Pathogenic variants in human DNA damage repair genes mostly arose in recent human history

Bojin Zhao; Jiaheng Li; Siddharth Sinha; Zixin Qin; Si Hoi Kou; Fengxia Xiao; Huijun Lei; Tianhui Chen; Wenming Cao; Xiaofan Ding; San Ming Wang

doi:10.1186/s12885-024-12160-6

Pathogenic variants in human DNA damage repair genes mostly arose in recent human history

BMC Cancer. 2024 Apr 4;24(1):415. doi: 10.1186/s12885-024-12160-6.

Authors

Bojin Zhao^#¹, Jiaheng Li^#¹, Siddharth Sinha¹, Zixin Qin¹, Si Hoi Kou¹, Fengxia Xiao¹, Huijun Lei^{1

2}, Tianhui Chen^{2

3}, Wenming Cao^{4

3}, Xiaofan Ding¹, San Ming Wang⁵

Affiliations

¹ Cancer Centre and Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Taipa, 999078, Macau SAR, China.
² Department of Cancer Prevention, Zhejiang Cancer Hospital, Hangzhou, 310022, China.
³ Hangzhou Institute of Medicine, Chinese Academy of Sciences, Hangzhou, 310018, China.
⁴ Department of Breast Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, 310022, China.
⁵ Cancer Centre and Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Taipa, 999078, Macau SAR, China. sanmingwang@um.edu.mo.

^# Contributed equally.

Abstract

Background: Genome stability is maintained by the DNA damage repair (DDR) system composed of multiple DNA repair pathways of hundreds of genes. Germline pathogenic variation (PV) in DDR genes damages function of the affected DDR genes, leading to genome instability and high risk of diseases, in particular, cancer. Knowing evolutionary origin of the PVs in human DDR genes is essential to understand the etiology of human diseases. However, answer to the issue remains largely elusive. In this study, we analyzed evolutionary origin for the PVs in human DDR genes.

Methods: We identified 169 DDR genes by referring to various databases and identified PVs in the DDR genes of modern humans from ClinVar database. We performed a phylogenetic analysis to analyze the conservation of human DDR PVs in 100 vertebrates through cross-species genomic data comparison using the phyloFit program of the PHAST package and visualized the results using the GraphPad Prism software and the ggplot module. We identified DDR PVs from over 5000 ancient humans developed a database to host the DDR PVs ( https://genemutation.fhs.um.edu.mo/dbDDR-AncientHumans ). Using the PV data, we performed a molecular archeological analysis to compare the DDR PVs between modern humans and ancient humans. We analyzed evolution selection of DDR genes across 20 vertebrates using the CodeML in PAML for phylogenetic analysis.

Results: Our phylogenic analysis ruled out cross-species conservation as the origin of human DDR PVs. Our archeological approach identified rich DDR PVs shared between modern and ancient humans, which were mostly dated within the last 5000 years. We also observed similar pattern of quantitative PV distribution between modern and ancient humans. We further detected a set of ATM, BRCA2 and CHEK2 PVs shared between human and Neanderthals.

Conclusions: Our study reveals that human DDR PVs mostly arose in recent human history. We propose that human high cancer risk caused by DDR PVs can be a by-product of human evolution.

Keywords: Archaeological; DNA damage repair; Evolutionary origin; Pathogenic variants; Phylogenetic.

MeSH terms

DNA Damage / genetics
DNA Repair* / genetics
Genes, BRCA2
Genetic Predisposition to Disease
Genomic Instability
Humans
Neoplasms* / genetics
Phylogeny