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Secondary structural ensembles of the SARS-CoV-2 RNA genome in infected cells.

Whitehead Institute for Biomedical Research, Cambridge, MA, USA. Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA. Department of Microbiology, Harvard Medical School, Boston, MA, USA. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. Computational and Systems Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. National Emerging Infectious Diseases Laboratories, Boston University School of Medicine, Boston University, Boston, MA, USA. Department of Nutritional Sciences & Toxicology, University of California, Berkley, CA, 94720, USA. Innovative Genomics Institute, University of California, Berkeley, CA, 94720, USA. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. Department of Electrical Engineering & Computer Science, Massachusetts Institute of Technology, Cambridge, MA, USA. Department of Neuroscience, Yale University School of Medicine, New Haven, CT, USA. Whitehead Institute for Biomedical Research, Cambridge, MA, USA. silvi_rouskin@hms.harvard.edu. Department of Microbiology, Harvard Medical School, Boston, MA, USA. silvi_rouskin@hms.harvard.edu.

Nature communications. 2022;(1):1128
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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.