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

Author:

Liu Silvia123,Yu Yan-Ping123,Ren Bao-Guo123,Ben-Yehezkel Tuval4,Obert Caroline4,Smith Mat4,Wang Wenjia5,Ostrowska Alina13,Soto-Gutierrez Alejandro13,Luo Jian-Hua123ORCID

Affiliation:

1. Department of Pathology, University of Pittsburgh

2. High Throughput Genome Center, University of Pittsburgh

3. Pittsburgh Liver Research Center, University of Pittsburgh

4. Element Biosciences Inc

5. Biostatistics, University of Pittsburgh

Abstract

The protein diversity of mammalian cells is determined by arrays of isoforms from genes. Genetic 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 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 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.

Funder

National Cancer Institute

National Institute of Diabetes and Digestive and Kidney Diseases

National Institutes of Health

University of Pittsburgh

Publisher

eLife Sciences Publications, Ltd

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