Summary: New research shows that harmful genetic mutations in sperm become more common as men age, and some of these mutations are actually favored during sperm production, giving them a reproductive advantage. Using an ultra-accurate sequencing technique, scientists found that sperm from older men are significantly more likely to carry mutations linked to neurodevelopmental disorders and inherited cancer risks.
This process, described as “selfish selection,” allows specific mutations to expand within the testes and increases the likelihood that they will be passed to the next generation. The study provides important insights into how paternal age affects genetic inheritance and the mechanisms that drive mutation spread across generations.
Key Facts:
- Age-associated increase: The proportion of sperm carrying disease-causing mutations rises from about 2% in younger men to roughly 3–5% in middle-aged and older men.
- Selfish selection in the germline: Certain mutations gain a selective advantage during sperm production, enabling them to proliferate within the testes.
- Health implications: Many of the genes affected are linked to developmental disorders in children and to inherited cancer susceptibility.
Source: Wellcome Sanger Institute
Harmful genetic changes in sperm become substantially more common with age because some changes are actively favoured during sperm production, new research reveals.
In a landmark study published in Nature, researchers at the Wellcome Sanger Institute, working with the TwinsUK cohort at King’s College London, mapped how harmful DNA changes accumulate in sperm across the genome as men age. By applying an ultra-accurate sequencing approach, the team measured mutation patterns in unprecedented detail.
The results open pathways for studying how lifestyle and environmental exposures might alter the genetic risks carried forward by fathers. In renewing tissues, mutations can give cells a growth advantage, creating clones that expand and outcompete neighboring cells. When such selection occurs in sperm-producing cell lineages, those mutations can be transmitted to offspring.
Unlike mutations that occur only in somatic tissues—such as skin, muscle, or organs—mutations in sperm or eggs are heritable. Until now, measuring selection in the male germline has been difficult because standard sequencing methods lacked the sensitivity to detect rare, low-frequency mutations with high confidence.
To overcome this, the researchers used NanoSeq, a duplex sequencing method with extremely low error rates, to analyze sperm from 81 healthy men aged 24 to 75 years. Samples were drawn from the TwinsUK registry, the UK’s largest adult twin cohort, giving access to well-characterized participants and longitudinal data.
The study found that roughly 2% of sperm from men in their early 30s carried disease-causing mutations. That proportion increased to about 3–5% in middle-aged men (43–58 years) and older men (59–74 years). For example, in men around age 70, approximately 4.5% of sperm carried pathogenic mutations. This clear age trend underscores how paternal age contributes to elevated genetic risk for offspring.
This rise is not explained solely by the gradual accumulation of random DNA errors. Instead, the team identified a form of positive selection acting on spermatogonial cells: some mutations provide a competitive edge during spermatogenesis, enabling mutated cell lineages to expand and contribute disproportionately to the sperm pool.
Researchers detected 40 genes where specific DNA changes appear to be favored during sperm production, including many already known to be associated with severe neurodevelopmental conditions and inherited cancers. Thirteen of these genes had previously been linked to positive selection in the male germline; the new study expands the list considerably, revealing selection across diverse pathways related to cell growth and development.
Although the fraction of sperm carrying harmful mutations rises with age, not every mutated sperm results in fertilisation, a viable embryo, or a live birth. Some mutations may prevent fertilisation, impede early embryo development, or lead to pregnancy loss. More research is needed to define how the greater burden of sperm mutations translates into actual health outcomes for children.
The authors hope that mapping how germline variants arise and are shaped by selection will improve reproductive risk assessment and support studies on how environment and lifestyle influence heritable genetic risk.
A complementary study published simultaneously examined mutations already transmitted to children by analyzing tens of thousands of parent–child trios and hundreds of thousands of healthy individuals. That analysis corroborated many of the same genes subject to positive selection and showed how such mutations can dramatically increase the local mutation rate—explaining why some rare disorders arise even when parents do not carry the variant in their blood DNA.
The combined findings demonstrate that natural selection within the male germline can be observed both in sperm and in the DNA of children, shaping inheritance patterns and influencing the appearance of certain genetic disorders.
Dr Matthew Neville, first author at the Wellcome Sanger Institute, commented that the researchers expected to detect selection in sperm but were surprised by how much it increases the number of sperm carrying mutations linked to serious disease. Professor Matt Hurles, Director of the Wellcome Sanger Institute, highlighted that some DNA changes not only persist but proliferate in the testes, meaning fathers who conceive later in life may unknowingly carry a higher chance of passing harmful mutations to their children.
Professor Kerrin Small, Scientific Director of the TwinsUK study, thanked the participating twins for enabling longitudinal analysis and emphasized the value of large, population-based cohorts in advancing understanding of human development and inheritance. Senior author Dr Raheleh Rahbari noted that while the germline has a relatively low baseline mutation rate, the male germline is dynamic and can favor mutations with consequences for the next generation.
Funding: This research was part-funded by Wellcome. A full list of funders is provided in the publication acknowledgements.
Key Questions Answered:
A: Mutations accumulate over time, and some acquire a competitive advantage in sperm-producing cells, allowing those mutated cell lineages to expand and contribute more sperm.
A: Many affected genes are associated with neurodevelopmental disorders, including some conditions on the autism spectrum, and with inherited cancer predisposition.
A: Researchers believe environmental and lifestyle factors may play a role and plan further studies to evaluate how these exposures shape heritable genetic risk.
About this genetics and neurodevelopment research news
Author: Susannah Young
Source: Wellcome Sanger Institute
Contact: Susannah Young, Wellcome Sanger Institute
Image: Image credited to Neuroscience News
Original Research: Open access. “Sperm sequencing reveals extensive positive selection in the male germline” by Matthew Neville et al., Nature.
Abstract
Sperm sequencing reveals extensive positive selection in the male germline
Mutations that occur in the cell lineages of sperm or eggs can be transmitted to offspring. In humans, positive selection of driver mutations during spermatogenesis can increase the birth prevalence of certain developmental disorders.
Previous attempts to characterise selection in sperm were limited by sequencing error rates. Using the duplex sequencing method NanoSeq, the authors sequenced 81 bulk sperm samples from individuals aged 24–75 years.
They observed a linear accumulation of approximately 1.67 mutations per year per haploid genome driven by two mutational signatures associated with ageing. Deep targeted and exome NanoSeq identified over 35,000 germline coding mutations.
The study detected 40 genes (31 newly identified) under significant positive selection in the male germline. These genes act through activating or loss-of-function mechanisms and participate in diverse cellular pathways. Most positively selected genes are linked to developmental disorders or cancer predisposition in children; four showed increased frequencies of protein-truncating variants in healthy populations.
The authors show that positive selection during spermatogenesis increases the risk of known disease-causing mutations by roughly two- to threefold, resulting in 3–5% of sperm from middle-aged and older individuals carrying a pathogenic exomic variant. These findings illuminate germline selection dynamics and point to a broader age-related disease risk for children born to older fathers than previously recognised.