Harmful genetic mutations accumulate during sperm production in older men

Genetic mutations that increase the risk of serious conditions have been found to proliferate in the sperm cells of ageing men.

Recent research from the Wellcome Sanger Institute, Cambridge, and published in Nature, details how genetic risks accumulate in sperm-producing cells as men age. Many of these mutations are associated with an increased risk of cancer in the children produced from the sperm. A separate study also published in Nature, found many of the same genetic mutations present in children fathered by older men (see BioNews 1310).

'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,' said Professor Matthew Hurles, director of the Wellcome Sanger Institute.

Sperm cells are regenerated relatively quickly compared to other cells in the body, meaning cells divide rapidly to produce them. Every time DNA is copied in dividing cells, there is a small chance that single-nucleotide mutations will be introduced, but the study found that some of these mutations allowed the cells to divide faster, meaning they end up being present in an increasing proportion of the sperm produced.

'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,' said the study's first author, Dr Matthew Neville.

The study used a sequencing technology called NanoSeq. Sperm DNA was collected from men aged 24 to 75 participating in the TwinsUK study at King's College London. This was compared to blood DNA in men of different ages to quantify and categorise the difference in the genomes of the two cell types.

'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.' said Professor Kerrin Smalls, scientific director of the TwinsUK study at King's College London. 'This collaboration highlights the power of large, population-based cohorts for advancing our understanding of human development and inheritance.'

The authors point out that although mutations in the sperm are present, they pose a modest risk to birth outcomes, with around five percent of sperm from men older than 60 carrying a mutation. They hope that this research provides a baseline for future studies to generate knowledge about ageing sperm that could inform future clinical guidance.