Dynamically evolving novel overlapping gene as a factor in the SARS-CoV-2 pandemic

  1. Chase W Nelson  Is a corresponding author
  2. Zachary Ardern  Is a corresponding author
  3. Tony L Goldberg
  4. Chen Meng
  5. Chen-Hao Kuo
  6. Christina Ludwig
  7. Sergios-Orestis Kolokotronis
  8. Xinzhu Wei  Is a corresponding author
  1. Academia Sinica, Taiwan
  2. Technical University of Munich, Germany
  3. University of Wisconsin-Madison, United States
  4. American Museum of Natural History, United States
  5. University of California, Berkeley, United States

Abstract

Understanding the emergence of novel viruses requires an accurate and comprehensive annotation of their genomes. Overlapping genes (OLGs) are common in viruses and have been associated with pandemics, but are still widely overlooked. We identify and characterize ORF3d, a novel OLG in SARS-CoV-2 that is also present in Guangxi pangolin-CoVs but not other closely related pangolin-CoVs or bat-CoVs. We then document evidence of ORF3d translation, characterize its protein sequence, and conduct an evolutionary analysis at three levels: between taxa (21 members of Severe acute respiratory syndrome-related coronavirus), between human hosts (3978 SARS-CoV-2 consensus sequences), and within human hosts (401 deeply sequenced SARS-CoV-2 samples). ORF3d has been independently identified and shown to elicit a strong antibody response in COVID-19 patients. However, it has been misclassified as the unrelated gene ORF3b, leading to confusion. Our results liken ORF3d to other accessory genes in emerging viruses and highlight the importance of OLGs.

Data availability

All data generated or analyzed during this study are included in the manuscript and supplement. Scripts and source data for all analyses and figures are provided on GitHub at https://github.com/chasewnelson/SARS-CoV-2-ORF3d and Zenodo at https://zenodo.org/record/4052729.

The following previously published data sets were used
    1. Submitting laboratories
    (2020) EpiFluTM
    GISAID's EpiFluTM Database.
    1. Finkel et al
    (2020) Decoding SARS-CoV-2 coding capacity
    GEO database, sample IDs: SRR11713366, SRR11713367, SRR11713368, SRR11713369 from GSE149973.

Article and author information

Author details

  1. Chase W Nelson

    Biodiversity Research Center, Academia Sinica, Taipei, Taiwan
    For correspondence
    cwnelson88@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6287-1598
  2. Zachary Ardern

    Chair for Microbial Ecology, Technical University of Munich, Freising, Germany
    For correspondence
    zachary.ardern@tum.de
    Competing interests
    The authors declare that no competing interests exist.
  3. Tony L Goldberg

    University of Wisconsin-Madison, Madison, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Chen Meng

    Bavarian Center for Biomolecular Mass Spectrometry, Technical University of Munich, Freising, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Chen-Hao Kuo

    Biodiversity Research Center, Academia Sinica, Taipei, Taiwan
    Competing interests
    The authors declare that no competing interests exist.
  6. Christina Ludwig

    Bavarian Center for Biomolecular Mass Spectrometry, Technical University of Munich, Freising, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6131-7322
  7. Sergios-Orestis Kolokotronis

    Institute for Comparative Genomics, American Museum of Natural History, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3309-8465
  8. Xinzhu Wei

    Departments of Integrative Biology and Statistics, University of California, Berkeley, Berkeley, United States
    For correspondence
    aprilwei@berkeley.edu
    Competing interests
    The authors declare that no competing interests exist.

Funding

Academia Sinica (Postdoctoral Research Fellowship)

  • Chase W Nelson

National Philanthropic Trust (Grant)

  • Zachary Ardern

University of Wisconsin-Madison (John D. MacArthur Professorship Chair)

  • Tony L Goldberg

National Science Foundation (IOS grants #1755370 and #1758800)

  • Sergios-Orestis Kolokotronis

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Antonis Rokas, Vanderbilt University, United States

Publication history

  1. Received: June 3, 2020
  2. Accepted: September 30, 2020
  3. Accepted Manuscript published: October 1, 2020 (version 1)
  4. Version of Record published: November 10, 2020 (version 2)

Copyright

© 2020, Nelson et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Chase W Nelson
  2. Zachary Ardern
  3. Tony L Goldberg
  4. Chen Meng
  5. Chen-Hao Kuo
  6. Christina Ludwig
  7. Sergios-Orestis Kolokotronis
  8. Xinzhu Wei
(2020)
Dynamically evolving novel overlapping gene as a factor in the SARS-CoV-2 pandemic
eLife 9:e59633.
https://doi.org/10.7554/eLife.59633
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