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

Abstract

Background Genome stability is maintained by the DNA damage repair (DDR) system composed of multiple DNA repair pathways of hundreds of DDR genes. Germline pathogenic variation (PV) damages function of the affected DDR genes, leading to genome instability and high risk of cancer. Knowing evolutionary origin of human DDR PV is essential to understand the etiology of human cancer. However, answer to the issue remains largely elusive. In the study, we analyzed evolutionary origin for the PVs in human DDR genes. Methods We collected 169 DDR genes by referencing various databases, analyzing cross-species genomic data using the phyloFit program of the PHAST package, with visualization using GraphPad Prism software and the ggplot module. Ancient and modern human DDR PV detection and comparison using tools such as SAMtools and variant annotation databases. Evolution selection studies across 20 vertebrates used CodeML in PAML for phylogenetic analysis, and the MEGA were used for sequence alignment. We created an open-access database using a LAMP stack and performed statistical analyses using Pearson correlation and Kruskal-Wallis tests. Results Through phylogenic analysis, we ruled out cross-species conservation as the origin; using archeological approach, we identified rich DDR PVs shared between modern and ancient humans, which were mostly dated within the last 10,000 years. We observed similar pattern of quantitative PV distribution between modern and ancient humans. We also detected a group of ATM, BRCA2 and CHEK2 PVs shared between human and Neanderthals. Conclusions Our study reveals that human DDR pathogenic variation mostly arose in recent human history, and human high cancer risk caused by DDR PVs can be a by-product of human evolution.