Sperm sequencing reveals extensive positive selection in the human germline -TargetedNanoSeq

Mutations that occur during human ageing in the cell lineages of sperm or eggs have the potential to be transmitted to offspring. In males, positive selection of driver mutations during spermatogenesis is known to increase the birth prevalence of certain developmental disorders and cancer predisposition syndromes. However, direct observation of the scope of this selection in sperm has been limited by the error rates of sequencing technologies. Using the duplex sequencing method known as NanoSeq, we sequenced bulk sperm samples from individuals aged 24 to 75 years. Our findings revealed a linear accumulation mutations per year and mutational signatures consistent with pedigree studies. Deep targeted and deep exome NanoSeq of sperm samples identified genes subject to significant positive selection in the male germline, which are linked to diverse cellular pathways including RAS/MAPK and BMP signaling. Strikingly, nearly all positively selected genes are associated with developmental or cancer predisposition disorders in children. We find that this effect drives an elevated risk of known likely disease-causing mutations in sperm across a wide age range. This implies that the disorders attributed to these genes likely exhibit elevated birth prevalence in human populations, particularly among older fathers. These findings shed light on the dynamics of germline mutations and highlight an increased disease risk for children born to fathers of advanced age.

• 13/05/2025
• 11 samples
• DAC: EGAC00001000274
• Technology: Illumina NovaSeq 6000