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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 Holmes  1 , Stephen A Goldstein  2 , Angela L Rasmussen  3 , David L Robertson  4 , Alexander Crits-Christoph  5 , Joel O Wertheim  6 , Simon J Anthony  7 , Wendy S Barclay  8 , Maciej F Boni  9 , Peter C Doherty  10 , Jeremy Farrar  11 , Jemma L Geoghegan  12 , Xiaowei Jiang  13 , Julian L Leibowitz  14 , Stuart J D Neil  15 , Tim Skern  16 , Susan R Weiss  17 , Michael Worobey  18 , Kristian G Andersen  19 , Robert F Garry  20 , Andrew Rambaut  21
Affiliations
Review

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

Edward C Holmes et al. Cell. .

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
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
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

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