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1. nature
2. nature medicine
3. correspondence
4. article

The proximal origin of SARS-CoV-2
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* Correspondence
* Published: 17 March 2020

THE PROXIMAL ORIGIN OF SARS-COV-2

* Kristian G. Andersen1,2,
* Andrew Rambaut ORCID: orcid.org/0000-0003-4337-37073,
* W. Ian Lipkin4,
* Edward C. Holmes ORCID: orcid.org/0000-0001-9596-35525 &
* …
* Robert F. Garry6,7

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Nature Medicine volume 26, pages 450–452 (2020)Cite this article

* 5.88m Accesses

* 2887 Citations

* 35131 Altmetric

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To the Editor — Since the first reports of novel pneumonia (COVID-19) in Wuhan,
Hubei province, China1,2, there has been considerable discussion on the origin
of the causative virus, SARS-CoV-23 (also referred to as HCoV-19)4. Infections
with SARS-CoV-2 are now widespread, and as of 11 March 2020, 121,564 cases have
been confirmed in more than 110 countries, with 4,373 deaths5.

SARS-CoV-2 is the seventh coronavirus known to infect humans; SARS-CoV, MERS-CoV
and SARS-CoV-2 can cause severe disease, whereas HKU1, NL63, OC43 and 229E are
associated with mild symptoms6. Here we review what can be deduced about the
origin of SARS-CoV-2 from comparative analysis of genomic data. We offer a
perspective on the notable features of the SARS-CoV-2 genome and discuss
scenarios by which they could have arisen. Our analyses clearly show that
SARS-CoV-2 is not a laboratory construct or a purposefully manipulated virus.

NOTABLE FEATURES OF THE SARS-COV-2 GENOME

Our comparison of alpha- and betacoronaviruses identifies two notable genomic
features of SARS-CoV-2: (i) on the basis of structural studies7,8,9 and
biochemical experiments1,9,10, SARS-CoV-2 appears to be optimized for binding to
the human receptor ACE2; and (ii) the spike protein of SARS-CoV-2 has a
functional polybasic (furin) cleavage site at the S1–S2 boundary through the
insertion of 12 nucleotides8, which additionally led to the predicted
acquisition of three O-linked glycans around the site.

1. MUTATIONS IN THE RECEPTOR-BINDING DOMAIN OF SARS-COV-2

The receptor-binding domain (RBD) in the spike protein is the most variable part
of the coronavirus genome1,2. Six RBD amino acids have been shown to be critical
for binding to ACE2 receptors and for determining the host range of
SARS-CoV-like viruses7. With coordinates based on SARS-CoV, they are Y442, L472,
N479, D480, T487 and Y4911, which correspond to L455, F486, Q493, S494, N501 and
Y505 in SARS-CoV-27. Five of these six residues differ between SARS-CoV-2 and
SARS-CoV (Fig. 1a). On the basis of structural studies7,8,9 and biochemical
experiments1,9,10, SARS-CoV-2 seems to have an RBD that binds with high affinity
to ACE2 from humans, ferrets, cats and other species with high receptor
homology7.

Fig. 1: Features of the spike protein in human SARS-CoV-2 and related
coronaviruses.

a, Mutations in contact residues of the SARS-CoV-2 spike protein. The spike
protein of SARS-CoV-2 (red bar at top) was aligned against the most closely
related SARS-CoV-like coronaviruses and SARS-CoV itself. Key residues in the
spike protein that make contact to the ACE2 receptor are marked with blue boxes
in both SARS-CoV-2 and related viruses, including SARS-CoV (Urbani strain). b,
Acquisition of polybasic cleavage site and O-linked glycans. Both the polybasic
cleavage site and the three adjacent predicted O-linked glycans are unique to
SARS-CoV-2 and were not previously seen in lineage B betacoronaviruses.
Sequences shown are from NCBI GenBank, accession codes MN908947, MN996532,
AY278741, KY417146 and MK211376. The pangolin coronavirus sequences are a
consensus generated from SRR10168377 and SRR10168378 (NCBI BioProject
PRJNA573298)29,30.

Full size image

While the analyses above suggest that SARS-CoV-2 may bind human ACE2 with high
affinity, computational analyses predict that the interaction is not ideal7 and
that the RBD sequence is different from those shown in SARS-CoV to be optimal
for receptor binding7,11. Thus, the high-affinity binding of the SARS-CoV-2
spike protein to human ACE2 is most likely the result of natural selection on a
human or human-like ACE2 that permits another optimal binding solution to arise.
This is strong evidence that SARS-CoV-2 is not the product of purposeful
manipulation.

2. POLYBASIC FURIN CLEAVAGE SITE AND O-LINKED GLYCANS

The second notable feature of SARS-CoV-2 is a polybasic cleavage site (RRAR) at
the junction of S1 and S2, the two subunits of the spike8 (Fig. 1b). This allows
effective cleavage by furin and other proteases and has a role in determining
viral infectivity and host range12. In addition, a leading proline is also
inserted at this site in SARS-CoV-2; thus, the inserted sequence is PRRA (Fig.
1b). The turn created by the proline is predicted to result in the addition of
O-linked glycans to S673, T678 and S686, which flank the cleavage site and are
unique to SARS-CoV-2 (Fig. 1b). Polybasic cleavage sites have not been observed
in related ‘lineage B’ betacoronaviruses, although other human
betacoronaviruses, including HKU1 (lineage A), have those sites and predicted
O-linked glycans13. Given the level of genetic variation in the spike, it is
likely that SARS-CoV-2-like viruses with partial or full polybasic cleavage
sites will be discovered in other species.

The functional consequence of the polybasic cleavage site in SARS-CoV-2 is
unknown, and it will be important to determine its impact on transmissibility
and pathogenesis in animal models. Experiments with SARS-CoV have shown that
insertion of a furin cleavage site at the S1–S2 junction enhances cell–cell
fusion without affecting viral entry14. In addition, efficient cleavage of the
MERS-CoV spike enables MERS-like coronaviruses from bats to infect human
cells15. In avian influenza viruses, rapid replication and transmission in
highly dense chicken populations selects for the acquisition of polybasic
cleavage sites in the hemagglutinin (HA) protein16, which serves a function
similar to that of the coronavirus spike protein. Acquisition of polybasic
cleavage sites in HA, by insertion or recombination, converts low-pathogenicity
avian influenza viruses into highly pathogenic forms16. The acquisition of
polybasic cleavage sites by HA has also been observed after repeated passage in
cell culture or through animals17.

The function of the predicted O-linked glycans is unclear, but they could create
a ‘mucin-like domain’ that shields epitopes or key residues on the SARS-CoV-2
spike protein18. Several viruses utilize mucin-like domains as glycan shields
involved immunoevasion18. Although prediction of O-linked glycosylation is
robust, experimental studies are needed to determine if these sites are used in
SARS-CoV-2.

THEORIES OF SARS-COV-2 ORIGINS

It is improbable that SARS-CoV-2 emerged through laboratory manipulation of a
related SARS-CoV-like coronavirus. As noted above, the RBD of SARS-CoV-2 is
optimized for binding to human ACE2 with an efficient solution different from
those previously predicted7,11. Furthermore, if genetic manipulation had been
performed, one of the several reverse-genetic systems available for
betacoronaviruses would probably have been used19. However, the genetic data
irrefutably show that SARS-CoV-2 is not derived from any previously used virus
backbone20. Instead, we propose two scenarios that can plausibly explain the
origin of SARS-CoV-2: (i) natural selection in an animal host before zoonotic
transfer; and (ii) natural selection in humans following zoonotic transfer. We
also discuss whether selection during passage could have given rise to
SARS-CoV-2.

1. NATURAL SELECTION IN AN ANIMAL HOST BEFORE ZOONOTIC TRANSFER

As many early cases of COVID-19 were linked to the Huanan market in Wuhan1,2, it
is possible that an animal source was present at this location. Given the
similarity of SARS-CoV-2 to bat SARS-CoV-like coronaviruses2, it is likely that
bats serve as reservoir hosts for its progenitor. Although RaTG13, sampled from
a Rhinolophus affinis bat1, is ~96% identical overall to SARS-CoV-2, its spike
diverges in the RBD, which suggests that it may not bind efficiently to human
ACE27 (Fig. 1a).

Malayan pangolins (Manis javanica) illegally imported into Guangdong province
contain coronaviruses similar to SARS-CoV-221. Although the RaTG13 bat virus
remains the closest to SARS-CoV-2 across the genome1, some pangolin
coronaviruses exhibit strong similarity to SARS-CoV-2 in the RBD, including all
six key RBD residues21 (Fig. 1). This clearly shows that the SARS-CoV-2 spike
protein optimized for binding to human-like ACE2 is the result of natural
selection.

Neither the bat betacoronaviruses nor the pangolin betacoronaviruses sampled
thus far have polybasic cleavage sites. Although no animal coronavirus has been
identified that is sufficiently similar to have served as the direct progenitor
of SARS-CoV-2, the diversity of coronaviruses in bats and other species is
massively undersampled. Mutations, insertions and deletions can occur near the
S1–S2 junction of coronaviruses22, which shows that the polybasic cleavage site
can arise by a natural evolutionary process. For a precursor virus to acquire
both the polybasic cleavage site and mutations in the spike protein suitable for
binding to human ACE2, an animal host would probably have to have a high
population density (to allow natural selection to proceed efficiently) and an
ACE2-encoding gene that is similar to the human ortholog.

2. NATURAL SELECTION IN HUMANS FOLLOWING ZOONOTIC TRANSFER

It is possible that a progenitor of SARS-CoV-2 jumped into humans, acquiring the
genomic features described above through adaptation during undetected
human-to-human transmission. Once acquired, these adaptations would enable the
pandemic to take off and produce a sufficiently large cluster of cases to
trigger the surveillance system that detected it1,2.

All SARS-CoV-2 genomes sequenced so far have the genomic features described
above and are thus derived from a common ancestor that had them too. The
presence in pangolins of an RBD very similar to that of SARS-CoV-2 means that we
can infer this was also probably in the virus that jumped to humans. This leaves
the insertion of polybasic cleavage site to occur during human-to-human
transmission.

Estimates of the timing of the most recent common ancestor of SARS-CoV-2 made
with current sequence data point to emergence of the virus in late November 2019
to early December 201923, compatible with the earliest retrospectively confirmed
cases24. Hence, this scenario presumes a period of unrecognized transmission in
humans between the initial zoonotic event and the acquisition of the polybasic
cleavage site. Sufficient opportunity could have arisen if there had been many
prior zoonotic events that produced short chains of human-to-human transmission
over an extended period. This is essentially the situation for MERS-CoV, for
which all human cases are the result of repeated jumps of the virus from
dromedary camels, producing single infections or short transmission chains that
eventually resolve, with no adaptation to sustained transmission25.

Studies of banked human samples could provide information on whether such
cryptic spread has occurred. Retrospective serological studies could also be
informative, and a few such studies have been conducted showing low-level
exposures to SARS-CoV-like coronaviruses in certain areas of China26.
Critically, however, these studies could not have distinguished whether
exposures were due to prior infections with SARS-CoV, SARS-CoV-2 or other
SARS-CoV-like coronaviruses. Further serological studies should be conducted to
determine the extent of prior human exposure to SARS-CoV-2.

3. SELECTION DURING PASSAGE

Basic research involving passage of bat SARS-CoV-like coronaviruses in cell
culture and/or animal models has been ongoing for many years in biosafety level
2 laboratories across the world27, and there are documented instances of
laboratory escapes of SARS-CoV28. We must therefore examine the possibility of
an inadvertent laboratory release of SARS-CoV-2.

In theory, it is possible that SARS-CoV-2 acquired RBD mutations (Fig. 1a)
during adaptation to passage in cell culture, as has been observed in studies of
SARS-CoV11. The finding of SARS-CoV-like coronaviruses from pangolins with
nearly identical RBDs, however, provides a much stronger and more parsimonious
explanation of how SARS-CoV-2 acquired these via recombination or mutation19.

The acquisition of both the polybasic cleavage site and predicted O-linked
glycans also argues against culture-based scenarios. New polybasic cleavage
sites have been observed only after prolonged passage of low-pathogenicity avian
influenza virus in vitro or in vivo17. Furthermore, a hypothetical generation of
SARS-CoV-2 by cell culture or animal passage would have required prior isolation
of a progenitor virus with very high genetic similarity, which has not been
described. Subsequent generation of a polybasic cleavage site would have then
required repeated passage in cell culture or animals with ACE2 receptors similar
to those of humans, but such work has also not previously been described.
Finally, the generation of the predicted O-linked glycans is also unlikely to
have occurred due to cell-culture passage, as such features suggest the
involvement of an immune system18.

CONCLUSIONS

In the midst of the global COVID-19 public-health emergency, it is reasonable to
wonder why the origins of the pandemic matter. Detailed understanding of how an
animal virus jumped species boundaries to infect humans so productively will
help in the prevention of future zoonotic events. For example, if SARS-CoV-2
pre-adapted in another animal species, then there is the risk of future
re-emergence events. In contrast, if the adaptive process occurred in humans,
then even if repeated zoonotic transfers occur, they are unlikely to take off
without the same series of mutations. In addition, identifying the closest viral
relatives of SARS-CoV-2 circulating in animals will greatly assist studies of
viral function. Indeed, the availability of the RaTG13 bat sequence helped
reveal key RBD mutations and the polybasic cleavage site.

The genomic features described here may explain in part the infectiousness and
transmissibility of SARS-CoV-2 in humans. Although the evidence shows that
SARS-CoV-2 is not a purposefully manipulated virus, it is currently impossible
to prove or disprove the other theories of its origin described here. However,
since we observed all notable SARS-CoV-2 features, including the optimized RBD
and polybasic cleavage site, in related coronaviruses in nature, we do not
believe that any type of laboratory-based scenario is plausible.

More scientific data could swing the balance of evidence to favor one hypothesis
over another. Obtaining related viral sequences from animal sources would be the
most definitive way of revealing viral origins. For example, a future
observation of an intermediate or fully formed polybasic cleavage site in a
SARS-CoV-2-like virus from animals would lend even further support to the
natural-selection hypotheses. It would also be helpful to obtain more genetic
and functional data about SARS-CoV-2, including animal studies. The
identification of a potential intermediate host of SARS-CoV-2, as well as
sequencing of the virus from very early cases, would similarly be highly
informative. Irrespective of the exact mechanisms by which SARS-CoV-2 originated
via natural selection, the ongoing surveillance of pneumonia in humans and other
animals is clearly of utmost importance.

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Download references

ACKNOWLEDGEMENTS

We thank all those who have contributed sequences to the GISAID database
(https://www.gisaid.org/) and analyses to Virological.org
(http://virological.org/). We thank M. Farzan for discussions, and the Wellcome
Trust for support. K.G.A. is a Pew Biomedical Scholar and is supported by NIH
grant U19AI135995. A.R. is supported by the Wellcome Trust (Collaborators Award
206298/Z/17/Z―ARTIC network) and the European Research Council (grant agreement
no. 725422―ReservoirDOCS). E.C.H. is supported by an ARC Australian Laureate
Fellowship (FL170100022). R.F.G. is supported by NIH grants U19AI135995, U54
HG007480 and U19AI142790.

AUTHOR INFORMATION

AUTHORS AND AFFILIATIONS

1. Department of Immunology and Microbiology, The Scripps Research Institute,
La Jolla, CA, USA

Kristian G. Andersen

2. Scripps Research Translational Institute, La Jolla, CA, USA

Kristian G. Andersen

3. Institute of Evolutionary Biology, University of Edinburgh, Edinburgh, UK

Andrew Rambaut

4. Center for Infection and Immunity, Mailman School of Public Health of
Columbia University, New York, NY, USA

W. Ian Lipkin

5. Marie Bashir Institute for Infectious Diseases and Biosecurity, School of
Life and Environmental Sciences and School of Medical Sciences, The
University of Sydney, Sydney, Australia

Edward C. Holmes

6. Tulane University, School of Medicine, Department of Microbiology and
Immunology, New Orleans, LA, USA

Robert F. Garry

7. Zalgen Labs, Germantown, MD, USA

Robert F. Garry

Authors
1. Kristian G. Andersen
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2. Andrew Rambaut
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3. W. Ian Lipkin
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4. Edward C. Holmes
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5. Robert F. Garry
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CORRESPONDING AUTHOR

Correspondence to Kristian G. Andersen.

ETHICS DECLARATIONS

COMPETING INTERESTS

R.F.G. is co-founder of Zalgen Labs, a biotechnology company that develops
countermeasures to emerging viruses.

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Andersen, K.G., Rambaut, A., Lipkin, W.I. et al. The proximal origin of
SARS-CoV-2. Nat Med 26, 450–452 (2020).
https://doi.org/10.1038/s41591-020-0820-9

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* DOI: https://doi.org/10.1038/s41591-020-0820-9

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* Notable features of the SARS-CoV-2 genome
* Theories of SARS-CoV-2 origins
* Conclusions
* References
* Acknowledgements
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* Fig. 1: Features of the spike protein in human SARS-CoV-2 and related
coronaviruses.

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