A new review highlights how human evolution has shaped the presence of pathogenic mutations in DNA damage repair (DDR) genes, providing a new perspective on why modern humans face increased cancer incidence. By linking genetic changes to the history of human populations, this paper 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 and protecting cells from damage caused by environmental and internal factors. These genes function through multiple coordinated pathways that repair different types of DNA damage and ensure normal cellular function. However, mutations within these genes can disrupt their function, lead to genomic instability, and increase the likelihood of developing disease, especially cancer.
This review highlights that many of these pathogenic mutations are not ancient remnants inherited from distant species, but have emerged during modern human evolution. There is evidence that most of these mutations are not present in other species, including closely related primates, indicating a unique human origin. This discovery 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 and modern humans. data summarized in Timeline visualization (6 pages) Most of the holders of these fluctuations have emerged within the past 10,000 years, and are shown to be particularly concentrated in recent periods. This suggests that many of the genetic factors associated with cancer risk have developed relatively recently from an evolutionary perspective.
This review also links the increase in these mutations to major milestones in human history. Events such as population expansion, migration, and genetic admixture played important roles in spreading these variants throughout the world’s population. For example, genetic admixture between populations allows certain high-risk variants to spread beyond their region of origin, contributing to the widespread presence of variants today.
Importantly, the paper highlights that some of these mutations may be influenced by evolutionary selection, and that genetic changes may confer advantages in areas such as immunity and development. However, these benefits may come with trade-offs, such as increased vulnerability to disease later in life.
Overall, this study positions pathogenic mutations in the DDR gene as a byproduct of human evolutionary history. By linking genetics, evolution, and disease risk, this review provides a deeper understanding of how modern health problems are rooted in the biological processes of our species and opens new avenues for improving prevention and treatment strategies.
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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 mutations in human DNA damage repair genes arose from the evolutionary process of modern humans, Genes & Disease, Volume 13, Issue 3, 2026; 101916, https://doi.org/10.1016/j.gendis.2025.101916
