Intestinal stem cell division and genetic diversity. A computer and experimental analysis

Abstract

Somatic mutations are expected to arise with age. This process is accelerated in mice lacking the DNA mismatch repair gene Pms2. The distributions of microsatellite alleles present in small patches of normal Pms2 -/- intestines revealed a general increase in genetic diversity or the number of mutations with age. However, the patterns were complex with different distributions and variances present within a single mouse. Computer simulations indicate that the experimental data are consistent with mutation rates between 0.0020 and 0.0025 mutations per division, nonrandom cell death, and an effective population size of 20 or fewer cells. Small numbers of cells exacerbate the random accumulation of mutations expected of a stochastic mutation process. The computer simulations and experimental data are consistent with known patterns of intestinal development and renewal by small numbers of stem cells and demonstrate relatively high mutation rates in histologically normal epithelium. These findings provide background for the analysis of microsatellite mutations in normal and tumor tissue lacking mismatch repair and further support the hypothesis that microsatellite loci can function as molecular tumor clocks.