Microsatellites are repeats of 1- to 6-bp units, and approximately 10 million microsatellites have been identified across the human genome. Microsatellites are vulnerable to DNA mismatch errors and have thus been used to detect cancers with mismatch repair deficiency. To reveal the mutational landscape of microsatellite repeat regions at the genome level, we analyzed approximately 20.1 billion microsatellites in 2717 whole genomes of pan-cancer samples across 21 tissue types. First, we developed a new insertion and deletion caller (MIMcall) that takes into consideration the error patterns of different types of microsatellites. Among the 2717 pan-cancer samples, our analysis identified 31 samples, including colorectal, uterus, and stomach cancers, with a higher proportion of mutated microsatellite (≥0.03), which we defined as microsatellite instability (MSI) cancers of genome-wide level. Next, we found 20 highly mutated microsatellites that can be used to detect MSI cancers with high sensitivity. Third, we found that replication timing and DNA shape were significantly associated with mutation rates of microsatellites. Last, analysis of mutations in mismatch repair genes showed that somatic SNVs and short indels had larger functional impacts than germline mutations and structural variations. Our analysis provides a comprehensive picture of mutations in the microsatellite regions and reveals possible causes of mutations, as well as provides a useful marker set for MSI detection.

中文翻译：

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综合分析全基因组微卫星区域中的插入缺失和21种癌症类型的微卫星不稳定性

微卫星是1至6 bp单位的重复序列，并且已经在整个人类基因组中鉴定出大约1000万个微卫星。微卫星容易受到DNA错配错误的影响，因此已被用于检测错配修复缺陷的癌症。为了揭示基因组水平上微卫星重复区域的突变态势，我们分析了21种组织类型的全癌样本的2717个全基因组中的约201亿个微卫星。首先，我们开发了一种新的插入和删除调用程序（MIMcall），其中考虑了不同类型的微卫星的错误模式。在2717个全癌样本中，我们的分析确定了31个样本，包括大肠癌，子宫癌和胃癌，其中微卫星突变的比例更高（≥0.03），我们将其定义为全基因组水平的微卫星不稳定性（MSI）癌症。接下来，我们发现了20个高度变异的微卫星，可用于以高灵敏度检测MSI癌症。第三，我们发现复制时间和DNA形状与微卫星的突变率显着相关。最后，错配修复基因突变的分析表明，与种系突变和结构变异相比，体细胞SNV和短indel具有更大的功能影响。我们的分析提供了微卫星区域中突变的全面情况，揭示了突变的可能原因，并为MSI检测提供了有用的标记物。我们发现复制时间和DNA形状与微卫星的突变率显着相关。最后，错配修复基因突变的分析表明，与种系突变和结构变异相比，体细胞SNV和短indel具有更大的功能影响。我们的分析为微卫星区域的突变提供了全面的图片，并揭示了可能的突变原因，并为MSI检测提供了有用的标记物。我们发现复制时间和DNA形状与微卫星的突变率显着相关。最后，错配修复基因突变的分析表明，与种系突变和结构变异相比，体细胞SNV和短indel具有更大的功能影响。我们的分析提供了微卫星区域中突变的全面情况，揭示了突变的可能原因，并为MSI检测提供了有用的标记物。