Identification of diverse alphacoronaviruses and genomic characterization of a novel severe acute respiratory syndrome-like coronavirus from bats in China. Isolation of SARS-CoV-2-related coronavirus from Malayan pangolins. Viruses 11, 174 (2019). Nature 583, 282285 (2020). Google Scholar. One study suggests that over a century ago, one lineage of coronavirus circulating in bats gave rise to SARS-CoV-2, RaTG13 and a Pangolin coronavirus known as Pangolin-2019, Live Science . A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence. 68, 10521061 (2019). Concatenated region ABC is NRR1. Results and discussion Genomic surveillance has been a hallmark of the COVID-19 pandemic that, in contrast to other pandemics, achieves tracking of the virus evolution and spread worldwide almost in real-time ( 4 ). Biol. Slider with three articles shown per slide. Accurate estimation of ages for deeper nodes would require adequate accommodation of time-dependent rate variation. Zhang, Y.-Z. Zhou et al.2 concluded from the genetic proximity of SARS-CoV-2 to RaTG13 that a bat origin for the current COVID-19 outbreak is probable. Calibration of priors can be performed using other coronaviruses (SARS-CoV, MERS-CoV and HCoV-OC43), but estimated rates vary with the timescale of sample collection. 13, e1006698 (2017). performed Srecombination analysis. Article SARS-CoV-2 is an appropriate name for the new coronavirus. We extracted a total of 2189 full-length SARS-CoV-2 viral genomes from various states of India from the EpiCov repository of the GISAID initiative on 12 June 2020. Genetics 172, 26652681 (2006). Uncertainty measures are shown in Extended Data Fig. Instead, similarity in codon usage metrics between the SARS-CoV-2 and eukaryotes analyzed was correlated with coding sequence GC content of the eukaryote, with more similar codon usage being identified in eukaryotes with low GC content similar to that of the coronavirus (b). However, formal testing using marginal likelihood estimation41 does provide some evidence of a temporal signal, albeit with limited log Bayes factor support of 3 (NRR1), 10 (NRR2) and 3 (NRA3); see Supplementary Table 1. At present, we analyzed the diversity of SARS-CoV-2 viral genomes in India to know the evolutionary patterns of viruses in the country through their pangolin lineage and GISAID-Clade. Indeed, the rates reported by these studies are in line with the short-term SARS rates that we estimate (Fig. master 4 branches 94 tags Code AngieHinrichs Add entries for pangolin-data/-assignment 1.18.1.1 ( #512) ad16752 4 days ago 990 commits .github/ workflows Update pangolin.yml 7 months ago docs docs need guide tree now 3 years ago pangolin While there is involvement of other mammalian speciesspecifically pangolins for SARS-CoV-2as a plausible conduit for transmission to humans, there is no evidence that pangolins are facilitating adaptation to humans. Conservatively, we combined the three BFRs >2kb identified above into non-recombining region1 (NRR1). Wong, A. C. P., Li, X., Lau, S. K. P. & Woo, P. C. Y. Yres, D. L. et al. =0.00025. This is notable because the variable-loop region contains the six key contact residues in the RBD that give SARS-CoV-2 its ACE2-binding specificity27,37. (Yes, Pango is a tongue-in-cheek reference to pangolins, which were briefly suspected to have had a role in the coronavirus's originseveral of the team's computational tools are named after. M.F.B., P.L. J. Med. In light of these time-dependent evolutionary rate dynamics, a slower rate is appropriate for calibration of the sarbecovirus evolutionary history. Evol. It allows a user to assign a SARS-CoV-2 genome sequence the most likely lineage (Pango lineage) to SARS-CoV-2 query sequences. https://doi.org/10.1038/s41564-020-0771-4, DOI: https://doi.org/10.1038/s41564-020-0771-4. Specifically, using a formal Bayesian approach42 (see Methods), we estimate a fast evolutionary rate (0.00169 substitutions per siteyr1, 95% highest posterior density (HPD) interval (0.00131,0.00205)) for SARS viruses sampled over a limited timescale (1year), a slower rate (0.00078 (0.00063,0.00092) substitutions per siteyr1) for MERS-CoV on a timescale of about 4years and the slowest rate (0.00024 (0.00019,0.00029) substitutions per siteyr1) for HCoV-OC43 over almost five decades. The virus then. The coronavirus genome that these researchers had assembled, from pangolin lung-tissue samples, contained some gene regions that were ninety-nine per cent similar to equivalent parts of the SARS . MERS-CoV data were subsampled to match sample sizes with SARS-CoV and HCoV-OC43. It is available as a command line tool and a web application. Robertson, D. nCoVs relationship to bat coronaviruses & recombination signals (no snakes) no evidence the 2019-nCoV lineage is recombinant. EPI_ISL_410538, EPI_ISL_410539, EPI_ISL_410540, EPI_ISL_410541 and EPI_ISL_410542) for the use of sequence data via the GISAID platform. Regions AC were further examined for mosaic signals by 3SEQ, and all showed signs of mosaicism. pango-designation Public Repository for suggesting new lineages that should be added to the current scheme Python 968 73 pangolin Public Software package for assigning SARS-CoV-2 genome sequences to global lineages. Software package for assigning SARS-CoV-2 genome sequences to global lineages. Even before the COVID-19 pandemic, pangolins have been making headlines. Over relatively shallow timescales, such differences can primarily be explained by varying selective pressure, with mildly deleterious variants being eliminated more strongly by purifying selection over longer timescales44,45,46. Published. We find that the sarbecovirusesthe viral subgenus containing SARS-CoV and SARS-CoV-2undergo frequent recombination and exhibit spatially structured genetic diversity on a regional scale in China. PubMed Central Nat. 1 Phylogenetic relationships in the C-terminal domain (CTD). The presence of SARS-CoV-2-related viruses in Malayan pangolins, in silico analysis of the ACE2 receptor polymorphism and sequence similarities between the Receptor Binding Domain (RBD) of the spike proteins of pangolin and human Sarbecoviruses led to the proposal of pangolin as intermediary. In other words, a true breakpoint is less likely to be called as such (this is breakpoint-conservative), and thus the construction of a non-recombining region may contain true recombination breakpoints (with insufficient evidence to call them as such). This statement informs us of the possibility that a virus has spilled over from a very rare and shy reptile-looking mammal . Trends Microbiol. Two exceptions can be seen in the relatively close relationship of Hong Kong viruses to those from Zhejiang Province (with two of the latter, CoVZC45 and CoVZXC21, identified as recombinants) and a recombinant virus from Sichuan for which part of the genome (regionB of SC2018 in Fig. 6, eabb9153 (2020). Based on the identified breakpoints in each genome, only the major non-recombinant region is kept in each genome while other regions are masked. matics program called Pangolin was developed. The web application was developed by the Centre for Genomic Pathogen Surveillance. wrote the first draft of the manuscript, and all authors contributed to manuscript editing. Lond. Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. 87, 62706282 (2013). The unsampled diversity descended from the SARS-CoV-2/RaTG13 common ancestor forms a clade of bat sarbecoviruses with generalist propertieswith respect to their ability to infect a range of mammalian cellsthat facilitated its jump to humans and may do so again. Microbiol. Maclean, O. Subsequently a bat sarbecovirusRaTG13, sampled from a Rhinolophus affinis horseshoe bat in 2013 in Yunnan Provincewas reported that clusters with SARS-CoV-2 in almost all genomic regions with approximately 96% genome sequence identity2. 3). BEAST inferences made use of the BEAGLE v.3 library68 for efficient likelihood computations. Chernomor, O. et al. Biol. Thank you for visiting nature.com. Are pangolins the intermediate host of the 2019 novel coronavirus (SARS-CoV-2)? Divergence time estimates based on the three regions/alignments where the effects of recombination have been removed. Viruses 11, 979 (2019). Using the most conservative approach (NRR1), the divergence time estimate for SARS-CoV-2 and RaTG13 is 1969 (95% HPD: 19302000), while that between SARS-CoV and its most closely related bat sequence is 1962 (95% HPD: 19321988); see Fig. Are you sure you want to create this branch? Proc. J. Med Virol. Intragenomic rearrangements involving 5-untranslated region segments in SARS-CoV-2, other betacoronaviruses, and alphacoronaviruses, Crystal structure of the CoV-Y domain of SARS-CoV-2 nonstructural protein 3, Association of underlying comorbidities and progression of COVID-19 infection amongst 2586 patients hospitalised in the National Capital Region of India: a retrospective cohort study, Molecular characterization of horse nettle virus A, a new member of subgroup B of the genus Nepovirus, Molecular phylogeny of coronaviruses and host receptors among domestic and close-contact animals reveals subgenome-level conservation, crossover, and divergence. Unfortunately, a response that would achieve containment was not possible. PLoS Pathog. Evolutionary origins of the SARS-CoV-2 sarbecovirus lineage responsible for the COVID-19 pandemic, https://doi.org/10.1038/s41564-020-0771-4. But some theories suggest that pangolins may be the source of the novel coronavirus. We demonstrate that the sarbecoviruses circulating in horseshoe bats have complex recombination histories as reported by others15,20,21,22,23,24,25,26. This boundary appears to be rarely crossed. Anderson, K. G. nCoV-2019 codon usage and reservoir (not snakes v2). GitHub - cov-lineages/pangolin: Software package for assigning SARS-CoV-2 genome sequences to global lineages. Global epidemiology of bat coronaviruses. The fact that they are geographically relatively distant is in agreement with their somewhat distant TMRCA, because the spatial structure suggests that migration between their locations may be uncommon. Despite the SARS-CoV-2 lineages acquisition of residues in its Spike (S) proteins receptor-binding domain (RBD) permitting the use of human ACE2 (ref. In December 2019, a cluster of pneumonia cases epidemiologically linked to an open-air live animal market in the city of Wuhan (Hubei Province), China1,2 led local health officials to issue an epidemiological alert to the Chinese Center for Disease Control and Prevention and the World Health Organizations (WHO) China Country Office. We use three bioinformatic approaches to remove the effects of recombination, and we combine these approaches to identify putative non-recombinant regions that can be used for reliable phylogenetic reconstruction and dating. Pink, green and orange bars show BFRs, with regionA (nt 13,29119,628) showing two trimmed segments yielding regionA (nt13,29114,932, 15,40517,162, 18,00919,628). Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. When the first genome sequence of SARS-CoV-2, Wuhan-Hu-1, was released on 10January 2020 (GMT) on Virological.org by a consortium led by Zhang6, it enabled immediate analyses of its ancestry. We considered (1) the possibility that BFRs could be combined into larger non-recombinant regions and (2) the possibility of further recombination within each BFR. These datasets were subjected to the same recombination masking approach as NRA3 and were characterized by a strong temporal signal (Fig. 5 Comparisons of GC content across taxa. All four of these breakpoints were also identified with the tree-based recombination detection method GARD35. Xiao, K. et al. Among the 68sequences in the aligned sarbecovirus sequence set, 67 show evidence of mosaicism (all DunnSidak-corrected P<4104 and 3SEQ14), indicating involvement in homologous recombination either directly with identifiable parentals or in their deeper shared evolutionary historythat is, due to shared ancestral recombination events. J. Virol. Except for specifying that sequences are linear, all settings were kept to their defaults. The ongoing pandemic spread of a new human coronavirus, SARS-CoV-2, which is associated with severe pneumonia/disease (COVID-19), has resulted in the generation of tens of thousands of virus . RegionB is 5,525nt long. The sizes of the black internal node circles are proportional to the posterior node support. The assumption of long-term purifying selection would imply that coronaviruses are in endemic equilibrium with their natural host species, horseshoe bats, to which they are presumably well adapted. By 2009, however, rapid genomic analysis had become a routine component of outbreak response. N. Engl. Ji, W., Wang, W., Zhao, X., Zai, J. Boni, M. F., de Jong, M. D., van Doorn, H. R. & Holmes, E. C. Guidelines for identifying homologous recombination events in influenza A virus. 27) receptors and its RBD being genetically closer to a pangolin virus than to RaTG13 (refs. Identifying the origins of an emerging pathogen can be critical during the early stages of an outbreak, because it may allow for containment measures to be precisely targeted at a stage when the number of daily new infections is still low. Google Scholar. =0.00075 and one with a mean of 0.00024 and s.d. J. Gen. Virol. In regionA, we removed subregion A1 (ntpositions 3,8724,716 within regionA) and subregion A4 (nt1,6422,113) because both showed PI signals with other subregions of regionA. With horseshoe bats currently the most plausible origin of SARS-CoV-2, it is important to consider that sarbecoviruses circulate in a variety of horseshoe bat species with widely overlapping species ranges57. This underscores the need for a global network of real-time human disease surveillance systems, such as that which identified the unusual cluster of pneumonia in Wuhan in December 2019, with the capacity to rapidly deploy genomic tools and functional studies for pathogen identification and characterization. The lineage B.1 has been the major basal and widespread lineage from the initial SARS-CoV-2 spread and it became the more prevalent lineage in Colombia ( 13 ), while the B.1.111 lineage, first detected in the USA from a sample collected on March 7, 2020 and subsequently in Colombia on March 13, 2020 is currently circulating and mainly represented To examine temporal signal in the sequenced data, we plotted root-to-tip divergence against sampling time using TempEst39 v.1.5.3 based on a maximum likelihood tree. Google Scholar. Maciej F. Boni, Philippe Lemey, Andrew Rambaut or David L. Robertson. Med. The variable-loop region in SARS-CoV-2 shows closer identity to the 2019 pangolin coronavirus sequence than to the RaTG13 bat virus, supported by phylogenetic inference (Fig. 11,12,13,22,28)a signal that suggests recombinationthe divergence patterns in the Sprotein do not show evidence of recombination between the lineage leading to SARS-CoV-2 and known sarbecoviruses. Divergence dates between SARS-CoV-2 and the bat sarbecovirus reservoir were estimated as 1948 (95% highest posterior density (HPD): 18791999), 1969 (95% HPD: 19302000) and 1982 (95% HPD: 19482009), indicating that the lineage giving rise to SARS-CoV-2 has been circulating unnoticed in bats for decades. The histogram allows for the identification of non-recombining regions (NRRs) by revealing regions with no breakpoints. 725422-ReservoirDOCS). Open reading frames are shown above the breakpoint plot, with the variable-loop region indicated in the Sprotein. A hypothesis of snakes as intermediate hosts of SARS-CoV-2 was posited during the early epidemic phase54, but we found no evidence of this55,56; see Extended Data Fig. 3). Mol. NTD, N-terminal domain; CTD, C-terminal domain. Nat Microbiol 5, 14081417 (2020). Originally, PANGOLIN used a maximum-likelihood-based assignment algorithm to assign query SARS-CoV-2 the most likely lineage sequence. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. A., Filip, I., AlQuraishi, M. & Rabadan, R. Recombination and lineage-specific mutations led to the emergence of SARS-CoV-2. The estimated divergence times for the pangolin virus most closely related to the SARS-CoV-2/RaTG13 lineage range from 1851 (17301958) to 1877 (17461986), indicating that these pangolin lineages were acquired from bat viruses divergent to those that gave rise to SARS-CoV-2. Ge, X. et al. performed codon usage analysis. & Holmes, E. C. Recombination in evolutionary genomics. We used an uncorrelated relaxed clock model with log-normal distribution for all datasets, except for the low-diversity SARS data for which we specified a strict molecular clock model. PureBasic 53 13 constellations Public Python 42 17 The difficulty in inferring reliable evolutionary histories for coronaviruses is that their high recombination rate48,49 violates the assumption of standard phylogenetic approaches because different parts of the genome have different histories. Methods Ecol. One geographic clade includes viruses from provinces in southern China (Guangxi, Yunnan, Guizhou and Guangdong), with its major sister clade consisting of viruses from provinces in northern China (Shanxi, Henan, Hebei and Jilin) as well as Hubei Province in central China and Shaanxi Province in northwestern China. Biol. and D.L.R. To gauge the length of time this lineage has circulated in bats, we estimate the time to the most recent common ancestor (TMRCA) of SARS-CoV-2 and RaTG13. Emergence of SARS-CoV-2 through recombination and strong purifying selection. The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. 91, 10581062 (2010). Phylogenetic Assignment of Named Global Outbreak LINeages, The pangolin web app is maintained by the Centre for Genomic Pathogen Surveillance. Zhou, H. et al. PLoS ONE 5, e10434 (2010). 82, 48074811 (2008). 5). Graham, R. L. & Baric, R. S. Recombination, reservoirs, and the modular spike: mechanisms of coronavirus cross-species transmission. Background & objectives: Several phylogenetic classification systems have been devised to trace the viral lineages of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Below, we report divergence time estimates based on the HCoV-OC43-centred rate prior for NRR1, NRR2 and NRA3 and summarize corresponding estimates for the MERS-CoV-centred rate priors in Extended Data Fig. 1. Bayesian evolutionary rate and divergence date estimates were shown to be consistent for these three approaches and for two different prior specifications of evolutionary rates based on HCoV-OC43 and MERS-CoV. Wang, H., Pipes, L. & Nielsen, R. Synonymous mutations and the molecular evolution of SARS-Cov-2 origins. Identifying SARS-CoV-2-related coronaviruses in Malayan pangolins. The Sichuan (SC2018) virus appears to be a recombinant of northern/central and southern viruses, while the two Zhejiang viruses (CoVZXC21 and CoVZC45) appear to carry a recombinant region from southern or central China. Pangolin was developed to implement the dynamic nomenclature of SARS-CoV-2 lineages, known as the Pango nomenclature. Pangolin was developed to implement the dynamic nomenclature of SARS-CoV-2 lineages, known as the Pango nomenclature. Decimal years are shown on the x axis for the 1.2 years of SARS sampling in c. d, Mean evolutionary rate estimates plotted against sampling time range for the same three datasets (represented by the same colour as the data points in their respective RtT divergence plots), as well as for the comparable NRA3 using the two different priors for the rate in the Bayesian inference (red points). Without better sampling, however, it is impossible to estimate whether or how many of these additional lineages exist. Adv. Dis. Our results indicate the presence of a single lineage circulating in bats with properties that allowed it to infect human cells, as previously described for bat sarbecoviruses related to the first SARS-CoV lineage29,30,31. Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor. Because the SARS-CoV-2 S protein has been implicated in past recombination events or possibly convergent evolution12, we specifically investigated several subregions of the Sproteinthe N-terminal domain of S1, the C-terminal domain of S1, the variable-loop region of the C-terminal domain, and S2. M.F.B. To evaluate the performance procedure, we confirmed that the recombination masking resulted in (1) a markedly different outcome of the PHI test64, (2) removal of well-supported (bootstrap value >95%) incompatible splits in Neighbor-Net65 and (3) a near-complete reduction of mosaic signal as identified by 3SEQ. If stopping an outbreak in its early stages is not possibleas was the case for the COVID-19 epidemic in Hubeiidentification of origins and point sources is nevertheless important for containment purposes in other provinces and prevention of future outbreaks. The estimated divergence times for the pangolin virus most closely related to the SARS-CoV-2/RaTG13 lineage range from 1851 (1730-1958) to 1877 (1746-1986), indicating that these pangolin . . PubMed The inset represents divergence time estimates based on NRR1, NRR2 and NRA3. Complete genome sequence data were downloaded from GenBank and ViPR; accession numbers of all 68sequences are available in Supplementary Table 4. Center for Infectious Disease Dynamics, Department of Biology, Pennsylvania State University, University Park, PA, USA, Department of Microbiology, Immunology and Transplantation, KU Leuven, Rega Institute, Leuven, Belgium, Department of Biological Sciences, Xian Jiaotong-Liverpool University, Suzhou, China, State Key Laboratory of Emerging Infectious Diseases, School of Public Health, The University of Hong Kong, Hong Kong SAR, China, Department of Biology, University of Texas Arlington, Arlington, TX, USA, Institute of Evolutionary Biology, University of Edinburgh, Edinburgh, UK, MRC-University of Glasgow Centre for Virus Research, Glasgow, UK, You can also search for this author in SARS-CoV-2 and RaTG13 are the most closely related (their most recent common ancestor nodes denoted by green circles), except in the 222-nt variable-loop region of the C-terminal domain (bar graphs at bottom). 874850). Genetics 176, 10351047 (2007). Consistent with this, we estimate a concomitantly decreasing non-synonymous-to-synonymous substitution rate ratio over longer evolutionary timescales: 1.41 (1.20,1.68), 0.35 (0.30,0.41) and 0.133 (0.129,0.136) for SARS, MERS-CoV and HCoV-OC43, respectively. It allows a user to assign a SARS-CoV-2 genome sequence the most likely lineage (Pango lineage) to SARS-CoV-2 query sequences. 4 TMRCAs for SARS-CoV and SARS-CoV-2. 36, 17931803 (2019). 1a-c ), has the third-highest number of confirmed COVID-19 cases in the state of So. The coverage threshold and consensus sequence generation threshold were set to 20 and 90 respectively. We focused on these three non-recombining regions/alignments for divergence time estimation; this avoids inappropriate modelling of evolutionary processes with recombination on strictly bifurcating trees, which can result in different artefacts such as homoplasies that inflate branch lengths and lead to apparently longer evolutionary divergence times. Mol. 16, e1008421 (2020). 53), this is inferred to have occurred before the divergence of RaTG13 and SARS-CoV-2 and thus should not influence our inferences.
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