It was known for several decades that sperm deteriorates with age, but this study provides more details and how it develops over time. Probably, older men should have their sperm checked if they intend to become fathers.
"Harmful genetic changes in sperm become substantially more common as men age because some are actively favoured during sperm production, new research has revealed.
In a landmark study ... researchers ... have comprehensively mapped how harmful DNA changes in sperm cells can increase across the genome as men age. ...
In a new study, researchers used NanoSeq, an ultra-accurate DNA sequencing method to analyse sperm from 81 healthy men, aged between 24 and 75 years, with unprecedented precision. The sperm samples were collected as part of the TwinsUK cohort, the UK’s largest adult twin registry, providing a unique opportunity to study genetic variation across a diverse and well-characterised population.
The results show that around 2 per cent of sperm from men in their early 30s carried disease-causing mutations, but this rises to 3–5 per cent of sperm from middle-aged (43 to 58 years) and older men (59 to 74 years). Whilst men may be more likely to father children at a younger age, the researchers found that in those aged 70, 4.5 per cent of sperm carry disease-causing mutations. ...
This risk is driven not just by the steady build-up of random changes in DNA, but by a subtle form of natural selection acting on the sperm-producing cells in the testes, giving some mutations a competitive edge during sperm production.
The researchers identified 40 genes where certain changes in DNA are favoured during sperm production, including many linked to childhood diseases, severe neurodevelopmental disorders and inherited cancer risk. While 13 genes have already been associated with this process, the new findings show it is far more widespread than previously understood, affecting a broad range of genes important for cell growth and development. ..."
From the abstract:
"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. Until recently, characterizing the extent of this selection in sperm has been limited by the error rates of sequencing technologies.
Here we used the duplex sequencing method NanoSeq to sequence 81 bulk sperm samples from individuals aged 24–75 years.
Our findings revealed a linear accumulation of 1.67 (95% confidence interval of 1.41–1.92) mutations per year per haploid genome driven by two mutational signatures associated with human ageing.
Deep targeted and exome NanoSeq5 of sperm samples identified more than 35,000 germline coding mutations.
We detected 40 genes (31 newly identified) under significant positive selection in the male germline that have activating or loss-of-function mechanisms and are involved in diverse cellular pathways.
Most of the positively selected genes are associated with developmental or cancer predisposition disorders in children, whereas four of the genes exhibited increased frequencies of protein-truncating variants in healthy populations.
We show that positive selection during spermatogenesis drives a 2–3-fold increased risk of known disease-causing mutations, which results in 3–5% of sperm from middle-aged to older individuals with a pathogenic mutation across the exome.
These findings shed light on germline selection dynamics and highlight a broader increased disease risk for children born to fathers of advanced age than previously appreciated."
Fig. 1: Mutational burden and signature analysis in sperm and matched blood.
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