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.