Cannataro Vincent L, McKinley Scott A, St Mary Colette M
Department of Biology University of Florida Gainesville FL USA.
Department of Mathematics Tulane University New Orleans LA USA.
Evol Appl. 2016 Mar 8;9(4):565-82. doi: 10.1111/eva.12361. eCollection 2016 Apr.
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.
由于干细胞群体中突变的积累，体细胞组织在脊椎动物的一生中会发生进化。突变可能会改变细胞适应性，并导致肿瘤发生或衰老。体细胞内突变效应的分布尚不清楚。鉴于体细胞分裂的独特调控机制，我们推测体细胞组织中的突变效应与整个生物体的情况不同；在体细胞组织中，具有较大效应的突变更多。通过模拟分析，我们研究了使用适应性效应（DFE）的指数分布和幂律分布生成的肿瘤发生率曲线与已知肿瘤发生发生率的拟合情况。建模考虑因素包括干细胞群体的结构，即大量非常小的群体，以及在干细胞微环境中中性固定和不固定的突变。我们发现，在整个生物体中通常量化的DFE足以解释肿瘤发生发生率。此外，预计有害突变会通过遗传漂变积累，导致组织维持能力下降。因此，尽管整个肠道中有大量干细胞，但其分区结构会导致有害突变的积累和显著衰老，使肠道干细胞微环境成为缪勒棘轮的一个典型例子。
