Somatic mosaicism across mouse tissues during different life stages - ABSTRACT Somatic mosaicism arising from the accumulation of postzygotic DNA mutations in somatic cells (somatic mutations), leads to tissue genetic heterogeneity. Somatic mutations occur at different life stages and throughout an individual’s lifespan and are implicated in various human diseases, including cancers, monogenic diseases, neurodegenerative disorders, cardiovascular diseases, autoimmune diseases, skin diseases, and liver diseases. In addition, random somatic mutations were identified to accumulate with age in humans, and associated with environmental and genetic risk factors, for example, tobacco smoking, UV radiation and BRCA1/2 deficiency. However, it is still unclear whether somatic mutations are a cause of functional decline in human health, for instance, aging, although the hypothesis was proposed in the 1950s, due to several critical knowledge gaps and important challenges. Due to cell-to-cell heterogeneity, somatic mutations are unique in each cell of normal tissues and are extremely difficult to detect accurately, which leads to the large unknown about somatic mutation burdens per cell with respect to tissue types and life span in normal, non-cancer tissues of an organism. In addition, the causes of somatic mutations and how they evolve in normal tissues during different life stages remain unclear. With the experience and expertise in somatic mutations and genome instability, our goals for the next five years is to utilize cutting-edge DNA sequencing technologies, including single-cell whole-genome sequencing, Nanorate sequencing, and ultra-deep bulk whole-genome sequencing and computational analyses to 1) quantitatively explore somatic mutation burdens in normal, non-cancerous tissues in mice across different life stages; 2) identify mutational signatures and clusters, to infer molecular mechanisms and risk factors and to guide experimental validation in the future; 3) decipher the patterns of somatic mutation evolution, examining whether they are subject to random drift, positive selection or negative selection across tissue types and life stages. Based on the new discoveries, for the long-term goals, I will explore the health relevance of mutation burden, signature, and somatic evolution, quantify the risks of environmental factors, and develop new standards for drug safety. Additionally, I plan to select specific genes or genetic regions (with either higher or lower mutation burdens than expected) for testing their health relevance. These goals will be achieved using mouse as the model organism for testing and developing new interventions. Overall, the proposed projects will provide comprehensive insights into somatic mosaicism, laying the groundwork for understanding its role and the mechanisms of its impact on biology and health and shedding light on future interventions.
