Abstract
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, which can be used to infer normal human skin cell dynamics1-6. Here we present the first realistic mechanistic epidermal model, that uses the ‘Gattaca’ method to incorporate cell-genomes, that shows homeostasis imposes a characteristic log-linear subclone size distribution for both neutral and 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 reveal how driver mutations may persist and expand in normal epidermis while highlighting how the integration of mechanistic modeling with genomic data provides novel insights into evolutionary cell dynamics of normal human homeostatic tissues.
Footnotes
↵# Indicates the author to whom correspondence and material requests should be addressed.
↵† These authors share senior authorship.
Supplemental Figure 1 has been integrated into Figure 1 of the manuscript. The Supplemental Information has been added to the body of the manuscript where appropriate. Introduction of the "Gattaca" method has been integrated throughout the manuscript to describe the method of integrating genomes into in silico cells.
