231: Transcription start sites as a germline mutational hotspot

️Episode 231: Transcription start sites as a germline mutational hotspot In this episode of PaperCast Base by Base, we explore This study identifies a pronounced germline mutational hotspot centered on transcription start sites (TSSs) driven in part by early embryonic mosaic variants and transcription-associated DNA damage Study Highlights:Extremely rare variants show a localized excess of non(CpG > TpG) mutations around TSSs extending several hundred base pairs, reaching ~35% enrichment at the 100-bp scale and ~14% at 1 kb. The hotspot is largely absent from de novo mutation calls because early mosaic variants are significantly enriched downstream of the TSS and are often filtered from family sequencing data. Regression and feature analyses link the TSS excess to divergent transcription, RNA polymerase II stalling, R-loop formation and somatic (mitotic) double-strand breaks rather than meiotic PRDM9-associated breaks. Mutational signature decomposition implicates non-canonical DSB repair (including TMEJ) and transcription-associated processes, and the hotspot preferentially affects genes related to cancer and developmental phenotypes. Conclusion:Transcription initiation regions are focal points of heritable variation shaped by early-development mosaicism and transcription-linked mitotic DNA damage, with implications for disease genetics and evolutionary constraint Music:Enjoy the music based on this article at the end of the episode. Reference:Cortés Guzmán M, Castellano D, Serrano Colomé C, Seplyarskiy V, Weghorn D. Transcription start sites experience a high influx of heritable variants fueled by early development. Nat Commun. 2025;16:10120. https://doi.org/10.1038/s41467-025-66201-0 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 On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

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