PROJECT SUMMARY Chronic liver disease is common and its pathogenic mechanisms are complex. There are no high throughput genetic methods to uncover mechanisms that drive progression to cirrhosis. As a result, therapies that slow the progression of liver disease are not currently available for most etiologies. The observation that our tissues accumulate a large number of somatic mutations with age and chronic injury could provide a genetic window into this process. Diseased livers harbor innumerable isolated islands of mosaic clones, but the identity and functional importance of the somatic alterations within these clones remain undiscovered. In the past, somatic mutations were generally assumed to be detrimental to health or drive cancer, but recently, some mutations have been shown to exert adaptive effects that might benefit tissue health. In the liver, deep sequencing experiments are beginning to reveal diverse somatic alterations, visually exemplified by the innumerable nodules on cirrhotic livers. Stimulated by this landscape of mutations, we have developed in vivo genetic screens to identify somatic mutations that have the greatest functional impact. Preliminary studies show that some mutations can increase tissue regeneration and others can prevent metabolic liver disease. An emerging concept is that cells can select for mutations that ameliorate, rather than cause, diseases such as steatohepatitis or cancer. We believe that somatic mosaicism is an open frontier for human genetics, and represents a potential source of unidentified disease genes and therapeutic targets. Using new technologies developed in my lab, we propose to exploit somatic mosaicism as a genetic strategy to 1) identify adaptive genetic pathways that are specific to particular liver disease etiologies, and 2) understand how mutant clones expand within chronically damaged tissues, and potentially protect from disease in a therapeutic fashion.