The origins of SARS-CoV-2: A critical review

doi:10.1016/j.cell.2021.08.017

Review

. 2021 Sep 16;184(19):4848-4856.

doi: 10.1016/j.cell.2021.08.017. Epub 2021 Aug 19.

The origins of SARS-CoV-2: A critical review

Edward C Holmes¹, Stephen A Goldstein², Angela L Rasmussen³, David L Robertson⁴, Alexander Crits-Christoph⁵, Joel O Wertheim⁶, Simon J Anthony⁷, Wendy S Barclay⁸, Maciej F Boni⁹, Peter C Doherty¹⁰, Jeremy Farrar¹¹, Jemma L Geoghegan¹², Xiaowei Jiang¹³, Julian L Leibowitz¹⁴, Stuart J D Neil¹⁵, Tim Skern¹⁶, Susan R Weiss¹⁷, Michael Worobey¹⁸, Kristian G Andersen¹⁹, Robert F Garry²⁰, Andrew Rambaut²¹

Affiliations

¹ Marie Bashir Institute for Infectious Diseases and Biosecurity, School of Life and Environmental Sciences and School of Medical Sciences, The University of Sydney, Sydney, NSW 2006, Australia. Electronic address: edward.holmes@sydney.edu.au.
² Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA.
³ Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, SK S7N 5E3, Canada.
⁴ MRC-University of Glasgow Centre for Virus Research, Glasgow G61 1QH, UK.
⁵ Department of Plant and Microbial Biology, University of California-Berkeley, Berkeley, CA 94704, USA.
⁶ Department of Medicine, University of California-San Diego, La Jolla, CA 92093, USA.
⁷ Department of Pathology, Microbiology, and Immunology, University of California-Davis School of Veterinary Medicine, Davis, CA 95616, USA.
⁸ Department of Infectious Disease, Imperial College, London W2 1PG, UK.
⁹ Center for Infectious Disease Dynamics, Department of Biology, The Pennsylvania State University, University Park, PA 16802, USA.
¹⁰ Department of Microbiology and Immunology, The University of Melbourne at the Doherty Institute, 792 Elizabeth Street, Melbourne, VIC 3000, Australia.
¹¹ The Wellcome Trust, London NW1 2BE, UK.
¹² Department of Microbiology and Immunology, University of Otago, Dunedin 9010, New Zealand; Institute of Environmental Science and Research, Wellington 5022, New Zealand.
¹³ Department of Biological Sciences, Xi'an Jiaotong-Liverpool University (XJTLU), Suzhou, China.
¹⁴ Department of Microbial Pathogenesis and Immunology, Texas A&M University, College Station, TX 77807, USA.
¹⁵ Department of Infectious Diseases, King's College London, Guy's Hospital, London SE1 9RT, UK.
¹⁶ Max Perutz Labs, Medical University of Vienna, Vienna Biocenter, Dr. Bohr-Gasse 9/3, 1030 Vienna, Austria.
¹⁷ Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹⁸ Department of Ecology and Evolutionary Biology, University of Arizona, Tucson, AZ 85721, USA.
¹⁹ Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
²⁰ Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA 70112, USA; Zalgen Labs, Germantown, MD 20876, USA.
²¹ Institute of Evolutionary Biology, University of Edinburgh, Edinburgh EH9 3FL, UK. Electronic address: a.rambaut@ed.ac.uk.

PMID: 34480864
PMCID: PMC8373617
DOI: 10.1016/j.cell.2021.08.017

Review

The origins of SARS-CoV-2: A critical review

Edward C Holmes et al. Cell. 2021.

. 2021 Sep 16;184(19):4848-4856.

doi: 10.1016/j.cell.2021.08.017. Epub 2021 Aug 19.

Authors

Affiliations

¹ Marie Bashir Institute for Infectious Diseases and Biosecurity, School of Life and Environmental Sciences and School of Medical Sciences, The University of Sydney, Sydney, NSW 2006, Australia. Electronic address: edward.holmes@sydney.edu.au.
² Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA.
³ Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, SK S7N 5E3, Canada.
⁴ MRC-University of Glasgow Centre for Virus Research, Glasgow G61 1QH, UK.
⁵ Department of Plant and Microbial Biology, University of California-Berkeley, Berkeley, CA 94704, USA.
⁶ Department of Medicine, University of California-San Diego, La Jolla, CA 92093, USA.
⁷ Department of Pathology, Microbiology, and Immunology, University of California-Davis School of Veterinary Medicine, Davis, CA 95616, USA.
⁸ Department of Infectious Disease, Imperial College, London W2 1PG, UK.
⁹ Center for Infectious Disease Dynamics, Department of Biology, The Pennsylvania State University, University Park, PA 16802, USA.
¹⁰ Department of Microbiology and Immunology, The University of Melbourne at the Doherty Institute, 792 Elizabeth Street, Melbourne, VIC 3000, Australia.
¹¹ The Wellcome Trust, London NW1 2BE, UK.
¹² Department of Microbiology and Immunology, University of Otago, Dunedin 9010, New Zealand; Institute of Environmental Science and Research, Wellington 5022, New Zealand.
¹³ Department of Biological Sciences, Xi'an Jiaotong-Liverpool University (XJTLU), Suzhou, China.
¹⁴ Department of Microbial Pathogenesis and Immunology, Texas A&M University, College Station, TX 77807, USA.
¹⁵ Department of Infectious Diseases, King's College London, Guy's Hospital, London SE1 9RT, UK.
¹⁶ Max Perutz Labs, Medical University of Vienna, Vienna Biocenter, Dr. Bohr-Gasse 9/3, 1030 Vienna, Austria.
¹⁷ Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹⁸ Department of Ecology and Evolutionary Biology, University of Arizona, Tucson, AZ 85721, USA.
¹⁹ Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
²⁰ Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA 70112, USA; Zalgen Labs, Germantown, MD 20876, USA.
²¹ Institute of Evolutionary Biology, University of Edinburgh, Edinburgh EH9 3FL, UK. Electronic address: a.rambaut@ed.ac.uk.

PMID: 34480864
PMCID: PMC8373617
DOI: 10.1016/j.cell.2021.08.017

Abstract

Since the first reports of a novel severe acute respiratory syndrome (SARS)-like coronavirus in December 2019 in Wuhan, China, there has been intense interest in understanding how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in the human population. Recent debate has coalesced around two competing ideas: a "laboratory escape" scenario and zoonotic emergence. Here, we critically review the current scientific evidence that may help clarify the origin of SARS-CoV-2.

Keywords: COVID-19; SARS-CoV-2; evolution; origins; zoonosis.

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Conflict of interest statement

Declaration of interests E.C.H. is an honorary visiting professor at Fudan University (Shanghai Public Health Clinical Center), Shanghai, China and, from 2014–2020, was a guest professor at the Chinese Center for Disease Control and Prevention, Beijing, China. These affiliations are only used in papers co-authored with Prof. Yong-Zhen Zhang (Shanghai Public Health Clinical Center) and involve no formal appointment, no duties, and no remuneration nor research funding. J.O.W. receives funding from the U.S. Centers for Disease Control and Prevention (ongoing) via grants and contracts to his institution unrelated to this research. S.R.W. consults for Immunome and Ocugen. A.R., A.L.R., M.F.B., S.A.G., and K.G.A. have received consulting fees and compensation for expert testimony on SARS-CoV-2 and the COVID-19 pandemic. R.F.G. is co-founder of Zalgen Labs.

Figures

**Figure 1**
Phylogenetic and epidemiological data on the early COVID-19 pandemic in Wuhan (A) Phylogenetic tree of early SARS-CoV-2 genomes sampled from Wuhan during December 2019–January 2020. The split between lineages A and B is labeled with the coordinates and base of the two differentiating nucleotide mutations. Cases with a known association to the Huanan or other markets are denoted by symbols (reported in World Health Organization, 2021). (B) Map of districts of Wuhan showing the location of markets, the Wuhan National Biosafety Laboratory at the Zhengdian Scientific Park of the Wuhan Institute of Virology (denoted WIV), where the coronavirus isolation and culture work of Dr. Shi Zhengli is performed, and the earliest known cases. (C–E) Location of recorded COVID-19 cases in Wuhan from December 8 to December 31, 2019. Cases with a home address outside of Wuhan city are not shown. (F–H) Map of districts of Wuhan indicating the first record of excess deaths due to pneumonia (shaded green) from January 15, 2020. Case and excess death data were extracted and redrawn from figures provided in World Health Organization (2021). See also Document S1.

**Figure 2**
Evolution of the furin cleavage site in the spike protein of betacoronaviruses (A) Sequence alignment of the region around the furin cleavage site (FCS) in SARS-CoV-2 (NCBI: MN908947) and bat coronavirus RaTG13 (NCBI: MN996532) showing that the former was the result of an out-of-frame nucleotide sequence insertion. (B) Amino acid sequence alignment of the FCS region in representative members of the different subgenera of betacoronaviruses, highlighting the evolutionary volatility of this site and that the relevant amino acid motif (RRAR) in SARS-CoV-2 is functionally suboptimal. The residues predicted to be O-linked glycans are also marked. See also Document S1.

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References

1. Andersen K.G., Rambaut A., Lipkin W.I., Holmes E.C., Garry R.F. The proximal origin of SARS-CoV-2. Nat. Med. 2020;26:450–452. - PMC - PubMed
1. Bao L., Deng W., Huang B., Gao H., Liu J., Ren L., Wei Q., Yu P., Xu Y., Qi F., et al. The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice. Nature. 2020;583:830–833. - PubMed
1. Belouzard S., Chu V.C., Whittaker G.R. Activation of the SARS coronavirus spike protein via sequential proteolytic cleavage at two distinct sites. Proc. Natl. Acad. Sci. USA. 2009;106:5871–5876. - PMC - PubMed
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1. Boni M.F., Lemey P., Jiang X., Lam T.T.-Y., Perry B.W., Castoe T.A., Rambaut A., Robertson D.L. Evolutionary origins of the SARS-CoV-2 sarbecovirus lineage responsible for the COVID-19 pandemic. Nat. Microbiol. 2020;5:1408–1417. - PubMed

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[1] Andersen K.G., Rambaut A., Lipkin W.I., Holmes E.C., Garry R.F. The proximal origin of SARS-CoV-2. Nat. Med. 2020;26:450–452. - PMC - PubMed

[2] Andersen K.G., Rambaut A., Lipkin W.I., Holmes E.C., Garry R.F. The proximal origin of SARS-CoV-2. Nat. Med. 2020;26:450–452. - PMC - PubMed

[3] Bao L., Deng W., Huang B., Gao H., Liu J., Ren L., Wei Q., Yu P., Xu Y., Qi F., et al. The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice. Nature. 2020;583:830–833. - PubMed

[4] Bao L., Deng W., Huang B., Gao H., Liu J., Ren L., Wei Q., Yu P., Xu Y., Qi F., et al. The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice. Nature. 2020;583:830–833. - PubMed

[5] Belouzard S., Chu V.C., Whittaker G.R. Activation of the SARS coronavirus spike protein via sequential proteolytic cleavage at two distinct sites. Proc. Natl. Acad. Sci. USA. 2009;106:5871–5876. - PMC - PubMed

[6] Belouzard S., Chu V.C., Whittaker G.R. Activation of the SARS coronavirus spike protein via sequential proteolytic cleavage at two distinct sites. Proc. Natl. Acad. Sci. USA. 2009;106:5871–5876. - PMC - PubMed

[7] Blow J.A., Dohm D.J., Negley D.L., Mores C.N. Virus inactivation by nucleic acid extraction reagents. J. Virol. Methods. 2004;119:195–198. - PubMed

[8] Blow J.A., Dohm D.J., Negley D.L., Mores C.N. Virus inactivation by nucleic acid extraction reagents. J. Virol. Methods. 2004;119:195–198. - PubMed

[9] Boni M.F., Lemey P., Jiang X., Lam T.T.-Y., Perry B.W., Castoe T.A., Rambaut A., Robertson D.L. Evolutionary origins of the SARS-CoV-2 sarbecovirus lineage responsible for the COVID-19 pandemic. Nat. Microbiol. 2020;5:1408–1417. - PubMed

[10] Boni M.F., Lemey P., Jiang X., Lam T.T.-Y., Perry B.W., Castoe T.A., Rambaut A., Robertson D.L. Evolutionary origins of the SARS-CoV-2 sarbecovirus lineage responsible for the COVID-19 pandemic. Nat. Microbiol. 2020;5:1408–1417. - PubMed

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The origins of SARS-CoV-2: A critical review

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The origins of SARS-CoV-2: A critical review

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