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62,63), the GTR+ model and 100bootstrap replicateswas inferred for each BFR >500nt. 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). Identifying SARS-CoV-2-related coronaviruses in Malayan pangolins. Wan, Y., Shang, J., Graham, R., Baric, R. & Li, F. Receptor recognition by the novel Coronavirus from Wuhan: an analysis based on decade-long structural studies of SARS coronavirus. Zhou, H. et al. We thank originating laboratories at South China Agricultural University (Y. Shen, L. Xiao and W. Chen; no. New COVID-19 Variant Alert: Everything We Know About the IHU Variant In the presence of time-dependent rate variation, a widely observed phenomenon for viruses43,44,52, slower prior rates appear more appropriate for sarbecoviruses that currently encompass a sampling time range of about 18years. Coronavirus origins: genome analysis suggests two viruses may have combined Individual sequences such as RpShaanxi2011, Guangxi GX2013 and two sequences from Zhejiang Province (CoVZXC21/CoVZC45), as previously shown22,25, have strong phylogenetic recombination signals because they fall on different evolutionary lineages (with bootstrap support >80%) depending on what region of the genome is being examined. PubMedGoogle Scholar. # File containing the ID of the samples, the Sequence of the haplotype, the Continent, the country, the Region, the Data, the Lineage of Pangolin and Nextstrain clade, and the haplotype number # In this order # Could be obtained from the database 1a-c ), has the third-highest number of confirmed COVID-19 cases in the state of So. & Boni, M. F. Improved algorithmic complexity for the 3SEQ recombination detection algorithm. 5 Comparisons of GC content across taxa. This produced non-recombining alignment NRA3, which included 63 of the 68genomes. Alternatively, combining 3SEQ-inferred breakpoints, GARD-inferred breakpoints and the necessity of PI signals for inferring recombination, we can use the 9.9-kb region spanning nucleotides 11,88521,753 (NRR2) as a putative non-recombining region; this approach is breakpoint-conservative because it is conservative in identifying breakpoints but not conservative in identifying non-recombining regions. Evol. 2 Lack of root-to-tip temporal signal in SARS-CoV-2. 30, 21962203 (2020). Did Pangolin Trafficking Cause the Coronavirus Pandemic? Nat. Divergence time estimates based on the three regions/alignments where the effects of recombination have been removed. 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. Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor. Phylogenetic trees and exact breakpoints for all ten BFRs are shown in Supplementary Figs. SARS-CoV-2 and RaTG13 are also exceptions because they were sampled from Hubei and Yunnan, respectively. Extended Data Fig. Provided by the Springer Nature SharedIt content-sharing initiative, Molecular and Cellular Biochemistry (2023), Nature Microbiology (Nat Microbiol) Using a third consensus-based approach for identifying recombinant regions in individual sequenceswith six different recombination detection methods in RDP5 (ref. Two other bat viruses (CoVZXC21 and CoVZC45) from Zhejiang Province fall on this lineage as recombinants of the RaTG13/SARS-CoV-2 lineage and the clade of Hong Kong bat viruses sampled between 2005 and 2007 (Fig. Of the nine breakpoints defining these ten BFRs, four showed phylogenetic incongruence (PI) signals with bootstrap support >80%, adopting previously published criteria on using a combination of mosaic and PI signals to show evidence of past recombination events19. Lam, T. T. et al. Med. It allows a user to assign a SARS-CoV-2 genome sequence the most likely lineage (Pango lineage) to SARS-CoV-2 query sequences. SARS-CoV-2 Variant Classifications and Definitions S. China corresponds to Guangxi, Yunnan, Guizhou and Guangdong provinces. 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. Meet the people who warn the world about new covid variants A second breakpoint-conservative approach was conservative with respect to breakpoint identification, but this means that it is accepting of false-negative outcomes in breakpoint inference, resulting in less certainty that a putative NRR truly contains no breakpoints. Adv. A counting renaissance: combining stochastic mapping and empirical Bayes to quickly detect amino acid sites under positive selection. Share . 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 genome sequences. The existing diversity and dynamic process of recombination amongst lineages in the bat reservoir demonstrate how difficult it will be to identify viruses with potential to cause major human outbreaks before they emerge. Menachery, V. D. et al. N. China corresponds to Jilin, Shanxi, Hebei and Henan provinces, and the N. China clade also includes one sequence sampled in Hubei Province in 2004. . PubMed Central Evol. The Pango dynamic nomenclature is a popular system for classifying and naming genetically-distinct lineages of SARS-CoV-2, including variants of concern, and is based on the analysis of complete or near-complete virus genomes. Trafficked pangolins can carry coronaviruses closely related to Unlike other viruses that have emerged in the past two decades, coronaviruses are highly recombinogenic14,15,16. Identifying SARS-CoV-2 related coronaviruses in Malayan pangolins Sci. 3) clusters with viruses from provinces in the centre, east and northeast of China. Microbes Infect. Our approach resulted in similar posterior rates using two different prior means, implying that the sarbecovirus data do inform the rate estimate even though a root-to-tip temporal signal was not apparent. Posterior distributions were approximated through Markov chain Monte Carlo sampling, which were run sufficiently long to ensure effective sampling sizes >100. Proc. CAS Nature 579, 270273 (2020). Holmes, E. C. The Evolution and Emergence of RNA Viruses (Oxford Univ. Wu, F. et al. Because coronaviruses are known to be highly recombinant, we used three different approaches to identify non-recombinant regions for use in our Bayesian time-calibrated phylogenetic inference. 82, 18191826 (2008). Specifically, progenitors of the RaTG13/SARS-CoV-2 lineage appear to have recombined with the Hong Kong clade (with inferred breakpoints at 11.9 and 20.8kb) to form the CoVZXC21/CoVZC45-lineage. COVID-19: Time to exonerate the pangolin from the transmission of SARS 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. 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. July 26, 2021. wrote the first draft of the manuscript, and all authors contributed to manuscript editing. Nature 503, 535538 (2013). Proc. This long divergence period suggests there are unsampled virus lineages circulating in horseshoe bats that have zoonotic potential due to the ancestral position of the human-adapted contact residues in the SARS-CoV-2 RBD. 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. While pangolins could be acting as intermediate hosts for bat viruses to get into humansthey develop severe respiratory disease38 and commonly come into contact with people through traffickingthere is no evidence that pangolin infection is a requirement for bat viruses to cross into humans. The divergence time estimates for SARS-CoV-2 and SARS-CoV from their respective most closely related bat lineages are reasonably consistent among the three approaches we use to eliminate the effects of recombination in the alignment. This provides compelling support for the SARS-CoV-2 lineage being the consequence of a direct or nearly-direct zoonotic jump from bats, because the key ACE2-binding residues were present in viruses circulating in bats. 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. Emerg. 2a. These datasets were subjected to the same recombination masking approach as NRA3 and were characterized by a strong temporal signal (Fig. Because the estimated rates and divergence dates were highly similar in the three datasets analysed, we conclude that our estimates are robust to the method of identifying a genomes NRRs. 31922087). Although the human ACE2-compatible RBD was very likely to have been present in a bat sarbecovirus lineage that ultimately led to SARS-CoV-2, this RBD sequence has hitherto been found in only a few pangolin viruses. This dataset comprises an updated version of that used in Hon et al.15 and includes a cluster of genomes sampled in late 2003 and early 2004, but the evolutionary rate estimate without this cluster (0.00175 substitutions per siteyr1 (0.00117,0.00229)) is consistent with the complete dataset (0.00169 substitutions per siteyr1, (0.00131,0.00205)). Current Overview on Disease and Health Research Vol. 6 Another similarity between SARS-CoV and SARS-CoV-2 is their divergence time (4070years ago) from currently known extant bat virus lineages (Fig. Softw. However, on closer inspection, the relative divergences in the phylogenetic tree (Fig. PubMed https://doi.org/10.1093/molbev/msaa163 (2020). Python 379 102 pangoLEARN Public Store of the trained model for pangolin to access. 4 TMRCAs for SARS-CoV and SARS-CoV-2. Using the most conservative approach to identification of a non-recombinant genomic region (NRR1), SARS-CoV-2 forms a sister lineage with RaTG13, with genetically related cousin lineages of coronavirus sampled in pangolins in Guangdong and Guangxi provinces (Fig. Biol. 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. PubMed Central The rate of genome generation is unprecedented, yet there is currently no coherent nor accepted scheme for naming the expanding . PubMed Central 21, 15081514 (2015). 1, vev016 (2015). Now, the two researchers used genomic sequencing to compare the DNA of the new coronavirus in humans with that in animals and found a 99% match with pangolins. A tag already exists with the provided branch name. Current sampling of pangolins does not implicate them as an intermediate host. TMRCA estimates for SARS-CoV-2 and SARS-CoV from their respective most closely related bat lineages are reasonably consistent for the different data sets and different rate priors in our analyses. Furthermore, the other key feature thought to be instrumental in the ability of SARS-CoV-2 to infect humansa polybasic cleavage site insertion in the Sproteinhas not yet been seen in another close bat relative of the SARS-CoV-2 virus. Genet. The genetic distances between SARS-CoV-2 and Pangolin Guangdong 2019 are consistent across all regions except the N-terminal domain, implying that a recombination event between these two sequences in this region is unlikely. (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. Google Scholar. Membrebe, J. V., Suchard, M. A., Rambaut, A., Baele, G. & Lemey, P. Bayesian inference of evolutionary histories under time-dependent substitution rates. Intraspecies diversity of SARS-like coronaviruses in Rhinolophus sinicus and its implications for the origin of SARS coronaviruses in humans. 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. Sliding window analysis of changes in the patterns of sequence similarity between human SARS-CoV-2, and pangolin and bat coronaviruses as described further in Fig. Split diversity in constrained conservation prioritization using integer linear programming. 4 we compare these divergence time estimates to those obtained using the MERS-CoV-centred rate priors for NRR1, NRR2 and NRA3. We call this approach breakpoint-conservative, but note that this has the opposite effect to the construction of NRR1 in that this approach is the most likely to allow breakpoints to remain inside putative non-recombining regions. Novel Coronavirus (2019-nCoV) Situation Report 1, 21 January 2020 (World Health Organization, 2020). The canine viral genome was excluded from the Bayesian phylogenetic analyses because temporal signal analyses (see below) indicated that it was an outlier. 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. By mid-January 2020, the virus was spreading widely within Hubei province and by early March SARS-CoV-2 was declared a pandemic8. A new coronavirus associated with human respiratory disease in China. . =0.00025. PLoS Pathog. D.L.R. Zhou, P. et al. Cov-Lineages Combining regions A, B and C and removing the five named sequences gives us putative NRR1, as an alignment of 63sequences. Stamatakis, A. RAxML-VI-HPC: maximum likelihood-based phylogenetic analyses with thousands of taxa and mixed models. Evol. [12] 1 Phylogenetic relationships in the C-terminal domain (CTD). However, the coronavirus isolated from pangolin is similar at 99% in a specific region of the S protein, which corresponds to the 74 amino acids involved in the ACE (Angiotensin Converting Enzyme . Microbiol. Yu, H. et al. R. Soc. A reduced sequence set of 25sequences chosen to capture the breadth of diversity in the sarbecoviruses (obvious recombinants not involving the SARS-CoV-2 lineage were also excluded) was used because GARD is computationally intensive. Posterior means with 95% HPDs are shown in Supplementary Information Table 2. Boni, M. F., Zhou, Y., Taubenberger, J. K. & Holmes, E. C. Homologous recombination is very rare or absent in human influenza A virus. J. Virol. Developed by the Centre for Genomic Pathogen Surveillance. On first examination this would suggest that that SARS-CoV-2 is a recombinant of an ancestor of Pangolin-2019 and RaTG13, as proposed by others11,22. Despite the high frequency of recombination among bat viruses, the block-like nature of the recombination patterns across the genome permits retrieval of a clean subalignment for phylogenetic analysis. Except for specifying that sequences are linear, all settings were kept to their defaults. All three approaches to removal of recombinant genomic segments point to a single ancestral lineage for SARS-CoV-2 and RaTG13. 91, 10581062 (2010). Use of Genomics to Track Coronavirus Disease Outbreaks, New Zealand Trova, S. et al. For weather, science, and COVID-19 . A single 3SEQ run on the genome alignment resulted in 67 out of 68sequences supporting some recombination in the past, with multiple candidate breakpoint ranges listed for each putative recombinant. Host ecology determines the dispersal patterns of a plant virus. As illustrated by the dashed arrows, these two posteriors motivate our specification of prior distributions with standard deviations inflated 10-fold (light color). Pangolin relies on a novel algorithm called pangoLEARN. 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. RegionsAC had similar phylogenetic relationships among the southern China bat viruses (Yunnan, Guangxi and Guizhou provinces), the Hong Kong viruses, northern Chinese viruses (Jilin, Shanxi, Hebei and Henan provinces, including Shaanxi), pangolin viruses and the SARS-CoV-2 lineage. Article A., Lytras, S., Singer, J. B., Weaver, S. & Sergei, L. Evidence of significant natural selection in the evolution of SARS-CoV-2 in bats, not humans. 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. 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. While it is possible that pangolins, or another hitherto undiscovered species, may have acted as an intermediate host facilitating transmission to humans, current evidence is consistent with the virus having evolved in bats resulting in bat sarbecoviruses that can replicate in the upper respiratory tract of both humans and pangolins25,32. 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. Annu Rev. 2). 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 . A third approach attempted to minimize the number of regions removed while also minimizing signals of mosaicism and homoplasy. Biol. M.F.B. According to GISAID . 94, e0012720 (2020). J. Gen. Virol. Pangolin was developed to implement the dynamic nomenclature of SARS-CoV-2 lineages, known as the Pango nomenclature. Sibling lineages to RaTG13/SARS-CoV-2 include a pangolin sequence sampled in Guangdong Province in March 2019 and a clade of pangolin sequences from Guangxi Province sampled in 2017. Google Scholar. 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. Biol. Lemey, P., Minin, V. N., Bielejec, F., Pond, S. L. K. & Suchard, M. A. Evolutionary rate estimation can be profoundly affected by the presence of recombination50. As informative rate priors for the analysis of the sarbecovirus datasets, we used two different normal prior distributions: one with a mean of 0.00078 and s.d. Because there is no single accepted method of inferring breakpoints and identifying clean subregions with high certainty, we implemented several approaches to identifying three classic statistical signals of recombination: mosaicism, phylogenetic incongruence and excessive homoplasy51. N. Engl. 87, 62706282 (2013). Epidemiology, genetic recombination, and pathogenesis of coronaviruses. Press, 2009). Phylogenetic Assignment of Named Global Outbreak Lineages CNN . & Bedford, T. MERS-CoV spillover at the camelhuman interface. 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. We showed that severe acute respiratory syndrome coronavirus 2 is probably a novel recombinant virus. Sorting these breakpoint-free regions (BFRs) by length results in two segments >5kb: an ORF1a subregion spanning nucleotides (nt) 3,6259,150 and the first half of ORF1b spanning nt13,29119,628 (sequence numbering given in Source Data, https://github.com/plemey/SARSCoV2origins). Aiewsakun, P. & Katzourakis, A. Time-dependent rate phenomenon in viruses. 5). 3). You signed in with another tab or window. And this genotype pattern led to creating a new Pangolin lineage named B.1.640.2, a phylogenetic sister group to the old B.1.640 lineage renamed B.1.640.1. A dynamic nomenclature proposal for SARS-CoV-2 lineages to - PubMed While such models have recently been made available, we lack the information to calibrate the rate decline over time (for example, through internal node calibrations44). The shaded region corresponds to the Sprotein. Boni, M. F., de Jong, M. D., van Doorn, H. R. & Holmes, E. C. Guidelines for identifying homologous recombination events in influenza A virus. Trends Microbiol. Mol. Boxes show 95% HPD credible intervals. P.L. Green boxplots show the TMRCA estimate for the RaTG13/SARS-CoV-2 lineage and its most closely related pangolin lineage (Guangdong 2019), with the light and dark coloured version based on the HCoV-OC43 and MERS-CoV centred priors, respectively. 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. It is clear from our analysis that viruses closely related to SARS-CoV-2 have been circulating in horseshoe bats for many decades. Aside from RaTG13, Pangolin-CoV is the most closely related CoV to SARS-CoV-2. This is evidence for numerous recombination events occurring in the evolutionary history of the sarbecoviruses22,33; specifying all past events in their correct temporal order34 is challenging and not shown here. Identification of diverse alphacoronaviruses and genomic characterization of a novel severe acute respiratory syndrome-like coronavirus from bats in China. CAS We thank T. Bedford for providing M.F.B. Yuan, J. et al. The origins we present in Fig. In this approach, we considered a breakpoint as supported only if it had three types of statistical support: from (1) mosaic signals identified by 3SEQ, (2) PI signals identified by building trees around 3SEQs breakpoints and (3) the GARD algorithm35, which identifies breakpoints by identifying PI signals across proposed breakpoints. J. Med Virol. Maciej F. Boni, Philippe Lemey, Andrew Rambaut or David L. Robertson. Software package for assigning SARS-CoV-2 genome sequences to global lineages. The latter was reconstructed using IQTREE66 v.2.0 under a general time-reversible (GTR) model with a discrete gamma distribution to model inter-site rate variation. Nguyen, L.-T., Schmidt, H. A., Von Haeseler, A. Correspondence to The web application was developed by the Centre for Genomic Pathogen Surveillance. PubMed Emergence of SARS-CoV-2 through recombination and strong purifying selection. Concatenated region ABC is NRR1. The relatively fast evolutionary rate means that it is most appropriate to estimate shallow nodes in the sarbecovirus evolutionary history. 5. All sequence data analysed in this manuscript are available at https://github.com/plemey/SARSCoV2origins. 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. J. Med. This commit does not belong to any branch on this repository, and may belong to a fork outside of the repository. In the absence of a strong temporal signal, we sought to identify a suitable prior rate distribution to calibrate the time-measured trees by examining several coronaviruses sampled over time, including HCoV-OC43, MERS-CoV, and SARS-CoV virus genomes. 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. Extended Data Fig. We aimed to analyze 3 naso-oropharyngeal swab samples collected between August and December 2021 to describe the amino acid changes present in the sequence reads that may have a role in the emergence of new . Evol. & Andersen, K. G. Pandemics: spend on surveillance, not prediction. Extensive diversity of coronaviruses in bats from China. 68, 10521061 (2019). A phylogenetic treeusing RAxML v8.2.8 (ref. Figure 1 (top) shows the distribution of all identified breakpoints (using 3SEQs exhaustive triplet search) by the number of candidate recombinant sequences supporting them. Uncertainty measures are shown in Extended Data Fig. CAS Published. 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. Because 3SEQ identified ten BFRs >500nt, we used GARDs (v.2.5.0) inference on 10, 11 and 12 breakpoints. Webster, R. G., Bean, W. J., Gorman, O. T., Chambers, T. M. & Kawaoka, Y. Evolution and ecology of influenza A viruses. The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. & Holmes, E. C. Recombination in evolutionary genomics. performed recombination analysis for non-recombining alignment3, calibration of rate of evolution and phylogenetic reconstruction and dating. 95% credible interval bars are shown for all internal node ages. Slider with three articles shown per slide. Nature 538, 193200 (2016). 36, 7597 (2002). In our analyses of the sarbecovirus datasets, we incorporated the uncertainty of the sampling dates when exact dates were not available. RegionC showed no PI signals within it. Discovery and genetic analysis of novel coronaviruses in least horseshoe bats in southwestern China. G066215N, G0D5117N and G0B9317N)) and by the European Unions Horizon 2020 project MOOD (no. Lond. Extended Data Fig. Region A has been shortened to A (5,017nt) based on potential recombination signals within the region. Specifically, we used a combination of six methods implemented in v.5.5 of RDP5 (ref. 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. Its genome is closest to that of severe acute respiratory syndrome-related coronaviruses from horseshoe bats, and its receptor-binding domain is closest to that of pangolin viruses. and X.J. 36) (RDP, GENECONV, MaxChi, Bootscan, SisScan and 3SEQ) and considered recombination signals detected by more than two methods for breakpoint identification. 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. 874850). 88, 70707082 (2014). 21, 255265 (2004). We used TreeAnnotator to summarize posterior tree distributions and annotated the estimated values to a maximum clade credibility tree, which was visualized using FigTree. Graham, R. L. & Baric, R. S. Recombination, reservoirs, and the modular spike: mechanisms of coronavirus cross-species transmission. Researchers in the UK had just set the scientific world . Based on the identified breakpoints in each genome, only the major non-recombinant region is kept in each genome while other regions are masked. Ge, X. et al. 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. MERS-CoV data were subsampled to match sample sizes with SARS-CoV and HCoV-OC43. Holmes, E. C., Dudas, G., Rambaut, A. Virus Evol. Its origin and direct ancestral viruses have not been . Mol. 13, e1006698 (2017). Gray inset shows majority rule consensus trees with mean posterior branch lengths for the two regions, with posterior probabilities on the key nodes showing the relationships among SARS-CoV-2, RaTG13, and Pangolin 2019. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Li, Q. et al. Duchene, S. et al. T.T.-Y.L. 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. 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.