capitalizing on new emerging methodologies to study somatic mosaicism in human tissues, the SMaHT program includes an Ethical, Legal, Social Implications (ELSI) study to further our understanding of the ELSI factors in human tissue donation for somatic mosaicism research. To support the advancement of the SMaHT network project, this proposal will establish a Tissue Procurement Center (TPC) that will provide the SMaHT network with multiple, high quality human tissue samples from the same individual across all three developmental layers for their experimental analysis. To meet the challenges for SMaHT network, our proposal is utilizing a multi-institutional effort with extensive expertise in human tissue collection, research, pathology, imaging, biobanking, and ELSI study analysis. This span of expertise is essential for the TPC to successfully deliver well-annotated, suitable tissue samples to support the generation of reliable and reproducible results and data interpretations from the SMaHT network experimental procedures. In addition, the TPC will lead the SMaHT network ELSI study to shed light on the ELSI-specific factors in human tissue donation for somatic mosaicism research. To enable a more extensive analysis of these factors, the SMaHT network ELSI study will include evaluations on Tissue Requesters (TRs) and Family Decision Makers (FDMs). Collectively, our TPC team is committed to establishing an unequaled TPC for the SMaHT network program to support the advancement of somatic mosaicism research, the associated ELSI factors, and ultimately the development of new clinical approaches to treat disorders driven by genetic variations from somatic mosaicism in human tissues. Relevance: The Somatic Mosaicism across Human Tissues (SMaHT) network project will provide the first comprehensive public resource of analyzing genetic variation due to somatic mosaicism in human tissues from all three developmental layers. The SMaHT network program will create a new, state-of-the-art research resource to support new discoveries in the biology and disease mechanisms that are propelled by somatic genomic alterations in human tissues and facilitate the development of new clinical approaches for disorders derived from somatic genetic variations. OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page Continuation Format Page

Program Director/Principal Investigator (Bell, Thomas, J.): Project Narrative: The first major public resource studying somatic mosaicism in tissues from all development layers in the human body will be available to scientists upon the completion of the Somatic Mosaicism across Human Tissues (SMaHT) network project. To enable this groundbreaking effort, the SMaHT Tissue Procurement Center (TPC) will provide all human tissue samples to the SMaHT network centers for experimental analysis. This proposal supports the developmental and implementation of the SMaHT TPC. OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page Continuation Format Page