人类基因组中的DNA损伤修复（DDR）系统对于维持基因组完整性至关重要。 DDR 基因中的致病变异 (PV) 会损害其功能，导致基因组不稳定并增加对疾病（尤其是癌症）的易感性。了解DDR PV的进化起源和出现时间对于了解现代人类的疾病易感性至关重要。我们利用大数据方法来识别现代人类DDR基因中的PV。我们挖掘了来自 251,214 名非洲和非非洲现代人的多个基因组数据库。我们比较了非洲和非非洲国家的 DDR PV。我们还在 5,031 名古人类的基因组数据中挖掘了 DDR PV。我们使用古代人类的 DDR PV 作为中间体，以进一步促进非洲和非非洲之间的 DDR PV。我们在非洲和非非洲的现代人类中鉴定了 77 个 DDR 基因中的 1,060 个单碱基 DDR PV。直接比较非洲和非非洲的 DDR PV 表明，82.1% 的非非洲 PV 并不存在于非洲。我们进一步在距今 45,045 年至 100 年前生活在欧亚大陆的 5,031 名古人类的 56 个 DDR 基因中确定了 397 个单碱基 DDR PV，因此，最新走出非洲的人类移民的后代出现了 50,000-60,000几年前。通过参考古代 DDR PV，我们发现 397 个古代 DDR PV 中有 276 个 (70.3%) 是非非洲独有的，106 个 (26.7%) 在非非洲和非洲之间共享，只有 15 个 (3.8%)是非洲独有的。我们通过测试 BRCA 和 TP53（维持基因组稳定性的两个重要基因）在非洲、非非洲和古代人类中的 PV 进一步验证了分布模式。我们的研究表明，现代人类的 DDR PV 大多是在最近一次离开非洲的迁徙之后出现的。这些数据为了解现代人类疾病易感性（特别是癌症）的进化基础奠定了基础。版权所有 © 2024 He、Kou、Li、Ding 和 Wang。

The DNA damage repair (DDR) system in human genome is pivotal in maintaining genomic integrity. Pathogenic variation (PV) in DDR genes impairs their function, leading to genome instability and increased susceptibility to diseases, especially cancer. Understanding the evolution origin and arising time of DDR PV is crucial for comprehending disease susceptibility in modern humans.We used big data approach to identify the PVs in DDR genes in modern humans. We mined multiple genomic databases derived from 251,214 modern humans of African and non-Africans. We compared the DDR PVs between African and non-African. We also mined the DDR PVs in the genomic data derived from 5,031 ancient humans. We used the DDR PVs from ancient humans as the intermediate to further the DDR PVs between African and non-African.We identified 1,060 single-base DDR PVs across 77 DDR genes in modern humans of African and non-African. Direct comparison of the DDR PVs between African and non-African showed that 82.1% of the non-African PVs were not present in African. We further identified 397 single-base DDR PVs in 56 DDR genes in the 5,031 ancient humans dated between 45,045 and 100 years before present (BP) lived in Eurasian continent therefore the descendants of the latest out-of-Africa human migrants occurred 50,000-60,000 years ago. By referring to the ancient DDR PVs, we observed that 276 of the 397 (70.3%) ancient DDR PVs were exclusive in non-African, 106 (26.7%) were shared between non-African and African, and only 15 (3.8%) were exclusive in African. We further validated the distribution pattern by testing the PVs in BRCA and TP53, two of the important genes in genome stability maintenance, in African, non-African, and Ancient humans. Our study revealed that DDR PVs in modern humans mostly emerged after the latest out-of-Africa migration. The data provides a foundation to understand the evolutionary basis of disease susceptibility, in particular cancer, in modern humans.Copyright © 2024 He, Kou, Li, Ding and Wang.