The evolutionary trade‐off between stem cell niche size, aging, and tumorigenesis

Abstract

Many epithelial tissues within multicellular organisms are continually replenished by small independent populations of stem cells largely responsible for maintaining tissue homeostasis. These continually dividing populations are subject to mutations that can lead to tumorigenesis but also contribute to aging. Mutations accumulate in stem cell niches and change the rate of cell division and differentiation; the pace of this process and the fate of specific mutations depend strongly on niche population size. Here, we create a mathematical model of the intestinal stem cell niche, crypt system, and epithelium. We calculate the expected effect of fixed mutations in stem cell niches and their effect on tissue homeostasis throughout the intestinal epithelium over organismal lifetime. We find that, due to the small population size of stem cell niches, mutations predominantly fix via genetic drift and decrease stem cell fitness, leading to niche and tissue attrition, and contributing to organismal aging. We also explore mutation accumulation at various stem cell niche sizes and demonstrate that an evolutionary trade‐off exists between niche size, tissue aging, and the risk of tumorigenesis. Further, mouse and human niches exist at a size that minimizes the probability of tumorigenesis, at the expense of accumulating deleterious mutations due to genetic drift. Finally, we show that the trade‐off between the probability of tumorigenesis and the extent of aging depends on whether or not mutational effects confer a selective advantage in the stem cell niche.

Fixation probabilities in graph-structured populations under weak selection

“…This combinatorial explosion of modeling choices may seem daunting, but it also suggests an increased opportunity for applications of the theory. Different modeling choices will be relevant to animal, plant, and microbial populations, to somatic tissue [18][19][20], and to infectious diseases [15,21]. Given recent advances in theory [8-13, 26, 33], the toolkit now exists to apply evolutionary graph theory in a wide range of biological settings.…”

“…0 and n = h ! 1, with m = 2, the fixation probability jumps discontinuously from 0 to 1/3 as r crosses 1; the expression for r > 1 is given in Eq (20). For comparison we also show the upper bound ρ(r) � 1 − (r + 1) −1 , derived by Pavlogiannis et al [8], which applies to all weighted graphs with no self-loops under temperature initialization.…”

“…Spatial structure can also change the accumulation rate of neutral mutations, which do not affect fitness [14]. The effects of spatial structure on selection have consequences for microbial evolution [15], cancer [16][17][18][19][20], aging [19,20], and infectious disease [21].…”

Spectral analysis of transient amplifiers for death–birth updating constructed from regular graphs

“… 2013 ), ageing of tissues (Cannataro et al. 2016 , 2017 ), the spread of infections (Ottino-Löffler et al. 2017a , b ) and the microbial evolution of antibiotic resistance (Krieger et al.…”

The evolution of metapopulation dynamics and the number of stem cells in intestinal crypts and other tissue structures in multicellular bodies

“…Two crypts were in "mutator agreement" if they both had fixed mutator mutations or neither did. Overall agreement was higher in the smaller crypts suggesting that mutator clones were able to spread across the tissue representation of both quiescent and proliferative stem cells, transient amplifying cells, and a distribution of fitness effects of mutations found a balance between suppressing carcinogenesis with fewer stem cells and suppressing the fixation of deleterious alleles and tissue aging with more stem cells per crypt (Cannataro et al, 2016(Cannataro et al, , 2017. However, the story changes dramatically when there are few enough stem cells per crypt that crypts risk extinction and replacement by neighbor crypts.…”