Tsao J L, Davis S D, Baker S M, Liskay R M, Shibata D
Department of Pathology, University of Southern California School of Medicine, Los Angeles 90033, USA.
Am J Pathol. 1997 Aug;151(2):573-9.
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.
体细胞突变预计会随着年龄增长而出现。在缺乏DNA错配修复基因Pms2的小鼠中，这一过程会加速。正常Pms2 -/- 小肠小块区域中存在的微卫星等位基因分布显示，随着年龄增长，遗传多样性或突变数量普遍增加。然而，这些模式很复杂，在同一只小鼠体内存在不同的分布和方差。计算机模拟表明，实验数据与每次细胞分裂0.0020至0.0025个突变的突变率、非随机细胞死亡以及20个或更少细胞的有效群体大小一致。少量细胞会加剧随机突变过程中预期的突变随机积累。计算机模拟和实验数据与已知的少量干细胞进行肠道发育和更新的模式一致，并证明在组织学正常的上皮中存在相对较高的突变率。这些发现为分析缺乏错配修复的正常组织和肿瘤组织中的微卫星突变提供了背景，并进一步支持了微卫星位点可作为分子肿瘤时钟的假说。
