High throughput single cell long-read sequencing analyses of same-cell genotypes and phenotypes in human tumors

Cheng-Kai Shiau, Lina Lu, Rachel Kieser, Kazutaka Fukumura, Timothy Pan, Hsiao-Yun Lin, Jie Yang, Eric L. Tong, GaHyun Lee, Yuanqing Yan, Jason T. Huse and Ruli Gao ()
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Cheng-Kai Shiau: Northwestern University Feinberg School of Medicine
Lina Lu: Northwestern University Feinberg School of Medicine
Rachel Kieser: Houston Methodist Research Institute
Kazutaka Fukumura: University of Texas MD Anderson Cancer Center
Timothy Pan: Northwestern University Feinberg School of Medicine
Hsiao-Yun Lin: Northwestern University Feinberg School of Medicine
Jie Yang: New York University Langone School of Medicine
Eric L. Tong: University of Texas at Austin
GaHyun Lee: Northwestern University Feinberg School of Medicine
Yuanqing Yan: Northwestern University Feinberg School of Medicine
Jason T. Huse: University of Texas MD Anderson Cancer Center
Ruli Gao: Northwestern University Feinberg School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract Single-cell nanopore sequencing of full-length mRNAs transforms single-cell multi-omics studies. However, challenges include high sequencing errors and dependence on short-reads and/or barcode whitelists. To address these, we develop scNanoGPS to calculate same-cell genotypes (mutations) and phenotypes (gene/isoform expressions) without short-read nor whitelist guidance. We apply scNanoGPS onto 23,587 long-read transcriptomes from 4 tumors and 2 cell-lines. Standalone, scNanoGPS deconvolutes error-prone long-reads into single-cells and single-molecules, and simultaneously accesses both phenotypes and genotypes of individual cells. Our analyses reveal that tumor and stroma/immune cells express distinct combination of isoforms (DCIs). In a kidney tumor, we identify 924 DCI genes involved in cell-type-specific functions such as PDE10A in tumor cells and CCL3 in lymphocytes. Transcriptome-wide mutation analyses identify many cell-type-specific mutations including VEGFA mutations in tumor cells and HLA-A mutations in immune cells, highlighting the critical roles of different mutant populations in tumors. Together, scNanoGPS facilitates applications of single-cell long-read sequencing technologies.

Date: 2023
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DOI: 10.1038/s41467-023-39813-7

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