260: TSS hypermutability in human germline linked to RNAP II stalling, R-loops and early embryonic mosaics
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260: TSS hypermutability in human germline linked to RNAP II stalling, R-loops and early embryonic mosaics
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Cortés Guzmán M et al., Nat Commun - Human germline transcription start sites show a hotspot of non-CpG variants driven by the early embryonic mosaicism, RNAP II stalling, R-loops and mitotic DSBs.
Study Highlights:
The authors analysed extremely rare variants from gnomAD and UK Biobank, de novo mutations from family sequencing, mosaic variant catalogs, and pan-cancer somatic data to map mutation density around transcription start sites in humans. They used 5-mer sequence-context normalization, negative binomial regression with 38 genomic and epigenetic covariates, PRO-seq and somatic DSB maps, and mutational-signature decomposition to identify drivers. They report a pronounced TSS hotspot of non(CpG>TpG) ERVs reaching ~14% excess at 1 kb and up to ~35% in the first 100 bp, and a 52% enrichment of early embryonic mosaic variants immediately downstream of the TSS. Mechanistic associations implicate divergent transcription, RNAP II stalling, R-loops and mitotic double-strand breaks, and the hotspot disproportionately affects genes linked to cancer and developmental phenotypes.
Conclusion:
Transcription start sites are a distinct germline mutational hotspot enriched for early embryonic mosaic variants and transcription- and mitosis-associated DNA damage and repair processes.
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Reference:
Cortés Guzmán M, Castellano D, Serrano Colomé C, Seplyarskiy V & Weghorn D (2025) Transcription start sites experience a high influx of heritable variants fueled by early development. Nature Communications 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/
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