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Long-read single-cell sequencing reveals expressions of hypermutation clusters of isoforms in human liver cancer cells

Silvia Liu, Yan-Ping Yu, Bao-Guo Ren, Tuval Ben-Yehezkel, Caroline Obert, Mat Smith, Wenjia Wang, Alina Ostrowska, Alejandro Soto-Gutierrez, Jian-Hua Luo
doi: https://doi.org/10.1101/2023.03.16.532991
Silvia Liu
1Department of Pathology
2High Throughput Genome Center
3Pittsburgh Liver Research Center
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  • For correspondence: luoj@upmc.edu shl96@pitt.edu
Yan-Ping Yu
1Department of Pathology
2High Throughput Genome Center
3Pittsburgh Liver Research Center
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Bao-Guo Ren
1Department of Pathology
2High Throughput Genome Center
3Pittsburgh Liver Research Center
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Tuval Ben-Yehezkel
4University of Pittsburgh, 3550 Terrace Street, Pittsburgh, PA 15261; Element Biosciences, Inc, 10055 Barnes Canyon Road, Suite 100, San Diego, CA 92121
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Caroline Obert
4University of Pittsburgh, 3550 Terrace Street, Pittsburgh, PA 15261; Element Biosciences, Inc, 10055 Barnes Canyon Road, Suite 100, San Diego, CA 92121
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Mat Smith
4University of Pittsburgh, 3550 Terrace Street, Pittsburgh, PA 15261; Element Biosciences, Inc, 10055 Barnes Canyon Road, Suite 100, San Diego, CA 92121
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Wenjia Wang
5Biostatistics
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Alina Ostrowska
1Department of Pathology
3Pittsburgh Liver Research Center
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Alejandro Soto-Gutierrez
1Department of Pathology
3Pittsburgh Liver Research Center
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Jian-Hua Luo
1Department of Pathology
2High Throughput Genome Center
3Pittsburgh Liver Research Center
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  • For correspondence: luoj@upmc.edu shl96@pitt.edu
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Abstract

The protein diversity of mammalian cells is determined by arrays of isoforms from genes. Protein mutation is essential in species evolution and cancer development. Accurate Long-read transcriptome sequencing at single-cell level is required to decipher the spectrum of protein expressions in mammalian organisms. In this report, we developed a synthetic long-read single-cell sequencing technology based on LOOPseq technique. We applied this technology to analyze 447 transcriptomes of hepatocellular carcinoma (HCC) and benign liver from an individual. Through Uniform Manifold Approximation and Projection (UMAP) analysis, we identified a panel of mutation mRNA isoforms highly specific to HCC cells. The evolution pathways that led to the hyper-mutation clusters in single human leukocyte antigen (HLA) molecules were identified. Novel fusion transcripts were detected. The combination of gene expressions, fusion gene transcripts, and mutation gene expressions significantly improved the classification of liver cancer cells versus benign hepatocytes. In conclusion, LOOPseq single-cell technology may hold promise to provide a new level of precision analysis on the mammalian transcriptome.

Competing Interest Statement

Tuval Ben-Yehezkel, Caroline Obert, and Mat Smith are employees of Element Biosciences, Inc. Silvia Liu, Yan-Ping Yu, Bao-Guo Ren, Wenjia Wang, Alina Ostrowska, Alejandro Soto-Gutierrez, and Jian-Hua Luo declare no conflict of interest.

Footnotes

  • https://nam12.safelinks.protection.outlook.com/?url=https%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fgeo%2Fquery%2Facc.cgi%3Facc%3DGSE223743&data=05%7C01%7Cshl96%40pitt.edu%7Ca6bb7daab19b45e650ba08daffa85a48%7C9ef9f489e0a04eeb87cc3a526112fd0d%7C1%7C0%7C638103395780381805%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=8URuG5ndTGy77iCwriHTaVuqL7OPcNJMdALaYdejN6A%3D&reserved=0

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted March 20, 2023.
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Long-read single-cell sequencing reveals expressions of hypermutation clusters of isoforms in human liver cancer cells
Silvia Liu, Yan-Ping Yu, Bao-Guo Ren, Tuval Ben-Yehezkel, Caroline Obert, Mat Smith, Wenjia Wang, Alina Ostrowska, Alejandro Soto-Gutierrez, Jian-Hua Luo
bioRxiv 2023.03.16.532991; doi: https://doi.org/10.1101/2023.03.16.532991
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Long-read single-cell sequencing reveals expressions of hypermutation clusters of isoforms in human liver cancer cells
Silvia Liu, Yan-Ping Yu, Bao-Guo Ren, Tuval Ben-Yehezkel, Caroline Obert, Mat Smith, Wenjia Wang, Alina Ostrowska, Alejandro Soto-Gutierrez, Jian-Hua Luo
bioRxiv 2023.03.16.532991; doi: https://doi.org/10.1101/2023.03.16.532991

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