期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：35
DOI：10.1073/pnas.2006487119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Human skin is riddled with mutations creating subclones of variable sizes. Some of these mutations are driver mutations, implicated in cancer development and progression, that appear to be under positive selection due to their relative sizes. We show how these driver and nondriver “passenger” mutations encode their history of division and loss within the tissue using a simple model combined with realistic mutation tracking. Using a three-dimensional in silico homeostatic epidermis model, we reveal that many mutations likely lack functional heterogeneity and are, instead, simply those that arise earlier in life within the basal layer. We use our model to reveal how functional differences conveyed by driver mutations could lead to a persistence phenotype while maintaining homeostasis.
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.
