Recent studies have revealed that normal human tissues accumulate many somatic mutations. In particular, human skin is riddled with mutations, with multiple subclones of variable sizes. Driver mutations are frequent and tend to have larger subclone sizes, suggesting selection. To begin to understand the histories encoded by these complex somatic mutations, we incorporated genomes into a simple agent-based skin-cell model whose prime directive is homeostasis. In this model, stem-cell survival is random and dependent on proximity to the basement membrane. This simple homeostatic skin model recapitulates the observed log-linear distributions of somatic mutations, where most mutations are found in increasingly smaller subclones that are typically lost with time. Hence, neutral mutations are "passengers" whose fates depend on the random survival of their stem cells, where a rarer larger subclone reflects the survival and spread of mutations acquired earlier in life. The model can also maintain homeostasis and accumulate more frequent and larger driver subclones if these mutations (NOTCH1 and TP53) confer relatively higher persistence in normal skin or during tissue damage (sunlight). Therefore, a relatively simple model of epithelial turnover indicates how observed passenger and driver somatic mutations could accumulate without violating the prime directive of homeostasis in normal human tissues.
Keywords: carcinogenesis; keratinocyte biology; mathematical modeling; somatic evolution.