A new review highlights how human evolution has shaped the presence of pathogenic variations in DNA damage repair (DDR) genes, offering a new perspective on why modern populations face increased cancer susceptibility. By connecting genetic change with the history of human populations, the article reveals how biological processes that once supported survival now also influence disease risk.
DNA damage repair genes play a fundamental role in maintaining genome stability, protecting cells from damage caused by environmental and internal factors. These genes operate through multiple coordinated pathways that repair different types of DNA lesions, ensuring normal cellular function. However, variations within these genes can disrupt their function, leading to genome instability and increasing the likelihood of disease development, particularly cancer.
The review emphasizes that many of these pathogenic variations are not ancient remnants inherited from distant species but instead emerged during the course of modern human evolution. Evidence shows that the majority of these variants are absent in other species, including closely related primates, pointing to a uniquely human origin. This finding highlights the dynamic nature of the human genome and its continuous adaptation over time.
Further insights reveal that these genetic changes are widely shared between ancient humans and present-day populations. Data summarized in the timeline visualization on page 6 shows that most carriers of these variations appeared within the last 10,000 years, with a particularly strong concentration in more recent periods. This suggests that many of the genetic factors linked to cancer risk developed relatively recently in evolutionary terms.
The review also connects the rise of these variations to major milestones in human history. Events such as population expansion, migration, and genetic admixture played key roles in spreading these variants across global populations. For example, genetic mixing between populations enabled the transmission of certain high-risk variants beyond their original regions, contributing to their widespread presence today.
Importantly, the article highlights that some of these variations may have been influenced by evolutionary selection, where genetic changes provided advantages in areas such as immunity or development. However, these benefits may come with trade-offs, including increased vulnerability to disease later in life.
Overall, this work positions pathogenic variation in DDR genes as a by-product of human evolutionary history. By linking genetics, evolution, and disease risk, the review provides a deeper understanding of how modern health challenges are rooted in the biological journey of our species, opening new avenues for improved prevention and treatment strategies.
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Reference
Jiaheng Li, Bojin Zhao, Zixin Qin, Si Hoi Kou, Jia Sheng Chian, Fengxia Xiao, Huijun Lei, Stephanie Andaluz, Jun He, Siddharth Sinha, Xiaowei Mao, San Ming Wang, Pathogenic variation in human DNA damage repair genes was originated from the evolutionary process of modern humans, Genes & Diseases, Volume 13, Issue 3, 2026, 101916, https://doi.org/10.1016/j.gendis.2025.101916

Funding
Macau Science and Technology Development Fund (China) 085/2017/A2
Macau Science and Technology Development Fund (China) 0077/2019/AMJ
Macau Science and Technology Development Fund (China) 0032/2022/A1
University of Macau (China) (No. SRG2017–00097-FHS
University of Macau (China) MYRG2019–00018-FHS
University of Macau (China) MYRG2020–00094-FHS
Faculty of Health Sciences, University of Macau (China) FHSIG/SW/0007/2020P
MOE Frontiers Science Center for Precision Oncology pilot grant
Chengdu Research Base of Giant Panda Breeding (China) CPB2025–B15
National Natural Science Foundation of China T2322002
National Science and Technology Major Project of China 2024ZD0523900
Sichuan Science and Technology Program (China) 2024NSFTD0032
Sichuan Science and Technology Program (China) 2024ZYD0006
Sichuan Science and Technology Program (China) 2024NSFTD0032