Abstract
SARS-CoV-2 is a betacoronavirus with a single-stranded, positive-sense, 30-kilobase RNA genome responsible for the ongoing COVID-19 pandemic. Although population average structure models of the genome were recently reported, there is little experimental data on native structural ensembles, and most structures lack functional characterization. Here we report secondary structure heterogeneity of the entire SARS-CoV-2 genome in two lines of infected cells at single nucleotide resolution. Our results reveal alternative RNA conformations across the genome and at the critical frameshifting stimulation element (FSE) that are drastically different from prevailing population average models. Importantly, we find that this structural ensemble promotes frameshifting rates much higher than the canonical minimal FSE and similar to ribosome profiling studies. Our results highlight the value of studying RNA in its full length and cellular context. The genomic structures detailed here lay groundwork for coronavirus RNA biology and will guide the design of SARS-CoV-2 RNA-based therapeutics.
Highlights
11, Mark Bathe[4], Anders Näär[7,8], SARS-CoV-2 is a betacoronavirus with a single-stranded, positive-sense, 30-kilobase RNA genome responsible for the ongoing COVID-19 pandemic
Prior to the emergence of SARS-CoV-2, most studies on secondary structures within coronavirus RNA genomes focused on several conserved regions that are essential for viral replication: the 5′ untranslated region (UTR), the 3′ UTR, and the frameshifting stimulation element (FSE)[6,7]
We chose dimethyl sulfate (DMS) because it rapidly modifies unpaired adenines (As) and cytosines (Cs) in vivo at their Watson–Crick faces with negligible background effects[25] and has been shown to yield structures of similar or slightly higher accuracies compared to SHAPE20
Summary
11, Mark Bathe[4], Anders Näär[7,8], SARS-CoV-2 is a betacoronavirus with a single-stranded, positive-sense, 30-kilobase RNA genome responsible for the ongoing COVID-19 pandemic. We report secondary structure heterogeneity of the entire SARS-CoV-2 genome in two lines of infected cells at single nucleotide resolution. Our results reveal alternative RNA conformations across the genome and at the critical frameshifting stimulation element (FSE) that are drastically different from prevailing population average models. The genomic structures detailed here lay groundwork for coronavirus RNA biology and will guide the design of SARS-CoV-2 RNA-based therapeutics. Prior to the emergence of SARS-CoV-2, most studies on secondary structures within coronavirus RNA genomes focused on several conserved regions that are essential for viral replication: the 5′ UTR, the 3′ UTR, and the frameshifting stimulation element (FSE)[6,7]. A stop codon near the middle of ORF1 partitions it into an upstream ORF1a and downstream
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
