Rapid assembly of SARS-CoV-2 genomes reveals attenuation of the Omicron BA.1 variant through NSP6

Taha Y. Taha (), Irene P. Chen, Jennifer M. Hayashi, Takako Tabata, Keith Walcott, Gabriella R. Kimmerly, Abdullah M. Syed, Alison Ciling, Rahul K. Suryawanshi, Hannah S. Martin, Bryan H. Bach, Chia-Lin Tsou, Mauricio Montano, Mir M. Khalid, Bharath K. Sreekumar, G. Renuka Kumar, Stacia Wyman, Jennifer A. Doudna and Melanie Ott ()
Additional contact information
Taha Y. Taha: Gladstone Institutes
Irene P. Chen: Gladstone Institutes
Jennifer M. Hayashi: Gladstone Institutes
Takako Tabata: Gladstone Institutes
Keith Walcott: Gladstone Institutes
Gabriella R. Kimmerly: Gladstone Institutes
Abdullah M. Syed: Gladstone Institutes
Alison Ciling: Gladstone Institutes
Rahul K. Suryawanshi: Gladstone Institutes
Hannah S. Martin: Gladstone Institutes
Bryan H. Bach: Innovative Genomics Institute, University of California
Chia-Lin Tsou: Gladstone Institutes
Mauricio Montano: Gladstone Institutes
Mir M. Khalid: Gladstone Institutes
Bharath K. Sreekumar: Gladstone Institutes
G. Renuka Kumar: Gladstone Institutes
Stacia Wyman: Innovative Genomics Institute, University of California
Jennifer A. Doudna: Gladstone Institutes
Melanie Ott: Gladstone Institutes

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract Although the SARS-CoV-2 Omicron variant (BA.1) spread rapidly across the world and effectively evaded immune responses, its viral fitness in cell and animal models was reduced. The precise nature of this attenuation remains unknown as generating replication-competent viral genomes is challenging because of the length of the viral genome (~30 kb). Here, we present a plasmid-based viral genome assembly and rescue strategy (pGLUE) that constructs complete infectious viruses or noninfectious subgenomic replicons in a single ligation reaction with >80% efficiency. Fully sequenced replicons and infectious viral stocks can be generated in 1 and 3 weeks, respectively. By testing a series of naturally occurring viruses as well as Delta-Omicron chimeric replicons, we show that Omicron nonstructural protein 6 harbors critical attenuating mutations, which dampen viral RNA replication and reduce lipid droplet consumption. Thus, pGLUE overcomes remaining barriers to broadly study SARS-CoV-2 replication and reveals deficits in nonstructural protein function underlying Omicron attenuation.

Date: 2023
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DOI: 10.1038/s41467-023-37787-0

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