New findings reveal how paternal age affects sperm DNA
A landmark study published in Nature shows that harmful genetic changes in sperm become substantially more common as men age. Using ultra-accurate DNA sequencing, researchers mapped how bias in sperm production can favor mutations that may be passed on to future generations, overturning assumptions that the male germline is largely protected from genetic transitions.
What the study did and why it matters
The Wellcome Sanger Institute team, in collaboration with the TwinsUK study at King’s College London, analyzed sperm from 81 healthy men aged 24 to 75. They employed NanoSeq, a highly precise sequencing method, to measure mutations in sperm cells across the genome with unprecedented accuracy. The cohort, drawn from TwinsUK—the UK’s largest adult twin registry—provided a diverse, well-characterised population to explore how mutations accumulate over time.
Age-related rise in harmful sperm mutations
Researchers found that about 2% of sperm from men in their early 30s carried disease-causing mutations, rising to between 3% and 5% for middle-aged and older men. By age 70, roughly 4.5% of sperm carried such mutations. This pattern demonstrates a clear, age-related increase in the genetic risks that fathers may transmit to their children.
Natural selection within the testes
Crucially, the study shows that the rise is not solely due to random accumulation of changes. A subtle form of natural selection appears to favor certain DNA changes during sperm production, giving mutated sperm a competitive edge. The team pinpointed 40 genes where these mutations are more likely to be propagated in the germline, broadening the understanding beyond previously identified genes involved in development and disease.
Implications for offspring and risk assessment
Although an increasing proportion of sperm carries harmful mutations with age, not all such changes lead to fertilization, embryo development, or live birth. Some mutations may impair fertility or result in pregnancy loss. More research is needed to translate these findings into concrete risk assessments for prospective parents and to determine how lifestyle and environmental factors might influence this inherited risk.
Complementary perspectives and broader impact
A parallel study, looking at mutations passed to children rather than those detected in sperm, analyzed DNA from over 54,000 parent–child trios and 800,000 healthy individuals. It identified more than 30 genes where germline mutations confer a competitive advantage to sperm. The results suggest that these mutations can increase sperm mutation rates by up to 500-fold, helping explain certain rare genetic disorders that recur even when parents do not carry the mutations in their own DNA. This work emphasizes how natural selection in the male germline can shape the genetic landscape observed in offspring.
Looking ahead
By elucidating how mutations arise and are selected within sperm, researchers hope to refine reproductive risk assessments and explore how environmental and lifestyle factors influence inherited genetic risks. As scientists continue to map these processes, the findings may guide counseling for prospective parents and inform public health discussions about paternal age and genetic health across generations.
