ArticleEvolutionary applications2016
The implications of small stem cell niche sizes and the distribution of fitness effects of new mutations in aging and tumorigenesis.
Article in Evolutionary applications, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 20 citations in OpenAlex.
- Article
- Spectral dynamics of guided edge removals and identifying transient amplifiers for death-Birth updating.Journal of mathematical biology · 2023Article
- Article
- Spectral analysis of transient amplifiers for death-birth updating constructed from regular graphs.Journal of mathematical biology · 2021Article
- Fixation probabilities in graph-structured populations under weak selection.PLoS computational biology · 2021Article
- The evolution of metapopulation dynamics and the number of stem cells in intestinal crypts and other tissue structures in multicellular bodies.Evolutionary applications · 2020Review
- Molecular Biology and Evolution of Cancer: From Discovery to Action.Molecular biology and evolution · 2020Article
- Tumorigenesis as the Paradigm of Quasi-neutral Molecular Evolution.Molecular biology and evolution · 2019Article
- Article
- The evolutionary trade-off between stem cell niche size, aging, and tumorigenesis.Evolutionary applications · 2017Article
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Somatic tissue evolves over a vertebrate's lifetime due to the accumulation of mutations in stem cell populations. Mutations may alter cellular fitness and contribute to tumorigenesis or aging. The distribution of mutational effects within somatic cells is not known. Given the unique regulatory regime of somatic cell division, we hypothesize that mutational effects in somatic tissue fall into a different framework than whole organisms; one in which there are more mutations of large effect. Through simulation analysis, we investigate the fit of tumor incidence curves generated using exponential and power-law distributions of fitness effects (DFE) to known tumorigenesis incidence. Modeling considerations include the architecture of stem cell populations, that is, a large number of very small populations, and mutations that do and do not fix neutrally in the stem cell niche. We find that the typically quantified DFE in whole organisms is sufficient to explain tumorigenesis incidence. Further, deleterious mutations are predicted to accumulate via genetic drift, resulting in reduced tissue maintenance. Thus, despite there being a large number of stem cells throughout the intestine, its compartmental architecture leads to the accumulation of deleterious mutations and significant aging, making the intestinal stem cell niche a prime example of Muller's Ratchet.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.