Mutation is the source of genetic variation and fuels biological evolution. Many mutations first arise as DNA replication errors. These errors subsequently evade correction by cellular DNA repair, for example, by the well-known DNA mismatch repair (MMR) mechanism. Here, we determine the genome-wide effects of MMR on mutation. We first identify almost 9000 mutations accumulated over five generations in eight MMR-deficient mutation accumulation (MA) lines of the model plant species, Arabidopsis thaliana. We then show that MMR deficiency greatly increases the frequency of both smaller-scale insertions and deletions (indels) and of single-nucleotide variant (SNV) mutations. Most indels involve A or T nucleotides and occur preferentially in homopolymeric (poly A or poly T) genomic stretches. In addition, we find that the likelihood of occurrence of indels in homopolymeric stretches is strongly related to stretch length, and that this relationship causes ultrahigh localized mutation rates in specific homopolymeric stretch regions. For SNVs, we show that MMR deficiency both increases their frequency and changes their molecular mutational spectrum, causing further enhancement of the GC to AT bias characteristic of organisms with normal MMR function. Our final genome-wide analyses show that MMR deficiency disproportionately increases the numbers of SNVs in genes, rather than in nongenic regions of the genome. This latter observation indicates that MMR preferentially protects genes from mutation and has important consequences for understanding the evolution of genomes during both natural selection and human tumor growth.

突变是遗传变异的来源，是生物进化的燃料。许多突变首先是作为 DNA 复制错误出现的。这些错误随后通过细胞 DNA 修复逃避纠正，例如，通过众所周知的 DNA 错配修复 (MMR) 机制。在这里，我们确定了 MMR 对突变的全基因组影响。我们首先在模式植物拟南芥的 8 个 MMR 缺陷突变积累 (MA) 系中鉴定了近 9000 个突变，这些突变积累了 5 代。. 然后，我们表明 MMR 缺陷大大增加了小规模插入和缺失 (indel) 和单核苷酸变异 (SNV) 突变的频率。大多数插入缺失涉及 A 或 T 核苷酸，并优先出现在同聚（poly A 或 poly T）基因组片段中。此外，我们发现在均聚拉伸中出现插入缺失的可能性与拉伸长度密切相关，并且这种关系导致特定均聚拉伸区域中的超高局部突变率。对于 SNV，我们表明 MMR 缺陷既增加了它们的频率，又改变了它们的分子突变谱，导致具有正常 MMR 功能的生物体的 GC 对 AT 偏差特征的进一步增强。我们最终的全基因组分析表明，MMR 缺陷不成比例地增加了基因中 SNV 的数量，而不是基因组的非基因区域。后一种观察表明 MMR 优先保护基因免受突变，并且对于理解自然选择和人类肿瘤生长过程中基因组的进化具有重要意义。