The Implications of Small Stem Cell Niche Sizes and the Distribution of Fitness Effects of New Mutations in Aging and Tumorigenesis

Abstract

Somatic tissue evolves over a vertebrates 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 Mullers Ratchet.