Ministry of Education Frontiers Science Center for Precision Oncology, Cancer Centre and Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, 999078, China.
Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310018, Zhejiang, China.
Hum Genomics. 2024 Jan 29;18(1):5. doi: 10.1186/s40246-024-00573-0.
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.
错配修复（MMR）系统是为了维护基因组稳定性而进化保守的。导致 MMR 功能缺陷的 MMR 基因种系致病性变异（PVs）与高癌症风险相关。了解人类 MMR 基因中种系 PVs 的进化起源将有助于理解癌症中 MMR 缺陷的生物学基础。然而，系统知识缺乏来解决这个问题。在这项研究中，我们进行了全面的分析，以了解人类 MMR PVs 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，并通过全面的数据挖掘获得了古代人类测序数据。基于 100 种脊椎动物的系统发育关系进行了跨物种保守性分析。使用重采样的古代测序数据对考古分析进行了变异调用。
使用系统发育方法，我们在 99 种非人类脊椎动物基因组中追踪了在现代人类中发现的 3369 种 MMR PVs，但没有发现跨物种保守性作为人类 MMR PVs 来源的证据。使用考古学方法，我们在超过 5000 个古代人类基因组中搜索了人类 MMR PVs，这些基因组的年代从距今 45045 年到 100 年前不等，确定了一组在现代人和古代人类之间共享的 MMR PVs，主要是在 10000 年内，具有相似的定量模式。
我们的研究表明，现代人类中的 MMR PVs 是在最近的人类进化史中产生的。
