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

Abstract

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 genesdamages function of the affected DDR genes, leading to genome instability and high risk of diseases, in particular, cancer. Knowing evolutionary origin of the PVs inhuman 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 inhuman DDR genes. We identified 169 DDR genes by referring tovarious databases and identified PVs in theDDR 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 resultsusing theGraphPad Prism software and the ggplot module. We identified DDR PVs from over 5000ancient humansdeveloped 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 tocompare theDDR PVs between modern humans and ancient humans. We analyzed evolution selection of DDR genes across 20 vertebrates using theCodeML in PAML for phylogenetic analysis. Ourphylogenic analysis ruled out cross-species conservation as the origin of human DDR PVs. Ourarcheological approach identified rich DDR PVs shared between modern and ancient humans, which were mostly dated within the last 5000 years. We alsoobserved similar pattern of quantitative PV distribution between modern and ancient humans. We furtherdetected a setof ATM, BRCA2 and CHEK2 PVs shared between human and Neanderthals. 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.