scONE-seq: A one-tube single-cell multi-omics method enables simultaneous dissection of genotype and phenotype heterogeneity from frozen tumor samples. scONE-seq: A one-tube single-cell multi-omics method enables simultaneous dissection of genotype and phenotype heterogeneity from frozen tumor samples

Both the genotypic and phenotypic cellular heterogeneity play important roles in normal tissue function as well as disease development. To be able to characterize these different forms of cellular heterogeneity in diverse types of samples, we developed scONE-seq, which enables simultaneous transcriptome and genome profiling in a one-tube reaction. We demonstrate the feasibility of scONE-seq by benchmarking it against existing methods using cell lines and lymphocytes from a healthy donor. Furthermore, we applied scONE-seq to a frozen years-old IDH1-mutant glioblastoma (GBM) sample and profiled over 1200 nuclei from a single sample, subsequently identifying a phenotypically normal-like tumor clone that was only distinguishable by superimposing paired clonal and transcriptomic data. Overall design: Validate the scONE-seq method with cell lines, lymphcytes from PBMC, and a frozen glioblastoma sample.

细胞的基因型与表型异质性，在正常组织功能维持与疾病发生发展进程中均发挥关键作用。为实现对多样本类型中这类多样化细胞异质性的表征分析，我们开发了scONE-seq技术，该技术可在单管反应中同步完成转录组与基因组的谱分析。我们通过采用细胞系与健康供体来源的淋巴细胞，将该技术与现有方法进行基准比对，验证了scONE-seq的可行性。此外，我们将scONE-seq应用于一份冻存多年的IDH1突变型胶质母细胞瘤（glioblastoma, GBM）样本，对单一样本中的逾1200个细胞核开展了谱分析，后续识别出一类表型近似正常的肿瘤克隆亚群，该亚群仅能通过整合配对的克隆与转录组数据加以区分。整体实验设计：通过细胞系、外周血单个核细胞（PBMC）来源的淋巴细胞以及冻存胶质母细胞瘤样本，对scONE-seq方法进行验证。