Charting somatic evolution via single-cell multiomics

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PROJECT SUMMARY This proposal outlines a five-year career development program for Caleb Lareau, Ph.D. to prepare him for an independent research career in human genomics to study cellular processes underlying complex disease. The candidate will conduct his postdoctoral training at Stanford University, which provides an outstanding environment to complete the proposed research and develop skills in massive-scale computational analyses, genomics technology development, and immunology. Dr. Lareau’s mentors and advisors, including Drs. Satpathy, Kundaje, Greenleaf, Howitt, Curtis, and Anderson, have diverse technical expertise relevant to all aspects of the proposal and track records of guiding trainees to independence. Further, the candidate will utilize world-class resources available through the Stanford School of Medicine, Office of Postdoctoral Affairs, and NHGRI-funded Centers at Stanford to acquire career development skills while interfacing with leaders in genomics. Additionally, the research infrastructure within his mentors’ labs will enable him to efficiently perform the scientific aims, receive training in areas encompassed by this proposal, and transition to independence. The goal of this work is to develop single-cell genomics methods to chart somatic evolution throughout the human body. Evidence from recent bulk sequencing studies has indicated that somatic evolution occurs in almost all tissues, but current approaches lack sensitivity to resolve clonal expansions, associated cell states, or their prevalence throughout the body. A key bottleneck in studying somatic evolution has been limitations of genomics technologies, which if addressed, may lead to insights into the pathogenesis of diseases like cancer. In Aim 1 (K99), the candidate will establish a new single-cell approach for measuring accessible chromatin, protein abundance, and mitochondrial DNA mutations to identify clonal expansions and related cell state changes. In Aim 2 (K99), the candidate will apply multi-omics technologies to identify the origins and expansions of macrophages within human gynecological tissues and tumors. After transitioning to a faculty position for Aim 3 (R00), the candidate will focus his effort on creating massive-scale single-cell whole-genome sequencing methods that are paired with functional measurements, including RNA or protein quantification. All Aims will utilize and build upon cutting-edge single-cell multi-omics technologies to study somatic evolution. Together, the pursuit of this research will result in tools and insights that will directly inform properties of human tissue physiology and aid in the early detection, characterization, and understanding of age-associated diseases, including cancer. All protocols, data, analytical frameworks, and software tools that are produced during the duration of this research will be freely distributed. In total, the proposal will lead to novel insights into the molecular signatures and regulation of somatic evolution and serve as an effective training program for Dr. Lareau to launch his independent career as a tenure-track investigator.