Understanding spontaneous somatic mutations and their effects on adult tissues – SoMuSeq-STEM

During aging, defects in stem cell function contribute to a decline in renewal and repair of adult tissues. It has long been postulated that the accumulation of somatic mutations might contribute to cellular aging. In support of this notion, induced DNA damage or mutations affecting DNA repair components can mimic some of the effects of aging on stem cell. However, a knowledge gap exists: it is unclear whether the rate of spontaneous mutations in adult tissues would be consistent with the detected functional decline. Moreover, the impact of the external environment on somatic mutation rate, the molecular mechanisms driving their formation, and their phenotypic impact on adult tissues, remains unclear. Thus, while somatic genetic mosaicism has been well studied in the context of cancers, its impact on developing and adult tissues is not well understood.

Our recent work, (Siudeja, et al., Cell Stem Cell, 2015) indicates that genetic mosaicism is prevalent within the Drosophila intestine and is mediated both by mitotic crossover events and spontaneous deletion and structural rearrangement of chromosomes. Thus the adult fly intestine provides an ideal model system in which to address important and outstanding questions regarding the mechanism and role of spontaneous mutations on adult tissues.

In the proposed work, we will use the Drosophila intestine as a model system to better understand the nature, initiating mechanisms and impact of somatic mutation on an adult organ and how somatic mutation is influenced by the environment. Our innovative proposal requires the collaboration of two partners each having important and complementary sets of expertise, thus making the collaborative ANR call well suited for this project: In particular, we will combine the precise assays developed by the Bardin team (Unit of Genetics and Developmental Biology, UMR3215 CNRS/ Inserm U934) to measure in vivo and sequence stem cell-derived spontaneous mutations with the bioinformatic tools developed by the Servant/Barillot team (U900 Institut Curie/ Inserm/ Mines ParisTech).