Cellular context shapes the transcriptomic impact of somatic variants
- 1MOE Key Lab for Intelligent Networks & Networks Security, Faculty of Electronic and Information Engineering, Xi'an Jiaotong University, Xi'an, China; School of
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 candidate 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 six 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.
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BibTeX
@misc{sun2026cellular,
title = {{Cellular context shapes the transcriptomic impact of somatic variants}},
author = {P. Sun and P. Jia and C. Lou and X. Li and M. Li and R. Zhang and H. Lin and X. Li and Y. Zhou and S. Cai and Z. Zhang and P. Zhang and T. Xu and S. Wang and Y. Wang and M. Li and Y. Gong and G. Sang and J. Yin and J. Li and Q. Xie and Z. Yue and D. Xu and X. Yang and S. J. Bush and S. Geng and D. Meng and X. Li and K. Ye},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.28.760887},
url = {https://www.biorxiv.org/content/10.64898/2026.10.28.760887v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Cellular context shapes the transcriptomic impact of somatic variants
AU - P. Sun
AU - P. Jia
AU - C. Lou
AU - X. Li
AU - M. Li
AU - R. Zhang
AU - H. Lin
AU - X. Li
AU - Y. Zhou
AU - S. Cai
AU - Z. Zhang
AU - P. Zhang
AU - T. Xu
AU - S. Wang
AU - Y. Wang
AU - M. Li
AU - Y. Gong
AU - G. Sang
AU - J. Yin
AU - J. Li
AU - Q. Xie
AU - Z. Yue
AU - D. Xu
AU - X. Yang
AU - S. J. Bush
AU - S. Geng
AU - D. Meng
AU - X. Li
AU - K. Ye
PY - 2026
DA - 2026/10/28
PB - bioRxiv
DO - 10.64898/2026.10.28.760887
UR - https://www.biorxiv.org/content/10.64898/2026.10.28.760887v1
AB - 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 candidate 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 six 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.
ER -