Cargando…

Homeostasis limits keratinocyte evolution

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Schenck, Ryan O., Kim, Eunjung, Bravo, Rafael R., West, Jeffrey, Leedham, Simon, Shibata, Darryl, Anderson, Alexander R. A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9436311/
https://www.ncbi.nlm.nih.gov/pubmed/35998218
http://dx.doi.org/10.1073/pnas.2006487119
_version_ 1784781332700725248
author Schenck, Ryan O.
Kim, Eunjung
Bravo, Rafael R.
West, Jeffrey
Leedham, Simon
Shibata, Darryl
Anderson, Alexander R. A.
author_facet Schenck, Ryan O.
Kim, Eunjung
Bravo, Rafael R.
West, Jeffrey
Leedham, Simon
Shibata, Darryl
Anderson, Alexander R. A.
author_sort Schenck, Ryan O.
collection PubMed
description 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.
format Online
Article
Text
id pubmed-9436311
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher National Academy of Sciences
record_format MEDLINE/PubMed
spelling pubmed-94363112022-09-02 Homeostasis limits keratinocyte evolution Schenck, Ryan O. Kim, Eunjung Bravo, Rafael R. West, Jeffrey Leedham, Simon Shibata, Darryl Anderson, Alexander R. A. Proc Natl Acad Sci U S A Biological Sciences 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. National Academy of Sciences 2022-08-23 2022-08-30 /pmc/articles/PMC9436311/ /pubmed/35998218 http://dx.doi.org/10.1073/pnas.2006487119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by/4.0/This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Biological Sciences
Schenck, Ryan O.
Kim, Eunjung
Bravo, Rafael R.
West, Jeffrey
Leedham, Simon
Shibata, Darryl
Anderson, Alexander R. A.
Homeostasis limits keratinocyte evolution
title Homeostasis limits keratinocyte evolution
title_full Homeostasis limits keratinocyte evolution
title_fullStr Homeostasis limits keratinocyte evolution
title_full_unstemmed Homeostasis limits keratinocyte evolution
title_short Homeostasis limits keratinocyte evolution
title_sort homeostasis limits keratinocyte evolution
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9436311/
https://www.ncbi.nlm.nih.gov/pubmed/35998218
http://dx.doi.org/10.1073/pnas.2006487119
work_keys_str_mv AT schenckryano homeostasislimitskeratinocyteevolution
AT kimeunjung homeostasislimitskeratinocyteevolution
AT bravorafaelr homeostasislimitskeratinocyteevolution
AT westjeffrey homeostasislimitskeratinocyteevolution
AT leedhamsimon homeostasislimitskeratinocyteevolution
AT shibatadarryl homeostasislimitskeratinocyteevolution
AT andersonalexanderra homeostasislimitskeratinocyteevolution