How Homeostasis Limits Keratinocyte Evolution

The skin is the largest human organ, functioning to serve as the protective barrier to the harsh, outside world. Recent studies have revealed that large numbers of somatic mutations accumulate in normal tissue, which can be used to infer skin cell dynamics1-5. Here we present the first realistic, cell-genome mechanistic epidermal model that shows homeostasis imposes a characteristic log-linear subclone size distribution for both neutral and oncogenic driver mutations, where the largest skin subclones are the oldest subclones. Because homeostasis inherently limits proliferation and therefore clonal sweeps, selection for driver mutations (NOTCH1 and TP53) in normal epidermis is instead conferred by greater persistence, which leads to larger subclone sizes. These results highlight how the integration of mechanistic modeling with genomic data provide novel insights into the evolutionary cell dynamics of normal human homeostatic tissues.