Mismatch repair (MMR) system is evolutionarily conserved for genome stability maintenance. Germline pathogenic variants (PVs) in MMR genes that lead to MMR functional deficiency are associated with high cancer risk. Knowing the evolutionary origin of germline PVs in human MMR genes will facilitate understanding the biological base of MMR deficiency in cancer. However, systematic knowledge is lacking to address the issue. In this study, we performed a comprehensive analysis to know the evolutionary origin of human MMR PVs. We retrieved MMR gene variants from the ClinVar database. The genomes of 100 vertebrates were collected from the UCSC genome browser and ancient human sequencing data were obtained through comprehensive data mining. Cross-species conservation analysis was performed based on the phylogenetic relationship among 100 vertebrates. Rescaled ancient sequencing data were used to perform variant calling for archeological analysis. Using the phylogenetic approach, we traced the 3369 MMR PVs identified in modern humans in 99 non-human vertebrate genomes but found no evidence for cross-species conservation as the source for human MMR PVs. Using the archeological approach, we searched the human MMR PVs in over 5000 ancient human genomes dated from 45,045 to 100 years before present and identified a group of MMR PVs shared between modern and ancient humans mostly within 10,000 years with similar quantitative patterns. Our study reveals that MMR PVs in modern humans were arisen within the recent human evolutionary history.

中文翻译：

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人类DNA错配修复基因种系致病变异的进化起源

错配修复（MMR）系统在进化上是保守的，用于维持基因组稳定性。MMR 基因中导致 MMR 功能缺陷的种系致病性变异 (PV) 与高癌症风险相关。了解人类 MMR 基因中种系 PV 的进化起源将有助于了解癌症中 MMR 缺陷的生物学基础。然而，缺乏系统知识来解决这个问题。在这项研究中，我们进行了全面的分析，以了解人类 MMR PV 的进化起源。我们从 ClinVar 数据库中检索了 MMR 基因变异。从UCSC基因组浏览器中收集了100种脊椎动物的基因组，并通过综合数据挖掘获得了古人类测序数据。基于100种脊椎动物之间的系统发育关系进行了跨物种保护分析。重新调整的古代测序数据用于执行考古分析的变异调用。使用系统发育方法，我们在 99 个非人类脊椎动物基因组中追踪了现代人类中发现的 3369 个 MMR PV，但没有发现跨物种保护的证据作为人类 MMR PV 的来源。利用考古学方法，我们在距今 45,045 至 100 年前的 5000 多个古代人类基因组中搜索了人类 MMR PV，并确定了一组现代人和古代人类之间共享的 MMR PV，这些 MMR PV 大多在 10,000 年内具有相似的数量模式。我们的研究表明，现代人类的 MMR PV 是在最近的人类进化史上出现的。