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El Origen Del Covid19
El Origen Del Covid19
Commentary
The ongoing pandemic of a new human coronavirus, SARS-CoV-2, has generated enormous global
concern. We and others in China were involved in the initial genome sequencing of the virus. Herein,
we describe what genomic data reveal about the emergence SARS-CoV-2 and discuss the gaps in
our understanding of its origins.
A New Human Coronavirus An important early association was toms (Wu et al., 2020). This patient was
The first reports of a novel pneumonia observed between the first reported cases experiencing fever, chest tightness,
(COVID-19) in Wuhan city, Hubei prov- of COVID-19 and the Huanan seafood and cough, pain, and weakness, along with
ince, China, occurred in late December wildlife market in Wuhan city (which we lung abnormalities indicative of pneu-
2019, although retrospective analyses both visited several years ago) where a va- monia that appear to be commonplace
have identified a patient with symptom riety of mammalian species were available in COVID-19 (Huang et al., 2020). Fortu-
onset as early as December 1st. Because for purchase at the time of the outbreak nately, next-generation meta-transcrip-
the number of SARS-CoV-2 cases is (Figure 1). Given that SARS-CoV-2 un- tomic sequencing enabled us to obtain a
growing rapidly and spreading globally, doubtedly has a zoonotic origin, the link complete viral genome from this patient
we will refrain from citing the number of to such a ‘‘wet’’ market should come as on January 5, 2020. Initial analysis re-
confirmed infections. However, it is likely no surprise. However, as not all of the early vealed that the virus was closely related
that the true number of cases will be sub- cases were market associated, it is to those of SARS-like viruses (family Co-
stantially greater than reported because possible that the emergence story is ronaviridae). This result was immediately
very mild or asymptomatic infections will more complicated than first suspected. reported to the relevant authorities, and
often be excluded from counts. Any un- Genome sequences of ‘‘environmental an annotated version of the genome
der-reporting of case numbers obviously samples’’—likely surfaces—from the mar- sequence (strain Wuhan-Hu-1) was sub-
means that the case fatality rate (CFR) ket have now been obtained, and phylo- mitted to NCBI/GenBank on the same
associated with COVID-19 in the worst- genetic analysis reveals that they are day. Although the GenBank sequence
hit regions will be lower than that currently very closely related to viruses sampled (GenBank: MN908947) was the first of
cited. CFRs will also vary geographically, from the earliest Wuhan patients. While SARS-CoV-2 available, it was subse-
between age groups and temporally. this again suggests that the market played quently corrected to ensure its accuracy.
Although these uncertainties will likely an important role in virus emergence, it is With the help of Dr. Andrew Rambaut
not be resolved without large-scale sero- not clear whether the samples were (University of Edinburgh), we released
logical surveys, from current data it is derived from people who inadvertently the genome sequence of the virus on the
clear that the CFR for COVID-19 is sub- deposited infectious material or from ani- open access Virological website (http://
stantially higher than that of seasonal mals or animal matter present at that loca- virological.org/) early on January 11,
influenza but lower than that of two tion. Unfortunately, the apparent lack of 2020. Afterwards, the China CDC similarly
closely related coronaviruses that have direct animal sampling in the market may released SARS-CoV-2 genome se-
similarly recently emerged in humans: mean that it will be difficult, perhaps quences (with associated epidemiolog-
SARS-CoV, responsible for the SARS even impossible, to accurately identify ical data) on the public access GISAID
outbreak of 2002–2003, and MERS-CoV any animal reservoir at this location. database (https://www.gisaid.org/). At
that since 2015 has been responsible for After clinical cases began to appear, the time of writing, almost 200 SARS-
the ongoing outbreak of MERS largely our research team, along with a number CoV-2 genomes are publicly available,
centered on the Arabian peninsula. How- of others, attempted to determine the representing the genomic diversity of the
ever, it is also evident that SARS-CoV-2 genome sequence of the causative path- virus in China and beyond and providing
is more infectious than both SARS-CoV ogen (Lu et al., 2020; Wu et al., 2020; a freely accessible global resource.
and MERS-CoV and that individuals can Zhou et al., 2020; Zhu et al., 2020). We Importantly, the release of the SARS-
transmit the virus when asymptomatic or focused on a patient admitted to the Cen- CoV-2 genome sequence data facilitated
presymptomatic, although how frequently tral Hospital of Wuhan on December 26, the rapid development of diagnostic tests
remains uncertain. 2019, six days after the onset of symp- (Corman et al., 2020) and now an
infectious clone (Thao et al., 2020). The of other betacoronaviruses, with the present in other human coronaviruses,
race to develop an effective vaccine and gene order 50 -replicase ORF1ab-S-enve- including HCoV-HKU1, as well as in highly
antivirals is ongoing, with trails of the latter lope(E)-membrane(M)-N-30 . The long repli- pathogenic strains of avian influenza virus.
underway (Wang et al., 2020). case ORF1ab gene of SARS-CoV-2 is over In addition, the receptor binding domain
21 kb in length and contains 16 predicted (RBD) of SARS-CoV-2 and RaTG13 are
Comparisons between SARS-CoV-2 non-structural proteins and a number of only 85% similar and share just one of
and Other Coronaviruses downstream open reading frames (ORFs) six critical amino acid residues. Both
The earliest genomic genome sequence likely of similar function to those of SARS- sequence and structural comparisons sug-
data made it clear that SARS-CoV-2 was CoV. Comparative genomic analysis has gest that the SARS-CoV-2 RBD is well
a member of the genus Betacoronavirus been greatly assisted by the availability of suited for binding to the human ACE2 re-
and fell within a subgenus (Sarbecovirus) a related virus from a Rhinolophus affinis ceptor that was also utilized by SARS-
that includes SARS-CoV (MERS-CoV falls (i.e., horseshoe) bat sampled in Yunnan CoV (Wrapp et al., 2020). Importantly, an in-
in a separate subgenus, Merbecovirus) province, China, in 2013 (Zhou et al., dependent insertion(s) of the amino acids
(Lu et al., 2020; Wu et al., 2020; Zhou 2020). This virus, denoted RaTG13, is PAA at the S1/S2 cleavage site was
et al., 2020; Zhu et al., 2020). Indeed, 96% similar to SARS-CoV-2 at the nucle- recently observed in a virus (RmYN02)
initial comparisons revealed that SARS- otide sequence level. Despite this sampled in mid-2019 from another Rhino-
CoV-2 was approximately 79% similar to sequence similarity, SARS-CoV-2 and lophus bat in Yunnan province, indicating
SARS-CoV at the nucleotide level. Of RaTG13 differ in a number of key genomic that these insertion events reflect a natural
course, patterns of similarity vary greatly features, arguably the most important of part of ongoing coronavirus evolution
between genes, and SARS-CoV and which is that SARS-CoV-2 contains a poly- (Zhou et al., 2020). While RmYN02 is rela-
SARS-CoV-2 exhibit only 72% nucleo- basic (furin) cleavage site insertion (resi- tively divergent from SARS-CoV-2 in the S
tide sequence similarity in the spike (S) dues PRRA) at the junction of the S1 and protein (72% sequence similarity), it is
protein, the key surface glycoprotein that S2 subunits of the S protein (Coutard the closest relative (97% nucleotide
interacts with host cell receptors. et al., 2020). This insertion, which may sequence similarity) of the human virus in
Given these close evolutionary relation- increase the infectivity of the virus, is not the long replicase gene.
ships, it is unsurprising that the genome present in related betacoronaviruses, Although SARS-CoV and MERS-CoV
structure of SARS-CoV-2 resembles those although similar polybasic insertions are are both closely related to SARS-CoV-2
mine using genomic comparisons alone ruses possess this capacity in comparison Grubaugh, N.D., Petrone, M.E., and Holmes, E.C.
whether the virus is fixing phenotypically to some other RNA viruses is unclear. Crit- (2020). We shouldn’t worry when a virus mutates
during disease outbreaks. Nat Microbiol. Pub-
important mutations as it spreads through ically, the surveillance of animal coronavi-
lished online February 18, 2020. https://doi.org/
the global population, and any such ruses should include animals other than 10.1038/s41564-020-0690-4.
claims require careful experimental verifi- bats, as the role of intermediate hosts is
Holmes, E.C., Dudas, G., Rambaut, A., and Ander-
cation. likely of major importance, providing a sen, K.G. (2016). The evolution of Ebola virus: In-
Given the high mutation rates that char- more direct pathway for the virus to sights from the 2013-2016 epidemic. Nature 538,
acterize RNA viruses, it is obvious that emerge in humans. Given the enormous 193–200.
many more mutations will appear in the diversity of viruses in wildlife and their Hu, B., Zeng, L.P., Yang, X.L., Ge, X.Y., Zhang, W.,
viral genome and that these will help us ongoing evolution, arguably the simplest Li, B., Xie, J.Z., Shen, X.R., Zhang, Y.Z., Wang, N.,
to track the spread of SARS-CoV-2 (Gru- and most cost-effective way to reduce et al. (2017). Discovery of a rich gene pool of bat
baugh et al., 2019). However, as the the risk of future outbreaks is to limit our SARS-related coronaviruses provides new insights
into the origin of SARS coronavirus. PLoS Pathog.
epidemic grows, our sample size of se- exposure to animal pathogens as much
13, e1006698.
quences will likely be so small relative to as possible. While our intimate relation-
Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu,
the total number of cases that it will be ship with the animal world means we
Y., Zhang, L., Fan, G., Xu, J., Gu, X., et al. (2020).
very difficult, if not impossible, to detect cannot build impregnable barriers, stron- Clinical features of patients infected with 2019
individual transmission chains. Caution ger action against the illegal wildlife trade novel coronavirus in Wuhan, China. Lancet 395,
must therefore always be exercised and removing all mammalian (and perhaps 497–506.
when attempting to infer exact transmis- avian) wildlife from wet markets will pro- Lam, T.T.-Y., Shum, M.H.-H., Zhu, H.-C., Tong,
sion events. As an aside, although coro- vide an important buffer. Y.-G., Ni, X.-B., Liao, Y.-S., Wei, W., Cheung,
naviruses likely have lower mutation rates W.Y.-M., Li, W.-J., Li, L.-F., et al. (2020). Identifi-
than other RNA viruses because of an ACKNOWLEDGMENTS cation of 2019-nCoV related coronaviruses in
Malayan pangolins in southern China. bioRxiv.
inherent capacity for some proof-reading
https://doi.org/10.1101/2020.02.13.945485.
activity due to a 30 -to-50 exoribonuclease This work was funded by the National Natural Sci-
ence Foundation of China (grants 81861138003 Lin, X.-D., Wang, W., Hao, Z.-Y., Wang, Z.-X., Guo,
(Minskaia et al., 2006), their long-term
and 31930001), the Special National Project on W.-P., Guan, X.-Q., Wang, M.-R., Wang, H.-W.,
rates of nucleotide substitution (i.e., of investigation of basic resources of China (grant Zhou, R.-H., Li, M.-H., et al. (2017). Extensive di-
molecular evolution) fall within the distri- 2019FY101500), and the Australian Research versity of coronaviruses in bats from China.
bution of those seen in other RNA viruses Council (grant FL170100022). Virology 507, 1–10.