New research reveals that genetic mutations in men's sperm, which can lead to diseases in offspring, increase with age due to evolutionary selection within the testes. Scientists used advanced sequencing to analyze sperm from 81 men aged 24 to 75, finding that harmful mutations affect 2 percent of sperm in early 30s men but rise to 4.5 percent in 70-year-olds. The findings, published October 8 in Nature, highlight risks for future generations.
In a study published on October 8 in Nature, researchers from the Wellcome Sanger Institute and the TwinsUK study at King's College London examined how DNA mutations accumulate in sperm as men age. Using NanoSeq, a precise DNA sequencing technology, the team analyzed samples from 81 healthy men aged 24 to 75, drawn from the UK's largest adult twin registry.
The data showed that approximately 2 percent of sperm from men in their early 30s carried disease-causing mutations. This proportion climbed to 3-5 percent in men aged 43 to 74, reaching 4.5 percent among 70-year-olds. Rather than random accumulation, the increase stems from natural selection in the testes, where certain mutations confer a reproductive advantage to sperm cells.
The researchers identified 40 genes under this selective pressure, many associated with neurodevelopmental disorders in children and inherited cancer risks. Thirteen of these genes were previously known, but the study expands understanding of how mutations in cell growth and development genes are favored.
A complementary study in the same journal, analyzing DNA from over 54,000 parent-child trios and 800,000 healthy individuals, confirmed over 30 similar genes. These mutations can boost sperm mutation rates by about 500-fold, explaining some rare genetic disorders in children whose parents lack the mutations elsewhere in their DNA.
Dr. Matthew Neville, first author from the Wellcome Sanger Institute, said: "We expected to find some evidence of selection shaping mutations in sperm. What surprised us was just how much it drives up the number of sperm carrying mutations linked to serious diseases."
Professor Matt Hurles, director of the institute, noted: "Our findings reveal a hidden genetic risk that increases with paternal age. Some changes in DNA not only survive but thrive within the testes, meaning that fathers who conceive later in life may unknowingly have a higher risk of passing on a harmful mutation to their children."
Professor Kerrin Small, scientific director of TwinsUK, emphasized the cohort's value: "We are incredibly grateful to the twins who took part in this study. By working with the TwinsUK cohort, we could include valuable longitudinal samples linked to rich health and genetic information."
Dr. Raheleh Rahbari, senior author, added: "There's a common assumption that because the germline has a low mutation rate, it is well protected. But in reality, the male germline is a dynamic environment where natural selection can favour harmful mutations, sometimes with consequences for the next generation."
The research opens paths to assess reproductive risks and explore environmental influences on genetic health across generations, though more studies are needed on impacts like miscarriage or child health outcomes.