Atypical Divergence of SARS-CoV-2 Orf8 from Orf7a within the Coronavirus Lineage Suggests Potential Stealthy Viral Strategies in Immune Evasion

Neches, Russell Y.; Kyrpides, Nikos C.; Ouzounis, Christos A.

doi:10.1128/mbio.03014-20

Atypical Divergence of SARS-CoV-2 Orf8 from Orf7a within the Coronavirus Lineage Suggests Potential Stealthy Viral Strategies in Immune Evasion

Journal Article · Mon Feb 22 23:00:00 EST 2021 · mBio

DOI:https://doi.org/10.1128/mbio.03014-20· OSTI ID:1798766

Neches, Russell Y. ^[1]; Kyrpides, Nikos C. ^[1]; ^[2]

USDOE Joint Genome Institute (JGI), Berkeley, CA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Centre for Research and Technology Hellas, Thessalonica (Greece)

Orf8, one of the most puzzling genes in the SARS lineage of coronaviruses, marks a unique and striking difference in genome organization between SARS-CoV-2 and SARS-CoV-1. Here, using sequence comparisons, we unequivocally reveal the distant sequence similarities between SARS-CoV-2 Orf8 with its SARS-CoV-1 counterparts and the X4-like genes of coronaviruses, including its highly divergent “paralog” gene Orf7a, whose product is a potential immune antagonist of known structure. Supervised sequence space walks unravel identity levels that drop below 10% and yet exhibit subtle conservation patterns in this novel superfamily, characterized by an immunoglobulin-like beta sandwich topology. We document the high accuracy of the sequence space walk process in detail and characterize the subgroups of the superfamily in sequence space by systematic annotation of gene and taxon groups. While SARS-CoV-1 Orf7a and Orf8 genes are most similar to bat virus sequences, their SARS-CoV-2 counterparts are closer to pangolin virus homologs, reflecting the fine structure of conservation patterns within the SARS-CoV-2 genomes. The divergence between Orf7a and Orf8 is exceptionally idiosyncratic, since Orf7a is more constrained, whereas Orf8 is subject to rampant change, a peculiar feature that may be related to hitherto-unknown viral infection strategies. Despite their common origin, the Orf7a and Orf8 protein families exhibit different modes of evolutionary trajectories within the coronavirus lineage, which might be partly attributable to their complex interactions with the mammalian host cell, reflected by a multitude of functional associations of Orf8 in SARS-CoV-2 compared to a very small number of interactions discovered for Orf7a.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER); Operational Program Competitiveness, Entrepreneurship, and Innovation; Greece; European Regional Development Fund (ERDF); USDOE National Nuclear Security Administration (NNSA)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1798766

Journal Information:: mBio, Journal Name: mBio Journal Issue: 1 Vol. 12; ISSN 2161-2129

Publisher:: American Society for Microbiology (ASM)Copyright Statement

Country of Publication:: United States

Language:: English

References (58)

Immunoglobulin superfamily members encoded by viruses and their multiple roles in immune evasion Farré, Domènec; Martínez-Vicente, Pablo; Engel, Pablo European Journal of Immunology, Vol. 47, Issue 5 https://doi.org/10.1002/eji.201746984	journal	May 2017
UCSF Chimera?A visualization system for exploratory research and analysis Pettersen, Eric F.; Goddard, Thomas D.; Huang, Conrad C. Journal of Computational Chemistry, Vol. 25, Issue 13 https://doi.org/10.1002/jcc.20084	journal	January 2004
Solution structure of the X4 protein coded by the SARS related coronavirus reveals an immunoglobulin like fold and suggests a binding activity to integrin I domains Hänel, Karen; Stangler, Thomas; Stoldt, Matthias Journal of Biomedical Science, Vol. 13, Issue 3 https://doi.org/10.1007/s11373-005-9043-9	journal	November 2005
Effects of a major deletion in the SARS-CoV-2 genome on the severity of infection and the inflammatory response: an observational cohort study Young, Barnaby E.; Fong, Siew-Wai; Chan, Yi-Hao The Lancet, Vol. 396, Issue 10251 https://doi.org/10.1016/S0140-6736(20)31757-8	journal	August 2020
Bioinformatics and functional analyses of coronavirus nonstructural proteins involved in the formation of replicative organelles Neuman, Benjamin W. Antiviral Research, Vol. 135 https://doi.org/10.1016/j.antiviral.2016.10.005	journal	November 2016
The Architecture of SARS-CoV-2 Transcriptome Kim, Dongwan; Lee, Joo-Yeon; Yang, Jeong-Sun Cell, Vol. 181, Issue 4 https://doi.org/10.1016/j.cell.2020.04.011	journal	May 2020
Identification of multiple large deletions in ORF7a resulting in in-frame gene fusions in clinical SARS-CoV-2 isolates Addetia, Amin; Xie, Hong; Roychoudhury, Pavitra Journal of Clinical Virology, Vol. 129 https://doi.org/10.1016/j.jcv.2020.104523	journal	August 2020
Structure and Intracellular Targeting of the SARS-Coronavirus Orf7a Accessory Protein Nelson, Christopher A.; Pekosz, Andrew; Lee, Chung A. Structure, Vol. 13, Issue 1 https://doi.org/10.1016/j.str.2004.10.010	journal	January 2005
The human severe acute respiratory syndrome coronavirus (SARS-CoV) 8b protein is distinct from its counterpart in animal SARS-CoV and down-regulates the expression of the envelope protein in infected cells Keng, Choong-Tat; Choi, Yook-Wah; Welkers, Matthijs R. A. Virology, Vol. 354, Issue 1 https://doi.org/10.1016/j.virol.2006.06.026	journal	October 2006
The 8ab protein of SARS-CoV is a luminal ER membrane-associated protein and induces the activation of ATF6 Sung, Shu-Chiun; Chao, Che-Yi; Jeng, King-Song Virology, Vol. 387, Issue 2 https://doi.org/10.1016/j.virol.2009.02.021	journal	May 2009
Accessory proteins 8b and 8ab of severe acute respiratory syndrome coronavirus suppress the interferon signaling pathway by mediating ubiquitin-dependent rapid degradation of interferon regulatory factor 3 Wong, Hui Hui; Fung, To Sing; Fang, Shouguo Virology, Vol. 515 https://doi.org/10.1016/j.virol.2017.12.028	journal	February 2018
Dimensionality reduction for visualizing single-cell data using UMAP Becht, Etienne; McInnes, Leland; Healy, John Nature Biotechnology, Vol. 37, Issue 1 https://doi.org/10.1038/nbt.4314	journal	December 2018
Overview of lethal human coronaviruses Chen, Bin; Tian, Er-Kang; He, Bin Signal Transduction and Targeted Therapy, Vol. 5, Issue 1 https://doi.org/10.1038/s41392-020-0190-2	journal	June 2020
SARS-Coronavirus Open Reading Frame-8b triggers intracellular stress pathways and activates NLRP3 inflammasomes Shi, Chong-Shan; Nabar, Neel R.; Huang, Ning-Na Cell Death Discovery, Vol. 5, Issue 1 https://doi.org/10.1038/s41420-019-0181-7	journal	June 2019
Virus against virus: a potential treatment for 2019-nCov (SARS-CoV-2) and other RNA viruses Nguyen, Tuan M.; Zhang, Yang; Pandolfi, Pier Paolo Cell Research, Vol. 30, Issue 3 https://doi.org/10.1038/s41422-020-0290-0	journal	February 2020
The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2 Gorbalenya, Alexander E.; Baker, Susan C. Nature Microbiology, Vol. 5, Issue 4, p. 536-544 https://doi.org/10.1038/s41564-020-0695-z	journal	March 2020
Evolutionary origins of the SARS-CoV-2 sarbecovirus lineage responsible for the COVID-19 pandemic Boni, Maciej F.; Lemey, Philippe; Jiang, Xiaowei Nature Microbiology, Vol. 5, Issue 11 https://doi.org/10.1038/s41564-020-0771-4	journal	July 2020
Origin and evolution of pathogenic coronaviruses Cui, Jie; Li, Fang; Shi, Zheng-Li Nature Reviews Microbiology, Vol. 17, Issue 3 https://doi.org/10.1038/s41579-018-0118-9	journal	December 2018
A new coronavirus associated with human respiratory disease in China Wu, Fan; Zhao, Su; Yu, Bin Nature, Vol. 579, Issue 7798 https://doi.org/10.1038/s41586-020-2008-3	journal	February 2020
A pneumonia outbreak associated with a new coronavirus of probable bat origin Zhou, Peng; Yang, Xing-Lou; Wang, Xian-Guang Nature, Vol. 579, Issue 7798 https://doi.org/10.1038/s41586-020-2012-7	journal	February 2020
A SARS-CoV-2 protein interaction map reveals targets for drug repurposing Gordon, David E.; Jang, Gwendolyn M.; Bouhaddou, Mehdi Nature, Vol. 583, Issue 7816 https://doi.org/10.1038/s41586-020-2286-9	journal	April 2020
Sequence analysis of SARS-CoV-2 genome reveals features important for vaccine design Kames, Jacob; Holcomb, David D.; Kimchi, Ofer Scientific Reports, Vol. 10, Issue 1 https://doi.org/10.1038/s41598-020-72533-2	journal	September 2020
Sequence evidence for common ancestry of eukaryotic endomembrane coatomers Promponas, Vasilis J.; Katsani, Katerina R.; Blencowe, Benjamin J. Scientific Reports, Vol. 6, Issue 1 https://doi.org/10.1038/srep22311	journal	March 2016
A Novel Coronavirus from Patients with Pneumonia in China, 2019 Zhu, Na; Zhang, Dingyu; Wang, Wenling New England Journal of Medicine, Vol. 382, Issue 8 https://doi.org/10.1056/NEJMoa2001017	journal	February 2020
Cross-host evolution of severe acute respiratory syndrome coronavirus in palm civet and human Song, H. -D.; Tu, C. -C.; Zhang, G. -W. Proceedings of the National Academy of Sciences, Vol. 102, Issue 7 https://doi.org/10.1073/pnas.0409608102	journal	February 2005
MAFFT online service: multiple sequence alignment, interactive sequence choice and visualization Katoh, Kazutaka; Rozewicki, John; Yamada, Kazunori D. Briefings in Bioinformatics, Vol. 20, Issue 4 https://doi.org/10.1093/bib/bbx108	journal	September 2017
MView: a web-compatible database search or multiple alignment viewer Brown, N. P.; Leroy, C.; Sander, C. Bioinformatics, Vol. 14, Issue 4 https://doi.org/10.1093/bioinformatics/14.4.380	journal	May 1998
CAST: an iterative algorithm for the complexity analysis of sequence tracts Promponas, V. J.; Enright, A. J.; Tsoka, S. Bioinformatics, Vol. 16, Issue 10 https://doi.org/10.1093/bioinformatics/16.10.915	journal	October 2000
BAli-Phy: simultaneous Bayesian inference of alignment and phylogeny Suchard, M. A.; Redelings, B. D. Bioinformatics, Vol. 22, Issue 16 https://doi.org/10.1093/bioinformatics/btl175	journal	May 2006
Jalview Version 2--a multiple sequence alignment editor and analysis workbench Waterhouse, A. M.; Procter, J. B.; Martin, D. M. A. Bioinformatics, Vol. 25, Issue 9 https://doi.org/10.1093/bioinformatics/btp033	journal	January 2009
trimAl: a tool for automated alignment trimming in large-scale phylogenetic analyses Capella-Gutierrez, S.; Silla-Martinez, J. M.; Gabaldon, T. Bioinformatics, Vol. 25, Issue 15 https://doi.org/10.1093/bioinformatics/btp348	journal	June 2009
dendextend: an R package for visualizing, adjusting and comparing trees of hierarchical clustering Galili, Tal Bioinformatics, Vol. 31, Issue 22 https://doi.org/10.1093/bioinformatics/btv428	journal	July 2015
IcyTree: rapid browser-based visualization for phylogenetic trees and networks Vaughan, Timothy G. Bioinformatics, Vol. 33, Issue 15 https://doi.org/10.1093/bioinformatics/btx155	journal	April 2017
VIRULIGN: fast codon-correct alignment and annotation of viral genomes Libin, Pieter J. K.; Deforche, Koen; Abecasis, Ana B. Bioinformatics, Vol. 35, Issue 10 https://doi.org/10.1093/bioinformatics/bty851	journal	October 2018
A Path toward SARS-CoV-2 Attenuation: Metabolic Pressure on CTP Synthesis Rules the Virus Evolution Ou, Zhihua; Ouzounis, Christos; Wang, Daxi Genome Biology and Evolution, Vol. 12, Issue 12 https://doi.org/10.1093/gbe/evaa229	journal	October 2020
ORF8-Related Genetic Evidence for Chinese Horseshoe Bats as the Source of Human Severe Acute Respiratory Syndrome Coronavirus Wu, Zhiqiang; Yang, Li; Ren, Xianwen Journal of Infectious Diseases, Vol. 213, Issue 4 https://doi.org/10.1093/infdis/jiv476	journal	October 2015
Gapped BLAST and PSI-BLAST: a new generation of protein database search programs Altschul, Stephen F.; Madden, Thomas L.; Schäffer, Alejandro A. Nucleic Acids Research, Vol. 25, Issue 17, p. 3389-3402 https://doi.org/10.1093/nar/25.17.3389	journal	September 1997
ClustVis: a web tool for visualizing clustering of multivariate data using Principal Component Analysis and heatmap Metsalu, Tauno; Vilo, Jaak Nucleic Acids Research, Vol. 43, Issue W1 https://doi.org/10.1093/nar/gkv468	journal	May 2015
The Pfam protein families database in 2019 El-Gebali, Sara; Mistry, Jaina; Bateman, Alex Nucleic Acids Research, Vol. 47, Issue D1 https://doi.org/10.1093/nar/gky995	journal	October 2018
NGPhylogeny.fr: new generation phylogenetic services for non-specialists Lemoine, Frédéric; Correia, Damien; Lefort, Vincent Nucleic Acids Research, Vol. 47, Issue W1 https://doi.org/10.1093/nar/gkz303	journal	April 2019
Database resources of the National Center for Biotechnology Information Sayers, Eric W.; Beck, Jeff; Brister, J. Rodney Nucleic Acids Research, Vol. 48, Issue D1 https://doi.org/10.1093/nar/gkz899	journal	October 2019
On the origin and continuing evolution of SARS-CoV-2 Tang, Xiaolu; Wu, Changcheng; Li, Xiang National Science Review, Vol. 7, Issue 6 https://doi.org/10.1093/nsr/nwaa036	journal	March 2020
Microreact: visualizing and sharing data for genomic epidemiology and phylogeography Argimón, Silvia; Abudahab, Khalil; Goater, Richard J. E. Microbial Genomics, Vol. 2, Issue 11 https://doi.org/10.1099/mgen.0.000093	journal	November 2016
Immunoglobulin domains in Escherichia coli and other enterobacteria: from pathogenesis to applications in antibody technologies Bodelón, Gustavo; Palomino, Carmen; Fernández, Luis Ángel FEMS Microbiology Reviews, Vol. 37, Issue 2 https://doi.org/10.1111/j.1574-6976.2012.00347.x	journal	March 2013
Emergence of SARS-CoV-2 through recombination and strong purifying selection Li, Xiaojun; Giorgi, Elena E.; Marichannegowda, Manukumar Honnayakanahalli Science Advances, Vol. 6, Issue 27 https://doi.org/10.1126/sciadv.abb9153	journal	May 2020
An 81-Nucleotide Deletion in SARS-CoV-2 ORF7a Identified from Sentinel Surveillance in Arizona (January to March 2020) Holland, LaRinda A.; Kaelin, Emily A.; Maqsood, Rabia Journal of Virology, Vol. 94, Issue 14 https://doi.org/10.1128/JVI.00711-20	journal	July 2020
Severe Acute Respiratory Syndrome (SARS) Coronavirus ORF8 Protein Is Acquired from SARS-Related Coronavirus from Greater Horseshoe Bats through Recombination Lau, Susanna K. P.; Feng, Yun; Chen, Honglin Journal of Virology, Vol. 89, Issue 20 https://doi.org/10.1128/JVI.01048-15	journal	August 2015
The 29-Nucleotide Deletion Present in Human but Not in Animal Severe Acute Respiratory Syndrome Coronaviruses Disrupts the Functional Expression of Open Reading Frame 8 Oostra, Monique; de Haan, Cornelis A. M.; Rottier, Peter J. M. Journal of Virology, Vol. 81, Issue 24 https://doi.org/10.1128/JVI.01631-07	journal	December 2007
Novel Immunoglobulin Domain Proteins Provide Insights into Evolution and Pathogenesis of SARS-CoV-2-Related Viruses Tan, Yongjun; Schneider, Theresa; Leong, Matthew mBio, Vol. 11, Issue 3 https://doi.org/10.1128/mBio.00760-20	journal	June 2020
AlignmentViewer: Sequence Analysis of Large Protein Families Reguant, Roc; Antipin, Yevgeniy; Sheridan, Rob F1000Research, Vol. 9 https://doi.org/10.12688/f1000research.22242.1	journal	January 2020
Genome-Wide Inference of Ancestral Recombination Graphs Rasmussen, Matthew D.; Hubisz, Melissa J.; Gronau, Ilan PLoS Genetics, Vol. 10, Issue 5 https://doi.org/10.1371/journal.pgen.1004342	journal	May 2014
FastTree 2 – Approximately Maximum-Likelihood Trees for Large Alignments Price, Morgan N.; Dehal, Paramvir S.; Arkin, Adam P. PLoS ONE, Vol. 5, Issue 3 https://doi.org/10.1371/journal.pone.0009490	journal	March 2010
Discovery of a rich gene pool of bat SARS-related coronaviruses provides new insights into the origin of SARS coronavirus Hu, Ben; Zeng, Lei-Ping; Yang, Xing-Lou PLOS Pathogens, Vol. 13, Issue 11 https://doi.org/10.1371/journal.ppat.1006698	journal	November 2017
Are pangolins the intermediate host of the 2019 novel coronavirus (SARS-CoV-2)? Liu, Ping; Jiang, Jing-Zhe; Wan, Xiu-Feng PLOS Pathogens, Vol. 16, Issue 5 https://doi.org/10.1371/journal.ppat.1008421	journal	May 2020
The COVID-19 Gene and Drug Set Library Kuleshov, Maxim; Clarke, Daniel J. B.; Kropiwnicki, Eryk SSRN Electronic Journal https://doi.org/10.2139/ssrn.3606799	journal	January 2020
SARS-CoV-2 ORF8 and SARS-CoV ORF8ab: Genomic Divergence and Functional Convergence Mohammad, Sameer; Bouchama, Abderrezak; Mohammad Alharbi, Bothina Pathogens, Vol. 9, Issue 9 https://doi.org/10.3390/pathogens9090677	journal	August 2020
Systematic Comparison of Two Animal-to-Human Transmitted Human Coronaviruses: SARS-CoV-2 and SARS-CoV Xu, Jiabao; Zhao, Shizhe; Teng, Tieshan Viruses, Vol. 12, Issue 2 https://doi.org/10.3390/v12020244	journal	February 2020
The Role of Severe Acute Respiratory Syndrome (SARS)-Coronavirus Accessory Proteins in Virus Pathogenesis McBride, Ruth; Fielding, Burtram Viruses, Vol. 4, Issue 11 https://doi.org/10.3390/v4112902	journal	November 2012

Cited By (8)

Additional file 1 of The 29-nucleotide deletion in SARS-CoV: truncated versions of ORF8 are under purifying selection Bykova, Anastassia; Saura, Andreu; Glazko, Galina V. figshare https://doi.org/10.6084/m9.figshare.23658188.v1	dataset	January 2023
Additional file 2 of The 29-nucleotide deletion in SARS-CoV: truncated versions of ORF8 are under purifying selection Bykova, Anastassia; Saura, Andreu; Glazko, Galina V. figshare https://doi.org/10.6084/m9.figshare.23658191.v1	dataset	January 2023
Additional file 3 of The 29-nucleotide deletion in SARS-CoV: truncated versions of ORF8 are under purifying selection Bykova, Anastassia; Saura, Andreu; Glazko, Galina V. figshare https://doi.org/10.6084/m9.figshare.23658197.v1	dataset	January 2023
Additional file 4 of The 29-nucleotide deletion in SARS-CoV: truncated versions of ORF8 are under purifying selection Bykova, Anastassia; Saura, Andreu; Glazko, Galina V. figshare https://doi.org/10.6084/m9.figshare.23658200.v1	dataset	January 2023
Additional file 5 of The 29-nucleotide deletion in SARS-CoV: truncated versions of ORF8 are under purifying selection Bykova, Anastassia; Saura, Andreu; Glazko, Galina V. figshare https://doi.org/10.6084/m9.figshare.23658206.v1	dataset	January 2023
Additional file 6 of The 29-nucleotide deletion in SARS-CoV: truncated versions of ORF8 are under purifying selection Bykova, Anastassia; Saura, Andreu; Glazko, Galina V. figshare https://doi.org/10.6084/m9.figshare.23658209.v1	dataset	January 2023
Additional file 7 of The 29-nucleotide deletion in SARS-CoV: truncated versions of ORF8 are under purifying selection Bykova, Anastassia; Saura, Andreu; Glazko, Galina V. figshare https://doi.org/10.6084/m9.figshare.23658212.v1	dataset	January 2023
Additional file 8 of The 29-nucleotide deletion in SARS-CoV: truncated versions of ORF8 are under purifying selection Bykova, Anastassia; Saura, Andreu; Glazko, Galina V. figshare https://doi.org/10.6084/m9.figshare.23658215.v1	dataset	January 2023

Similar Records

Structure of SARS-CoV-2 ORF8, a rapidly evolving immune evasion protein

Journal Article · Tue Dec 22 23:00:00 EST 2020 · Proceedings of the National Academy of Sciences of the United States of America · OSTI ID:1815732

Evolutionary history, potential intermediate animal host, and cross-species analyses of SARS-CoV-2

Journal Article · Wed Mar 11 00:00:00 EDT 2020 · Journal of Medical Virology · OSTI ID:1774437

Related Subjects

60 APPLIED LIFE SCIENCES
Orf7a
Orf8
SARS-CoV-2
X4-like
coronavirus
protein superfamily
structure prediction
virus evolution

Atypical Divergence of SARS-CoV-2 Orf8 from Orf7a within the Coronavirus Lineage Suggests Potential Stealthy Viral Strategies in Immune Evasion

Citation Formats

References (58)

Cited By (8)

Similar Records

Related Subjects