New research shows that as men age, sperm production does not just accumulate random DNA errors. It actively favours certain harmful genetic mutations, increasing inherited risk for children.
Harmful genetic mutations in sperm become increasingly common as men age. But new research suggests this rise is not simply the result of DNA wear and tear over time. Instead, some mutations appear to gain a biological advantage during sperm production itself. In other words, certain harmful genetic changes do not just occur more often with age.
A Closer Look at How Sperm DNA Changes With Age
In a major study published recently in Nature, researchers from the Wellcome Sanger Institute working with the TwinsUK study at King’s College London to mapped how damaging DNA mutations in sperm increase across the genome as men grow older.
The study provides one of the most detailed pictures so far of how paternal age influences genetic risk, and why children born to older fathers face a higher chance of rare genetic conditions.
Importantly, the findings also raise new questions about how lifestyle, environmental exposures, and long-term health may shape the genetic information passed to future generations.
Why Some Mutations Thrive
In tissues that constantly renew themselves, DNA mutations can sometimes give certain cells a growth advantage. When that happens, those cells multiply faster than their neighbours, forming clusters of genetically identical cells known as clones.
Scientists have long recognised this process in organs such as the skin and blood. In these tissues, most mutations occur in somatic cells that form tissues and organs and are not inherited.
Sperm and egg cells work differently. Mutations that arise in sperm can be passed directly to offspring.
Ultra-Accurate DNA Sequencing
Up until recently, scientists lacked the tools to measure whether some mutations were being favoured during sperm production, or how strong that effect might be.
For this study, researchers used NanoSeq1, an ultra-accurate DNA sequencing method, to examine sperm from 81 healthy men aged between 24 and 75 years old. These samples came from the TwinsUK cohort, the UK’s largest adult twin registry, offering detailed health and genetic data across decades.
This approach allowed the team to detect rare genetic changes with great accuracy, and was even able to track how the frequency of DNA mutations changed with age.
How Mutation Rates Increase With Age
The results show a clear age-related trend.
About 2% of sperm from men in their early 30s contained disease-causing mutations. That figure rose to between 3-5% in middle-aged men (43 to 58 years) and older men (59 to 74 years).
Among participants aged 70, researchers found that 4.5% of sperm carried harmful genetic changes.
While men are more likely to have children at younger ages, this steady increase in mutation rates highlights how genetic risks to offspring continue to rise as paternal age increases.
Natural Selection Within the Testes
This rise in mutations is not explained by random DNA errors alone.
Instead, there appears to be a form of natural selection occurring within the testes. Some mutations give sperm-producing cells a competitive edge, allowing those cells to produce more sperm than others. Over time, these mutations become over-represented in the sperm population, even if they are harmful when passed on to children.
The team identified 40 genes in which certain DNA changes are favoured during sperm production, many of which are linked to severe neurodevelopmental disorders and inherited cancer risk in children. The study shows that a much broader set of genes are being affected than previously recognised.
It also shows that the male germline is not a static, protected system, but a dynamic environment shaped by natural selection.
Not All Mutations Results in Live Birth
Although the proportion of sperm carrying harmful mutations increases with age, not every mutation results in fertilisation or a live birth.
Some mutations may reduce the chances of fertilisation, disrupt early embryo development, or lead to miscarriage. More research is needed to understand how the rise in mutation rates translate into specific health outcomes in children.
Still, researchers believe that the study findings help to shape the understanding of how mutations arise and spread within sperm. In future, this information can help improve reproductive risk assessments, and help scientists and clinicians understand how environmental and lifestyle factors influence inherited risk.
Complementary Study in Children’s DNA
Researchers from Harvard Medical School and the Sanger Institute examined the same process – this time instead of measuring mutations in sperm directly, they studied mutations already passed on to children.
Researchers identified over 30 genes where mutations give sperm cells a strong competitive advantage, many of which overlapped with those found in the sperm-based study and were similarly linked to rare developmental disorders and cancer. These mutations can raise sperm mutation rates by roughly 500-fold. This helps explain why some rare genetic disorders appear in children even when parents do not carry the mutations in their own DNA.
The high frequency of these mutations in sperm can make certain genes appear linked to disease, even when the association is driven by unusually high mutation rates rather than a direct disease-causing effect.
What This Means For Future Generations
Taken together, these findings reveal a hidden layer of genetic risk linked to paternal age. The increase in harmful sperm mutations is not simply a matter of DNA gradually wearing down over time. Instead, some mutations gain a biological advantage during sperm production, allowing them to become more common as men grow older.
While most children of older fathers are born healthy, understanding how genetic risk changes with age may eventually improve reproductive counselling and risk assessment. It also opens new avenues for research into how long-term health, environment, and lifestyle factors influence the genetic legacy passed on to the next generation.
References
- Neville, M.D.C., Lawson, A.R.J., Sanghvi, R. et al. Sperm sequencing reveals extensive positive selection in the male germline. Nature 647, 421–428 (2025). https://doi.org/10.1038/s41586-025-09448-3
- Seplyarskiy, V., Moldovan, M.A., Koch, E. et al. Hotspots of human mutation point to clonal expansions in spermatogonia. Nature 647, 429–435 (2025). https://doi.org/10.1038/s41586-025-09579-7
