Cellular context shapes the transcriptomic impact of somatic variants

  1. Peisen Sun
  2. Peng Jia
  3. Chuyuan Lou
  4. Xiaona Li
  5. Miaojing Li
  6. Ruifen Zhang
  7. Hui Lin
  8. Xiujuan Li
  9. Yunsong Zhou
  10. Shuzheng Cai
  11. Zexin Zhang
  12. Pengyu Zhang
  13. Tun Xu
  14. Songbo Wang
  15. Yudong Wang
  16. Mingxuan Li
  17. Yuyan Gong
  18. Guoqin Sang
  19. Jie Yin
  20. Jizhe Li
  21. Qi Xie
  22. Zongsheng Yue
  23. Dan Xu
  24. Xiaofei Yang
  25. Stephen J. Bush
  26. Songmei Geng
  27. Deyu Meng
  28. Xuexin Li
  29. Kai Ye
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Abstract

Somatic SNVs are commonly prioritized by recurrence or sequence annotation, leaving the molecular consequences of private variants unresolved. We developed PrismSNV and Ligo-Seq, a single-cell full-length transcriptome sequencing platform, to quantify transcriptomic displacement associated with within-cell SNV-state toggling. Across 26 samples from three cancer types, more than 60% of analyzed SNVs showed significant cell-type-specific displacement with over 30% variation in magnitude. Sequence-based deleteriousness was poorly aligned with cellular displacement, and fewer than 3% of top-displacement SNVs across three tumor types were catalogued in ClinVar. Displacement was strongest in transcriptionally plastic, less differentiated states. Analysis of 655,349 CD4+ T-cell transcriptomes further showed that SNV-gene associations changed in magnitude and sometimes direction during activation. Lack of recurrence or clinical annotation does not imply transcriptomic inertness; variant impact is shaped by cellular context rather than sequence alone, establishing the variant-cell pair as a critical unit for interpreting somatic variation.

Graphical Abstract

Highlights

  • Ligo-Seq jointly profiles transcript-wide RNA and chromatin accessibility

  • PrismSNV quantifies transcriptomic effects by toggling SNV states within cells

  • Somatic SNV-associated shifts are broadly cell-type-specific across samples

  • Less differentiated and transcriptionally plastic states are more sensitive to SNVs

Article activity feed

  1. Mentioned by @seekgene.bsky.social on Bluesky

    New preprint: a variant’s effect depends on the cell that carries it. Ligo-Seq + PrismSNV read variant and cell context in the same nucleus. 60%+ of candidate SNVs showed cell-type-specific transcriptomic displacement. www.biorxiv.org/content/10.6... #SingleCell

  2. Mentioned by @prepub-singlecell.bsky.social on Bluesky

    Cellular context shapes the transcriptomic impact of somatic variants #SingleCell 🧪🧬🖥️ https://www.biorxiv.org/content/10.64898/2026.10.28.760887v1

  3. Mentioned by @biorxiv-genetic.bsky.social on Bluesky

    Cellular context shapes the transcriptomic impact of somatic variants https://www.biorxiv.org/content/10.64898/2026.10.28.760887v1

  4. Mentioned by @biorxivpreprint.bsky.social on Bluesky

    Cellular context shapes the transcriptomic impact of somatic variants https://www.biorxiv.org/content/10.64898/2026.10.28.760887v1

  5. Version published to 10.64898/2026.10.28.760887v1 on bioRxiv