Discovering and Analyzing Development and Age-Associated CNAs in the All of Us Cohort

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Abstract Genomic variants in an individual may be either inherited (i.e., transmitted through the germline) or generated by mutagenesis in post-zygotic cells, which results in no two cells in any individual having the same genome. Clonal hematopoiesis is the phenomenon of age-related outgrowth of somatic clones in the blood. Such an outgrowth has been associated with increased all-cause mortality, risk of blood cancer and cardiovascular diseases but reduced risks of Alzheimer’s disease. In the proposed project we will discover and analyze somatic CNVs using whole genome sequencing (WGS) data in the All of Us cohort. We will apply CNVpytor to all All of Us WGS data to discover somatic CNVs and provide discovered CNVs as a resource to researchers in the All of Us Researcher Workbench. The resource will include a tiered list of CNVs, processed and small sized files for instant manual inspection of CNVs, and documentation and video tutorial with examples how to access, inspect, analyze and visualize the discovered CNVs in IGV. Additionally, we will include stratification of CNV types (i.e., deletions, duplications, LOHs) by age, defining their likely age of occurrence, determining their precise breakpoints, and analyzing sequences at the breakpoints to reveal their likely origin. Completing the described project will result in a large-scale assessment of somatic CNVs in the blood of individuals in the All of Us cohort and will provide a new insight into the etiology of such somatic CNVs. The developed methodologies can be applied to data generated in the future, as All of Us expands the collection of samples. 1