Apr 22, 2016

The implications of small stem cell niche sizes and the distribution of fitness effects of new mutations in aging and tumorigenesis

Evolutionary Applications
Vincent L CannataroColette M St Mary

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 accumul...Continue Reading

  • References50
  • Citations8

References

Mentioned in this Paper

Vertebrates
Genetic Drift
Size
Neoplasms
Intestinal Wall Tissue
Stem Cell Niche
Aging
Genetic Fitness
Simulation
Diploid Cell

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