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Comprehensive in-vivo secondary structure of the SARS-CoV-2 genome reveals novel regulatory motifs and mechanisms

View ORCID ProfileNicholas C. Huston, Han Wan, Rafael de Cesaris Araujo Tavares, Craig Wilen, Anna Marie Pyle
doi: https://doi.org/10.1101/2020.07.10.197079
Nicholas C. Huston
1Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA
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  • ORCID record for Nicholas C. Huston
Han Wan
2Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT, USA
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Rafael de Cesaris Araujo Tavares
3Department of Chemistry, Yale University, New Haven, CT, USA
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Craig Wilen
4Department of Laboratory Medicine, Yale School of Medicine, New Haven, CT, USA
5Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
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Anna Marie Pyle
2Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT, USA
3Department of Chemistry, Yale University, New Haven, CT, USA
6Howard Hughes Medical Institute, Chevy Chase, MD, USA
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  • For correspondence: anna.pyle@yale.edu
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Summary

SARS-CoV-2 is the positive-sense RNA virus that causes COVID-19, a disease that has triggered a major human health and economic crisis. The genome of SARS-CoV-2 is unique among viral RNAs in its vast potential to form stable RNA structures and yet, as much as 97% of its 30 kilobases have not been structurally explored in the context of a viral infection. Our limited knowledge of SARS-CoV-2 genomic architecture is a fundamental limitation to both our mechanistic understanding of coronavirus life cycle and the development of COVID-19 RNA-based therapeutics. Here, we apply a novel long amplicon strategy to determine for the first time the secondary structure of the SARS-CoV-2 RNA genome probed in infected cells. In addition to the conserved structural motifs at the viral termini, we report new structural features like a conformationally flexible programmed ribosomal frameshifting pseudoknot, and a host of novel RNA structures, each of which highlights the importance of studying viral structures in their native genomic context. Our in-depth structural analysis reveals extensive networks of well-folded RNA structures throughout Orf1ab and reveals new aspects of SARS-CoV-2 genome architecture that distinguish it from other single-stranded, positive-sense RNA viruses. Evolutionary analysis of RNA structures in SARS-CoV-2 shows that several features of its genomic structure are conserved across beta coronaviruses and we pinpoint individual regions of well-folded RNA structure that merit downstream functional analysis. The native, complete secondary structure of SAR-CoV-2 presented here is a roadmap that will facilitate focused studies on mechanisms of replication, translation and packaging, and guide the identification of new RNA drug targets against COVID-19.

Competing Interest Statement

A patent application on MarathonRT has been filed by Yale University.

Footnotes

  • https://github.com/pylelab/SARS-CoV-2_SHAPE_MaP_structure

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-ND 4.0 International license.
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Posted July 10, 2020.
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Comprehensive in-vivo secondary structure of the SARS-CoV-2 genome reveals novel regulatory motifs and mechanisms
Nicholas C. Huston, Han Wan, Rafael de Cesaris Araujo Tavares, Craig Wilen, Anna Marie Pyle
bioRxiv 2020.07.10.197079; doi: https://doi.org/10.1101/2020.07.10.197079
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Comprehensive in-vivo secondary structure of the SARS-CoV-2 genome reveals novel regulatory motifs and mechanisms
Nicholas C. Huston, Han Wan, Rafael de Cesaris Araujo Tavares, Craig Wilen, Anna Marie Pyle
bioRxiv 2020.07.10.197079; doi: https://doi.org/10.1101/2020.07.10.197079

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