Somatic_mutations_in_UV_exposed_mouse_skin_

Aging human tissues such as sun exposed epidermis harbour numerous somatic mutant clones, but how they establish and persist is unknown. Here, we tracked the behavior of single p53R245W/wt mutant (p53*) progenitors in normal mouse epidermis. Initially, p53* progenitors colonised the tissue due to their fate being imbalanced in favour of proliferation. Those mutant cells that did differentiate were retained in the epidermis due to a defect in shedding. Subsequently, the p53* phenotype became attenuated allowing the partly mutated epidermis to establish a new steady state. Exposure to physiological doses of ultraviolet (UV) light initially promoted the expansion of the p53* population. However, long term UV treatment resulted in a striking reduction in the proportion of p53* cells which were displaced by UV induced mutants with higher competitive fitness. We conclude that phenotypic adaptation and cell competition restrain p53 mutant progenitors, enabling tissue integrity to be maintained.