Discovery and Genomic Characterization of a 382-Nucleotide Deletion in ORF7b and ORF8 during the Early Evolution of SARS-CoV-2

To date, limited genetic changes in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome have been described. Here, we report a 382-nucleotide (nt) deletion in SARS-CoV-2 that truncates open reading frame 7b (ORF7b) and ORF8, removing the ORF8 transcription regulatory sequence (TR...

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Bibliographic Details
Published in:	mBio 2020-07, Vol.11 (4)
Main Authors:	Su, Yvonne C F, Anderson, Danielle E, Young, Barnaby E, Linster, Martin, Zhu, Feng, Jayakumar, Jayanthi, Zhuang, Yan, Kalimuddin, Shirin, Low, Jenny G H, Tan, Chee Wah, Chia, Wan Ni, Mak, Tze Minn, Octavia, Sophie, Chavatte, Jean-Marc, Lee, Raphael T C, Pada, Surinder, Tan, Seow Yen, Sun, Louisa, Yan, Gabriel Z, Maurer-Stroh, Sebastian, Mendenhall, Ian H, Leo, Yee-Sin, Lye, David Chien, Wang, Lin-Fa, Smith, Gavin J D
Format:	Article
Language:	eng
Subjects:	Base Sequence Betacoronavirus - genetics Betacoronavirus - immunology Betacoronavirus - physiology COVID-19 Ecological and Evolutionary Science Editor's Pick Genome, Viral Humans natural selection Open Reading Frames ORF8 phylogeny SARS-CoV-2 Sequence Deletion vaccines Virus Replication
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Summary:	To date, limited genetic changes in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome have been described. Here, we report a 382-nucleotide (nt) deletion in SARS-CoV-2 that truncates open reading frame 7b (ORF7b) and ORF8, removing the ORF8 transcription regulatory sequence (TRS) and eliminating ORF8 transcription. The earliest 382-nt deletion variant was detected in Singapore on 29 January 2020, with the deletion viruses circulating in the country and accounting for 23.6% (45/191) of SARS-CoV-2 samples screened in this study. SARS-CoV-2 with the same deletion has since been detected in Taiwan, and other ORF7b/8 deletions of various lengths, ranging from 62 nt to 345 nt, have been observed in other geographic locations, including Australia, Bangladesh, and Spain. Mutations or deletions in ORF8 of SARS-CoV have been associated with reduced replicative fitness and virus attenuation. In contrast, the SARS-CoV-2 382-nt deletion viruses showed significantly higher replicative fitness than the wild type, while no difference was observed in patient viral load, indicating that the deletion variant viruses retained their replicative fitness. A robust antibody response to ORF8 has been observed in SARS-CoV-2 infection, suggesting that the emergence of ORF8 deletions may be due to immune-driven selection and that further deletion variants may emerge during the sustained transmission of SARS-CoV-2 in humans. During the SARS epidemic in 2003/2004, a number of deletions were observed in ORF8 of SARS-CoV, and eventually deletion variants became predominant, leading to the hypothesis that ORF8 was an evolutionary hot spot for adaptation of SARS-CoV to humans. However, due to the successful control of the SARS epidemic, the importance of these deletions for the epidemiological fitness of SARS-CoV in humans could not be established. The emergence of multiple SARS-CoV-2 strains with ORF8 deletions, combined with evidence of a robust immune response to ORF8, suggests that the lack of ORF8 may assist with host immune evasion. In addition to providing a key insight into the evolutionary behavior of SARS-CoV-2 as the virus adapts to its new human hosts, the emergence of ORF8 deletion variants may also impact vaccination strategies.
ISSN:	2161-2129 2150-7511