The Implications of Small Stem Cell Niche Sizes and the Distribution of Fitness Effects of New Mutations in Aging and Tumorigenesis
Vincent L. Cannataro, Scott A. McKinley, Colette M. St. Mary
doi: http://dx.doi.org/10.1101/032813
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, i.e., 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, due to the effects of small
stem cell population sizes, i.e., strong genetic drift, deleterious
mutations are predicted to accumulate, resulting in reduced tissue
maintenance. Thus, despite there being a large number of stem cells
throughout the intestine, its compartmental architecture leads to
significant aging, a prime example of Muller's Ratchet.
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