High-throughput targeted long-read single cell sequencing reveals the clonal and transcriptional landscape of lymphocytes

Mandeep Singh, Ghamdan Al-Eryani, Shaun Carswell, James M. Ferguson, James Blackburn, Kirston Barton, Daniel Roden, Fabio Luciani, Tri Giang Phan, Simon Junankar, Katherine Jackson, Christopher C. Goodnow (), Martin A. Smith () and Alexander Swarbrick ()
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Mandeep Singh: Garvan Institute of Medical Research
Ghamdan Al-Eryani: Garvan Institute of Medical Research
Shaun Carswell: Garvan Institute of Medical Research
James M. Ferguson: Garvan Institute of Medical Research
James Blackburn: Garvan Institute of Medical Research
Kirston Barton: Garvan Institute of Medical Research
Daniel Roden: Garvan Institute of Medical Research
Fabio Luciani: UNSW
Tri Giang Phan: Garvan Institute of Medical Research
Simon Junankar: Garvan Institute of Medical Research
Katherine Jackson: Garvan Institute of Medical Research
Christopher C. Goodnow: Garvan Institute of Medical Research
Martin A. Smith: Garvan Institute of Medical Research
Alexander Swarbrick: Garvan Institute of Medical Research

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: Abstract High-throughput single-cell RNA sequencing is a powerful technique but only generates short reads from one end of a cDNA template, limiting the reconstruction of highly diverse sequences such as antigen receptors. To overcome this limitation, we combined targeted capture and long-read sequencing of T-cell-receptor (TCR) and B-cell-receptor (BCR) mRNA transcripts with short-read transcriptome profiling of barcoded single-cell libraries generated by droplet-based partitioning. We show that Repertoire and Gene Expression by Sequencing (RAGE-Seq) can generate accurate full-length antigen receptor sequences at nucleotide resolution, infer B-cell clonal evolution and identify alternatively spliced BCR transcripts. We apply RAGE-Seq to 7138 cells sampled from the primary tumor and draining lymph node of a breast cancer patient to track transcriptome profiles of expanded lymphocyte clones across tissues. Our results demonstrate that RAGE-Seq is a powerful method for tracking the clonal evolution from large numbers of lymphocytes applicable to the study of immunity, autoimmunity and cancer.

Date: 2019
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DOI: 10.1038/s41467-019-11049-4

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