200: Sperm Sequencing Reveals Extensive Positive Selection in the Male Germline

️ Episode 200: Sperm Sequencing Reveals Extensive Positive Selection in the Male Germline In this episode of PaperCast Base by Base, we explore how ultra-accurate duplex sequencing of human sperm reveals widespread positive selection in the male germline and its consequences for mutation burden and disease risk in offspring. Study Highlights:This Nature study uses NanoSeq duplex whole-genome and exome sequencing on sperm and matched blood samples from healthy men aged 24 to 75 years to quantify how mutations accumulate in the male germline. The authors show that sperm acquire about 1.67 substitutions per year per haploid genome, several-fold fewer than blood cells, with age-related signatures SBS1 and SBS5 dominating the mutation spectrum. By modeling nonsynonymous versus synonymous variants, they identify 40 genes under significant positive selection in spermatogonial lineages, many of which are classic cancer and developmental disorder genes enriched for activating and loss-of-function mutations. Aggregating variant allele fractions across these genes, they estimate that positive selection drives a two- to threefold enrichment of likely pathogenic mutations, such that roughly 3–5% of sperm from middle-aged to older men carry a potentially disease-causing coding variant. Conclusion:Positive selection in spermatogonial stem cells subtly reshapes the male germline over the lifespan, increasing the fraction of sperm that carry pathogenic mutations and refining how we think about paternal age, reproductive risk, and the shared genetic architecture of cancer and developmental disorders. Music:Enjoy the music based on this article at the end of the episode. Reference:Neville MDC, Lawson ARJ, Sanghvi R, Abascal F, Pham MH, Cagan A, et al. Sperm sequencing reveals extensive positive selection in the male germline. Nature. 2025;647:421–428. https://doi.org/10.1038/s41586-025-09448-3 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com Castos player https://basebybase.castos.com

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