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Altered Subgenomic RNA Expression in SARS-CoV-2 B.1.1.7 Infections

View ORCID ProfileMatthew D Parker, View ORCID ProfileBenjamin B. Lindsey, Dhruv R Shah, Sharon Hsu, Alexander J Keeley, David G Partridge, View ORCID ProfileShay Leary, Alison Cope, Amy State, Katie Johnson, Nasar Ali, Rasha Raghei, View ORCID ProfileJoe Heffer, Nikki Smith, Peijun Zhang, Marta Gallis, Stavroula F Louka, Hailey R Hornsby, Max Whiteley, Benjamin H Foulkes, Stella Christou, Paige Wolverson, Manoj Pohare, Samantha E Hansford, Luke R Green, Cariad Evans, Mohammad Raza, View ORCID ProfileDennis Wang, Silvana Gaudieri, Simon Mallal, The COVID-19 Genomics UK (COG-UK) consortium, View ORCID ProfileThushan I. de Silva
doi: https://doi.org/10.1101/2021.03.02.433156
Matthew D Parker
1Sheffield Biomedical Research Centre, The University of Sheffield
2Sheffield Bioinformatics Core, The University of Sheffield
3The Department of Neuroscience/Neuroscience Institute, The University of Sheffield
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Benjamin B. Lindsey
4Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
5The Florey Institute for Host-Pathogen Interactions & Department of Infection, Immunity and Cardiovascular Disease, Medical School, University of Sheffield, Sheffield, UK
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Dhruv R Shah
5The Florey Institute for Host-Pathogen Interactions & Department of Infection, Immunity and Cardiovascular Disease, Medical School, University of Sheffield, Sheffield, UK
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Sharon Hsu
2Sheffield Bioinformatics Core, The University of Sheffield
5The Florey Institute for Host-Pathogen Interactions & Department of Infection, Immunity and Cardiovascular Disease, Medical School, University of Sheffield, Sheffield, UK
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Alexander J Keeley
4Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
5The Florey Institute for Host-Pathogen Interactions & Department of Infection, Immunity and Cardiovascular Disease, Medical School, University of Sheffield, Sheffield, UK
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David G Partridge
4Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
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Shay Leary
6Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, Australia
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Alison Cope
4Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
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Amy State
4Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
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Katie Johnson
4Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
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Nasar Ali
4Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
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Rasha Raghei
4Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
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Joe Heffer
7IT Services, The University of Sheffield, Sheffield, UK
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Nikki Smith
5The Florey Institute for Host-Pathogen Interactions & Department of Infection, Immunity and Cardiovascular Disease, Medical School, University of Sheffield, Sheffield, UK
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Peijun Zhang
5The Florey Institute for Host-Pathogen Interactions & Department of Infection, Immunity and Cardiovascular Disease, Medical School, University of Sheffield, Sheffield, UK
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Marta Gallis
5The Florey Institute for Host-Pathogen Interactions & Department of Infection, Immunity and Cardiovascular Disease, Medical School, University of Sheffield, Sheffield, UK
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Stavroula F Louka
5The Florey Institute for Host-Pathogen Interactions & Department of Infection, Immunity and Cardiovascular Disease, Medical School, University of Sheffield, Sheffield, UK
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Hailey R Hornsby
5The Florey Institute for Host-Pathogen Interactions & Department of Infection, Immunity and Cardiovascular Disease, Medical School, University of Sheffield, Sheffield, UK
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Max Whiteley
5The Florey Institute for Host-Pathogen Interactions & Department of Infection, Immunity and Cardiovascular Disease, Medical School, University of Sheffield, Sheffield, UK
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Benjamin H Foulkes
5The Florey Institute for Host-Pathogen Interactions & Department of Infection, Immunity and Cardiovascular Disease, Medical School, University of Sheffield, Sheffield, UK
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Stella Christou
5The Florey Institute for Host-Pathogen Interactions & Department of Infection, Immunity and Cardiovascular Disease, Medical School, University of Sheffield, Sheffield, UK
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Paige Wolverson
5The Florey Institute for Host-Pathogen Interactions & Department of Infection, Immunity and Cardiovascular Disease, Medical School, University of Sheffield, Sheffield, UK
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Manoj Pohare
5The Florey Institute for Host-Pathogen Interactions & Department of Infection, Immunity and Cardiovascular Disease, Medical School, University of Sheffield, Sheffield, UK
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Samantha E Hansford
5The Florey Institute for Host-Pathogen Interactions & Department of Infection, Immunity and Cardiovascular Disease, Medical School, University of Sheffield, Sheffield, UK
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Luke R Green
5The Florey Institute for Host-Pathogen Interactions & Department of Infection, Immunity and Cardiovascular Disease, Medical School, University of Sheffield, Sheffield, UK
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Cariad Evans
4Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
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Mohammad Raza
4Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
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Dennis Wang
1Sheffield Biomedical Research Centre, The University of Sheffield
2Sheffield Bioinformatics Core, The University of Sheffield
3The Department of Neuroscience/Neuroscience Institute, The University of Sheffield
8Department of Computer Science, The University of Sheffield, Sheffield, UK
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Silvana Gaudieri
6Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, Australia
9Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
10School of Human Sciences, University of Western Australia, Crawley, Western Australia, Australia
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Simon Mallal
9Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
10School of Human Sciences, University of Western Australia, Crawley, Western Australia, Australia
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Thushan I. de Silva
4Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
5The Florey Institute for Host-Pathogen Interactions & Department of Infection, Immunity and Cardiovascular Disease, Medical School, University of Sheffield, Sheffield, UK
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  • For correspondence: t.desilva@sheffield.ac.uk
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Abstract

SARS-CoV-2 lineage B.1.1.7 viruses are more transmissible, may lead to greater clinical severity, and result in modest reductions in antibody neutralization. subgenomic RNA (sgRNA) is produced by discontinuous transcription of the SARS-CoV-2 genome and is a crucial step in the SARS-CoV-2 life cycle. Applying our tool (periscope) to ARTIC Network Oxford Nanopore genomic sequencing data from 4400 SARS-CoV-2 positive clinical samples, we show that normalised sgRNA expression profiles are significantly increased in B.1.1.7 infections (n=879). This increase is seen over the previous dominant circulating lineage in the UK, B.1.177 (n=943), which is independent of genomic reads, E gene cycle threshold and days since symptom onset at sampling. A noncanonical sgRNA which could represent ORF9b is found in 98.4% of B.1.1.7 SARS-CoV-2 infections compared with only 13.8% of other lineages, with a 16-fold increase in median expression. We hypothesise that this is a direct consequence of a triple nucleotide mutation in nucleocapsid (28280:GAT>CAT, D3L) creating a transcription regulatory-like sequence complementary to a region 3’ of the genomic leader. These findings provide a unique insight into the biology of B.1.1.7 and support monitoring of sgRNA profiles in sequence data to evaluate emerging potential variants of concern.

One Sentence Summary The recently emerged and more transmissible SARS-CoV-2 lineage B.1.1.7 shows greater subgenomic RNA expression in clinical infections and enhanced expression of a noncanonical subgenomic RNA near ORF9b.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵+ Full list of consortium names and affiliations located in the supplementary material

  • ↵11 https://www.cogconsortium.uk

  • Update to the abstract to match the PDF.

Copyright 
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-ND 4.0 International license.
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Altered Subgenomic RNA Expression in SARS-CoV-2 B.1.1.7 Infections
Matthew D Parker, Benjamin B. Lindsey, Dhruv R Shah, Sharon Hsu, Alexander J Keeley, David G Partridge, Shay Leary, Alison Cope, Amy State, Katie Johnson, Nasar Ali, Rasha Raghei, Joe Heffer, Nikki Smith, Peijun Zhang, Marta Gallis, Stavroula F Louka, Hailey R Hornsby, Max Whiteley, Benjamin H Foulkes, Stella Christou, Paige Wolverson, Manoj Pohare, Samantha E Hansford, Luke R Green, Cariad Evans, Mohammad Raza, Dennis Wang, Silvana Gaudieri, Simon Mallal, The COVID-19 Genomics UK (COG-UK) consortium, Thushan I. de Silva
bioRxiv 2021.03.02.433156; doi: https://doi.org/10.1101/2021.03.02.433156
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Altered Subgenomic RNA Expression in SARS-CoV-2 B.1.1.7 Infections
Matthew D Parker, Benjamin B. Lindsey, Dhruv R Shah, Sharon Hsu, Alexander J Keeley, David G Partridge, Shay Leary, Alison Cope, Amy State, Katie Johnson, Nasar Ali, Rasha Raghei, Joe Heffer, Nikki Smith, Peijun Zhang, Marta Gallis, Stavroula F Louka, Hailey R Hornsby, Max Whiteley, Benjamin H Foulkes, Stella Christou, Paige Wolverson, Manoj Pohare, Samantha E Hansford, Luke R Green, Cariad Evans, Mohammad Raza, Dennis Wang, Silvana Gaudieri, Simon Mallal, The COVID-19 Genomics UK (COG-UK) consortium, Thushan I. de Silva
bioRxiv 2021.03.02.433156; doi: https://doi.org/10.1101/2021.03.02.433156

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