Scientists uncover age-related rise in harmful sperm mutations
Groundbreaking research published in Nature reveals that harmful genetic changes in sperm become more common as men age. The study, conducted by the Wellcome Sanger Institute in collaboration with the TwinsUK cohort at King’s College London, shows a clear, genome-wide increase in disease-causing mutations in sperm cells as men grow older. This discovery opens new avenues for understanding how lifestyle and environmental factors could influence genetic risks passed to future generations.
In renewing tissues, mutations can give certain cells a competitive edge, forming clones that expand over time. Unlike mutations in ordinary body tissues, those that occur in sperm and egg cells can be transmitted to offspring. Until now, measuring how strongly these mutations are favored in sperm proved difficult due to limitations in sequencing accuracy. The new study changes that, using ultra-accurate DNA sequencing to map mutation patterns with unprecedented precision.
Ultra-accurate sequencing reveals an age-related spike
Researchers analyzed sperm from 81 healthy men, aged 24 to 75, leveraging samples from the TwinsUK study—the UK’s largest adult twin registry. This design provided a robust, diverse population to study how genetic variation accumulates with age. The findings are striking: around 2% of sperm from men in their early 30s carried disease-causing mutations, rising to 3–5% in middle-aged and older men (43–74 years). Notably, by age 70, about 4.5% of sperm carried harmful mutations, underscoring the age-related increase in inherited genetic risk.
The rise is not solely due to a steady, random accumulation of mutations. The team found evidence of a subtle form of natural selection acting within the testes, boosting certain mutations during sperm production. This means some genetic changes gain a competitive edge, becoming more prevalent in sperm as men age.
Which genes are affected?
The study identified 40 genes where specific DNA changes are favored during sperm production, including many linked to childhood diseases, neurodevelopmental disorders, and inherited cancer risk. While before this, only a dozen genes were thought to be influenced by selective forces in sperm, the new work shows a much broader impact across genes important for cell growth and development. This expands our understanding of how selection shapes the paternal germline and the potential risks carried into offspring.
Implications for fertility and offspring health
Although the overall proportion of sperm with harmful mutations increases with age, not all of these changes will fertilize an egg or lead to a live birth. Some mutations might impede fertilization, embryo development, or result in pregnancy loss. More research is needed to translate these findings into concrete health outcomes for children, but the trend clearly indicates that paternal age can influence genetic risk in the next generation.
Researchers stress that their results could inform reproductive risk assessment and broaden investigations into how lifestyle and environmental exposures affect inherited genetic risks. Ultimately, understanding how DNA variations arise and are shaped by selection in sperm could help individuals and clinicians better evaluate paternal age-related genetic risks.
Complementary findings and the bigger picture
A parallel Nature study from Harvard Medical School and the Sanger Institute looked at mutations already present in children, analyzing DNA from over 54,000 parent–child trios and 800,000 healthy individuals. They identified more than 30 genes where paternal-selective mutations can increase sperm mutation rates by up to about 500-fold, offering an explanation for some rare developmental disorders and cancers that appear in children whose parents do not carry the same mutations in their own DNA. This work highlights how natural selection within the sperm lineage can influence the DNA inherited by offspring, illustrating a direct link between paternal age, sperm mutations, and child health.
Researchers’ reflections
Dr. Matthew Neville, the study’s first author, remarked on the surprising extent of selection’s role in shaping sperm mutations. “We expected some evidence of selection,” he said, “but not the degree to which it drives up the number of sperm carrying mutations linked to serious diseases.” Professor Matt Hurles emphasized the potential for these findings to reshape risk assessment for prospective fathers, while Professor Kerrin Small highlighted the TwinsUK collaboration’s value in enabling long-term, population-based insights into human development and inheritance. The team’s work underscores that the male germline is a dynamic environment, where natural selection can have meaningful consequences for future generations.
As scientists continue to dissect how genetic risks accumulate with age, the research community hopes to translate these findings into practical guidance for reproductive health and public policy.
