RT Journal Article
SR Electronic
T1 How Homeostasis Limits Keratinocyte Evolution
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 548131
DO 10.1101/548131
A1 Schenck, Ryan O.
A1 Kim, Eunjung
A1 Bravo, Rafael R.
A1 West, Jeffrey
A1 Leedham, Simon
A1 Shibata, Darryl
A1 Anderson, Alexander R.A.
YR 2019
UL http://biorxiv.org/content/early/2019/06/25/548131.abstract
AB 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.