Year: 2026
Type: preprint
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.
Authors: Peisen Sun, Peng Jia, Chuyuan Lou, Xiaona Li, Miaojing Li, Ruifen Zhang, Hui Lin, Xiujuan Li, Yunsong Zhou, Shuzheng Cai, Zexin Zhang, Pengyu Zhang, Tun Xu, Songbo Wang, Yudong Wang, Mingxuan Li, Yuyan Gong, Guoqin Sang, Jie Yin, Jizhe Li, Qi Xie, Zongsheng Yue, Dan Xu, Xiaofei Yang, Stephen J. Bush, Songmei Geng, Deyu Meng, Xuexin Li, Kai Ye
Institutions: Xi'an Jiaotong University, First Affiliated Hospital of Xi'an Jiaotong University, Fourth Affiliated Hospital of China Medical University, China Medical University, Karolinska Institutet, Second Affiliated Hospital of Xi'an Jiaotong University, Macau University of Science and Technology
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7225106690