The likelihood of older fathers transmitting disease-causing mutations to their offspring is greater than previously believed. Genome sequencing indicates that, in men in their early 30s, approximately 1 in 50 sperm contain harmful mutations, escalating to nearly 1 in 20 by the age of 70.

Rahele Rabari

Matthew Neville, also affiliated with the Sanger Institute, states, “This is something families should consider when making their own choices.” For instance, younger men might want to consider freezing their sperm if they anticipate delays in having children until later in life, while older men aiming to start families could explore available testing methods.

Research indicates that each individual typically carries around 70 new mutations present in most body cells that their parents do not possess, with 80% of these mutations arising in the father’s testes (excluding large-scale chromosomal abnormalities that are more frequent in the mother’s eggs). It was previously thought that the number of mutations in sperm increased steadily with age due to random mutation, but certain genetic conditions, such as achondroplasia (dwarfism), are notably more prevalent than random mutation rates would suggest.

In 2003, Anne Goriely from the University of Oxford found that this phenomenon likely stems from specific stem cells that produce sperm becoming “selfish.” This behavior causes these particular stem cells to proliferate more than usual, leading to an exponential rise in the proportion of sperm exhibiting these mutations as a man ages, rather than a steady increase. Goriely demonstrated that mutations in various genes can induce this selfish behavior in sperm stem cells, suspecting that even more factors are at play.

To date, Rahbari, Neville, and their research team have sequenced over 100,000 sperm cells sourced from 81 men of differing ages, as well as blood cells. Utilizing a unique method to sequence both strands of the DNA double helix, they overcame the high error rates in standard sequencing techniques. Thus, if a mutation is present on both strands, it is extremely unlikely to be a sequencing error.

Despite these selfish mutations comprising only a small fraction of total mutations, their impact is significant.

Ruben Arslan from the University of Witten in Germany emphasizes the discovery that these selfish mutations increase in a non-linear fashion. He suggests that, in youth, adding a year to a father’s age has a lesser negative effect compared to adding a year during older age.

Another investigation, involving Ravari and Neville, employed new sequencing methods on skin cells in the mouth, uncovering a similar trend of growth-promoting mutations that raised the ratio of specific stem cell lineages.

“These patterns of selection appear to extend beyond sperm cells,” asserts Rahbari. Although growth-promoting mutations may progress toward malignancy, they can also lead to troubles and potentially accelerate aging, she explains.