Genetic mutations that can cause disease become increasingly common in sperm as men grow older, and new evidence suggests this happens because certain DNA changes are actually favored during sperm production, according to new research.
In a major study published on October 8 in Nature, scientists from the Wellcome Sanger Institute and the TwinsUK study at King's College London mapped how harmful DNA mutations accumulate across the entire sperm genome as men age.
The results open new avenues for studying how environmental and lifestyle factors might influence the genetic health of future generations.
In tissues that constantly renew, mutations (changes in DNA) can give some cells an advantage, allowing them to multiply faster than others. These groups of identical "clonal" cells then expand, eventually outnumbering their neighbors. While most mutations in the body's ordinary cells (such as those in organs, connective tissue, and bone) are not passed to children, mutations in sperm and egg cells can be inherited. Until recently, however, scientists lacked the precise tools to measure how strongly certain mutations are favored in sperm.
To overcome this, the team used NanoSeq1, a highly accurate DNA sequencing technology, to analyze sperm from 81 healthy men aged 24 to 75.2,3 The samples came from the TwinsUK cohort, the UK's largest adult twin registry, which provided a well-documented and diverse population for comparison.
The data revealed that about 2 percent of sperm from men in their early 30s carried disease-causing mutations. This proportion increased to 3-5 percent in men aged 43 to 74. Among 70-year-old participants, 4.5 percent of sperm contained harmful mutations, showing a clear link between age and genetic risk to offspring.
The increase is not caused solely by random DNA errors accumulating over time. Instead, a subtle form of natural selection within the testes appears to give certain mutations a reproductive advantage, allowing them to become more common during sperm formation.
Researchers pinpointed 40 genes that seem to benefit from this process, many of which are tied to serious neurodevelopmental disorders in children and inherited cancer risks. While 13 of these genes were previously known to be involved, the new study shows the phenomenon affects many more genes linked to cell growth and development than scientists once realized.
Although the number of sperm carrying harmful mutations rises with age, not every one of these mutations leads to conception or a healthy pregnancy. Some may prevent fertilization or normal embryo development, while others could cause miscarriage. More studies are needed to determine how the growing number of sperm mutations affects children's health outcomes.
By revealing how mutations arise and are shaped by selection within sperm, the researchers hope to refine reproductive risk assessments and better understand how genetics, lifestyle, and environment interact across generations.
In a complementary study, also published in Nature,4 scientists from Harvard Medical School and the Sanger Institute investigated the same phenomenon from a different angle by looking at mutations already passed on to children, rather than those measured directly in sperm. By analyzing DNA from over 54,000 parent-child trios and 800,000 healthy individuals, the team identified more than 30 genes where mutations give sperm cells a competitive edge, again including many linked to rare developmental disorders and cancer, and many overlapping the set of genes observed directly in sperm. The study found that these mutations can increase sperm mutation rates roughly 500-fold which helps explain why some rare genetic disorders appear when parents do not carry the mutations in their own DNA. Interestingly, the study notes that as these mutations are common in the sperm, it may look like some genes cause false-positive disease association due to the elevated mutation rate rather than a true disease link. The work highlights how natural selection within sperm can be directly observed in the DNA of children, influencing their chances of inheriting certain genetic disorders.
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 Wellcome Sanger Institute and co-author, said: "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, co-author and Scientific Director of the TwinsUK study at King's College London, said: "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, allowing us to explore how mutations accumulate and evolve with age in healthy individuals. This collaboration highlights the power of large, population-based cohorts for advancing our understanding of human development and inheritance."
Dr. Raheleh Rahbari, senior author and Group Leader at the Wellcome Sanger Institute, said: "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."
This research is part-funded by Wellcome. A full list of funders can be found in the acknowledgements in the publication.
Notes
- Launched in 2021 by the Wellcome Sanger Institute, nanorate sequencing (NanoSeq), is a method that makes it possible to study how genetic changes occur in human tissue whilst maintaining high accuracy. The method reduces error rates to less than five errors per billion calls which is much lower than typical somatic mutation rates.
- Blood samples were taken to ensure that mutations studied in sperm were only in sperm cells.
- The researchers split the data into age groups: 26-42 years (younger men), 43-58 years (middle-aged), and 59-74 years (older men).
- Sunyaev, S. et al. (2025) 'Hotspots of human mutation point to clonal expansions in spermatogonia'. Nature. DOI: 10.1038/s41586-025-09579-7
- In a complementary study (Lawson, A. et al) researchers at the Sanger Institute have reported using targeted NanoSeq to uncover hidden mutations that occur naturally in bodies, providing insight into the earliest steps of cancer development and the role of mutations in different diseases. This team also collaborated with the TwinsUK study at King's College London. They applied targeted NanoSeq to cheek and blood samples from more than 1,000 volunteers to uncover a rich landscape of mutations in healthy tissues, which can be applied to future research into aging and diseases. Targeted NanoSeq is the same tool used in the above study. DOI: 10.1038/s41586-025-09584-w
Genetic mutations that can cause disease become increasingly common in sperm as men grow older, and new evidence suggests this happens because certain DNA changes are actually favored during sperm production, according to new research.
In a major study published on October 8 in Nature, scientists from the Wellcome Sanger Institute and the TwinsUK study at King's College London mapped how harmful DNA mutations accumulate across the entire sperm genome as men age.
The results open new avenues for studying how environmental and lifestyle factors might influence the genetic health of future generations.
In tissues that constantly renew, mutations (changes in DNA) can give some cells an advantage, allowing them to multiply faster than others. These groups of identical "clonal" cells then expand, eventually outnumbering their neighbors. While most mutations in the body's ordinary cells (such as those in organs, connective tissue, and bone) are not passed to children, mutations in sperm and egg cells can be inherited. Until recently, however, scientists lacked the precise tools to measure how strongly certain mutations are favored in sperm.
To overcome this, the team used NanoSeq1, a highly accurate DNA sequencing technology, to analyze sperm from 81 healthy men aged 24 to 75.2,3 The samples came from the TwinsUK cohort, the UK's largest adult twin registry, which provided a well-documented and diverse population for comparison.
The data revealed that about 2 percent of sperm from men in their early 30s carried disease-causing mutations. This proportion increased to 3-5 percent in men aged 43 to 74. Among 70-year-old participants, 4.5 percent of sperm contained harmful mutations, showing a clear link between age and genetic risk to offspring.
The increase is not caused solely by random DNA errors accumulating over time. Instead, a subtle form of natural selection within the testes appears to give certain mutations a reproductive advantage, allowing them to become more common during sperm formation.
Researchers pinpointed 40 genes that seem to benefit from this process, many of which are tied to serious neurodevelopmental disorders in children and inherited cancer risks. While 13 of these genes were previously known to be involved, the new study shows the phenomenon affects many more genes linked to cell growth and development than scientists once realized.
Although the number of sperm carrying harmful mutations rises with age, not every one of these mutations leads to conception or a healthy pregnancy. Some may prevent fertilization or normal embryo development, while others could cause miscarriage. More studies are needed to determine how the growing number of sperm mutations affects children's health outcomes.
By revealing how mutations arise and are shaped by selection within sperm, the researchers hope to refine reproductive risk assessments and better understand how genetics, lifestyle, and environment interact across generations.
In a complementary study, also published in Nature,4 scientists from Harvard Medical School and the Sanger Institute investigated the same phenomenon from a different angle by looking at mutations already passed on to children, rather than those measured directly in sperm. By analyzing DNA from over 54,000 parent-child trios and 800,000 healthy individuals, the team identified more than 30 genes where mutations give sperm cells a competitive edge, again including many linked to rare developmental disorders and cancer, and many overlapping the set of genes observed directly in sperm. The study found that these mutations can increase sperm mutation rates roughly 500-fold which helps explain why some rare genetic disorders appear when parents do not carry the mutations in their own DNA. Interestingly, the study notes that as these mutations are common in the sperm, it may look like some genes cause false-positive disease association due to the elevated mutation rate rather than a true disease link. The work highlights how natural selection within sperm can be directly observed in the DNA of children, influencing their chances of inheriting certain genetic disorders.
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 Wellcome Sanger Institute and co-author, said: "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, co-author and Scientific Director of the TwinsUK study at King's College London, said: "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, allowing us to explore how mutations accumulate and evolve with age in healthy individuals. This collaboration highlights the power of large, population-based cohorts for advancing our understanding of human development and inheritance."
Dr. Raheleh Rahbari, senior author and Group Leader at the Wellcome Sanger Institute, said: "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."
This research is part-funded by Wellcome. A full list of funders can be found in the acknowledgements in the publication.
Notes
- Launched in 2021 by the Wellcome Sanger Institute, nanorate sequencing (NanoSeq), is a method that makes it possible to study how genetic changes occur in human tissue whilst maintaining high accuracy. The method reduces error rates to less than five errors per billion calls which is much lower than typical somatic mutation rates.
- Blood samples were taken to ensure that mutations studied in sperm were only in sperm cells.
- The researchers split the data into age groups: 26-42 years (younger men), 43-58 years (middle-aged), and 59-74 years (older men).
- Sunyaev, S. et al. (2025) 'Hotspots of human mutation point to clonal expansions in spermatogonia'. Nature. DOI: 10.1038/s41586-025-09579-7
- In a complementary study (Lawson, A. et al) researchers at the Sanger Institute have reported using targeted NanoSeq to uncover hidden mutations that occur naturally in bodies, providing insight into the earliest steps of cancer development and the role of mutations in different diseases. This team also collaborated with the TwinsUK study at King's College London. They applied targeted NanoSeq to cheek and blood samples from more than 1,000 volunteers to uncover a rich landscape of mutations in healthy tissues, which can be applied to future research into aging and diseases. Targeted NanoSeq is the same tool used in the above study. DOI: 10.1038/s41586-025-09584-w
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