Integrative genotyping of cancer and immune phenotypes by long-read sequencing

Livius Penter, Mehdi Borji, Adi Nagler, Haoxiang Lyu, Wesley S. Lu, Nicoletta Cieri, Katie Maurer, Giacomo Oliveira, Aziz M. Al’Khafaji, Kiran V. Garimella, Shuqiang Li, Donna S. Neuberg, Jerome Ritz, Robert J. Soiffer, Jacqueline S. Garcia, Kenneth J. Livak and Catherine J. Wu ()
Additional contact information
Livius Penter: Dana-Farber Cancer Institute
Mehdi Borji: Dana-Farber Cancer Institute
Adi Nagler: Dana-Farber Cancer Institute
Haoxiang Lyu: Dana-Farber Cancer Institute
Wesley S. Lu: Dana-Farber Cancer Institute
Nicoletta Cieri: Dana-Farber Cancer Institute
Katie Maurer: Dana-Farber Cancer Institute
Giacomo Oliveira: Dana-Farber Cancer Institute
Aziz M. Al’Khafaji: Broad Institute of Massachusetts Institute of Technology and Harvard University
Kiran V. Garimella: Broad Institute of Massachusetts Institute of Technology and Harvard University
Shuqiang Li: Dana-Farber Cancer Institute
Donna S. Neuberg: Dana-Farber Cancer Institute
Jerome Ritz: Dana-Farber Cancer Institute
Robert J. Soiffer: Dana-Farber Cancer Institute
Jacqueline S. Garcia: Dana-Farber Cancer Institute
Kenneth J. Livak: Dana-Farber Cancer Institute
Catherine J. Wu: Dana-Farber Cancer Institute

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract Single-cell transcriptomics has become the definitive method for classifying cell types and states, and can be augmented with genotype information to improve cell lineage identification. Due to constraints of short-read sequencing, current methods to detect natural genetic barcodes often require cumbersome primer panels and early commitment to targets. Here we devise a flexible long-read sequencing workflow and analysis pipeline, termed nanoranger, that starts from intermediate single-cell cDNA libraries to detect cell lineage-defining features, including single-nucleotide variants, fusion genes, isoforms, sequences of chimeric antigen and TCRs. Through systematic analysis of these classes of natural ‘barcodes’, we define the optimal targets for nanoranger, namely those loci close to the 5’ end of highly expressed genes with transcript lengths shorter than 4 kB. As proof-of-concept, we apply nanoranger to longitudinal tracking of subclones of acute myeloid leukemia (AML) and describe the heterogeneous isoform landscape of thousands of marrow-infiltrating immune cells. We propose that enhanced cellular genotyping using nanoranger can improve the tracking of single-cell tumor and immune cell co-evolution.

Date: 2024
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-023-44137-7

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DOI: 10.1038/s41467-023-44137-7

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