Methods Ecol. Temporal signal was tested using a recently developed marginal likelihood estimation procedure41 (Supplementary Table 1). 206298/Z/17/Z. 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 ). For weather, science, and COVID-19 . and D.L.R. Sequences were aligned by MAFTT58 v.7.310, with a final alignment length of 30,927, and used in the analyses below. 5). The construction of NRR1 is the most conservative as it is least likely to contain any remaining recombination signals. Biol. SARS-CoV-2 is an appropriate name for the new coronavirus. Sci. Nature 558, 180182 (2018). Correspondence to 3). Collectively our analyses point to bats being the primary reservoir for the SARS-CoV-2 lineage. Novel Coronavirus (2019-nCoV) Situation Report 1, 21 January 2020 (World Health Organization, 2020). Kosakovsky Pond, S. L., Posada, D., Gravenor, M. B., Woelk, C. H. & Frost, S. D. W. Automated phylogenetic detection of recombination using a genetic algorithm. A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence. 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. 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. 2, bottom) show that SARS-CoV-2 is unlikely to have acquired the variable loop from an ancestor of Pangolin-2019 because these two sequences are approximately 1015% divergent throughout the entire Sprotein (excluding the N-terminal domain). Emergence of SARS-CoV-2 through recombination and strong purifying selection. Trova, S. et al. In March, when covid cases began spiking around India, Bani Jolly went hunting for answers in the virus's genetic code. These residues are also in the Pangolin Guangdong 2019 sequence. These datasets were subjected to the same recombination masking approach as NRA3 and were characterized by a strong temporal signal (Fig. MERS-CoV data were subsampled to match sample sizes with SARS-CoV and HCoV-OC43. Genet. and JavaScript. 1) and thus likely to be the product of recombination, acquiring a divergent variable loop from a hitherto unsampled bat sarbecovirus28. T.T.-Y.L. Evol. CNN . A third approach attempted to minimize the number of regions removed while also minimizing signals of mosaicism and homoplasy. 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. The fact that these estimates lie between the rates for MERS-CoV and HCoV-OC43 is consistent with the intermediate sampling time range of about 18years (Fig. Open reading frames are shown above the breakpoint plot, with the variable-loop region indicated in the Sprotein. Stegeman, A. et al. 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. Google Scholar. Because 3SEQ identified ten BFRs >500nt, we used GARDs (v.2.5.0) inference on 10, 11 and 12 breakpoints. 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 . R. Soc. Google Scholar. 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). D.L.R. Virus Evol. In case of DRAGEN COVID Lineage tool, the minimum accepted alignment score was set to 22 and results with scores <22 were discarded. Add entries for pangolin-data/-assignment 1.18.1.1 (, Really add a document on testing strategy. 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. J. Virol. matics program called Pangolin was developed. 3) clusters with viruses from provinces in the centre, east and northeast of China. Anderson, K. G., Rambaut, A., Lipkin, W. I., Holmes, E. C. & Garry, R. F. The proximal origin of SARS-CoV-2. Nat. Annu Rev. The relatively fast evolutionary rate means that it is most appropriate to estimate shallow nodes in the sarbecovirus evolutionary history. Zhou, H. et al. ISSN 2058-5276 (online). These means are based on the mean rates estimated for MERS-CoV and HCoV-OC43, respectively, while the standard deviations are set ten times higher than empirical values to allow greater prior uncertainty and avoid strong bias (Extended Data Fig. It allows a user to assign a SARS-CoV-2 genome sequence the most likely lineage (Pango lineage) to SARS-CoV-2 query sequences. Lancet 383, 541548 (2013). 53), this is inferred to have occurred before the divergence of RaTG13 and SARS-CoV-2 and thus should not influence our inferences. Stamatakis, A. RAxML version 8: a tool for phylogenetic analysis and post-analysis of large phylogenies. Lin, X. et al. 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. Li, X. et al. 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. 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. Isolation of SARS-CoV-2-related coronavirus from Malayan pangolins. Grey tips correspond to bat viruses, green to pangolin, blue to SARS-CoV and red to SARS-CoV-2. When the genomic data included both coding and non-coding regions we used a single GTR+ substitution model; for concatenated coding genes we partitioned the alignment by codon position and specified an independent GTR+ model for each partition with a separate gamma model to accommodate inter-site rate variation. 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. 1a-c ), has the third-highest number of confirmed COVID-19 cases in the state of So. Microbiol. Zhou, P. et al. Viral metagenomics revealed Sendai virus and coronavirus infection of Malayan pangolins (Manis javanica). Dudas, G., Carvalho, L. M., Rambaut, A. 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 . Biol. Evolutionary rate estimation can be profoundly affected by the presence of recombination50. Centre for Genomic Pathogen Surveillance. Influenza viruses reassort17 but they do not undergo homologous recombination within RNA segments18,19, meaning that origins questions for influenza outbreaks can always be reduced to origins questions for each of influenzas eight RNA segments. In the absence of any reasonable prior knowledge on the TMRCA of the sarbecovirus datasets (which is required for grid specification in a skygrid model), we specified a simpler constant size population prior. To obtain RegionB showed no PI signals within the region, except one including sequence SC2018 (Sichuan), and thus this sequence was also removed from the set. 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. 1c). Evol. 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. Google Scholar. 62,63), the GTR+ model and 100bootstrap replicateswas inferred for each BFR >500nt. Martin, D. P., Murrell, B., Golden, M., Khoosal, A. Syst. Lam, T. T. et al. Phylogenetic supertree reveals detailed evolution of SARS-CoV-2, Origin and cross-species transmission of bat coronaviruses in China, Emerging SARS-CoV-2 variants follow a historical pattern recorded in outgroups infecting non-human hosts, Inferring the ecological niche of bat viruses closely related to SARS-CoV-2 using phylogeographic analyses of Rhinolophus species, Genomic recombination events may reveal the evolution of coronavirus and the origin of SARS-CoV-2, A Bayesian approach to infer recombination patterns in coronaviruses, Metagenomic identification of a new sarbecovirus from horseshoe bats in Europe, A comparative recombination analysis of human coronaviruses and implications for the SARS-CoV-2 pandemic, Pandemic-scale phylogenomics reveals the SARS-CoV-2 recombination landscape, https://github.com/plemey/SARSCoV2origins, https://doi.org/10.1101/2020.04.20.052019, https://doi.org/10.1101/2020.02.10.942748, https://doi.org/10.1101/2020.05.28.122366, http://virological.org/t/ncov-2019-codon-usage-and-reservoir-not-snakes-v2/339, http://virological.org/t/ncovs-relationship-to-bat-coronaviruses-recombination-signals-no-snakes-no-evidence-the-2019-ncov-lineage-is-recombinant/331. Nat. An initial genomic sequence analysis found that the reemergence of COVID-19 in New Zealand was caused by a SARS-CoV-2 from the (now ancestral) lineage B.1.1.1 of the pangolin nomenclature ( 17 ). 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. J. Virol. We demonstrate that the sarbecoviruses circulating in horseshoe bats have complex recombination histories as reported by others15,20,21,22,23,24,25,26. 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. =0.00075 and one with a mean of 0.00024 and s.d. GARD identified eight breakpoints that were also within 50nt of those identified by 3SEQ. Evol. Holmes, E. C., Dudas, G., Rambaut, A. The authors declare no competing interests. (2020) with additional (and higher quality) snake coding sequence data and several miscellaneous eukaryotes with low genomic GC content failed to find any meaningful clustering of the SARS-CoV-2 with snake genomes (a). The origins we present in Fig. Nguyen, L.-T., Schmidt, H. A., Von Haeseler, A. However, for several reasons, nucleotide sequences may be generated that cover only the spike gene of SARS-CoV-2. 04:20. According to GISAID . Relevant bootstrap values are shown on branches, and grey-shaded regions show sequences exhibiting phylogenetic incongruence along the genome. Software package for assigning SARS-CoV-2 genome sequences to global lineages. & Bedford, T. MERS-CoV spillover at the camelhuman interface. 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. Genetics 172, 26652681 (2006). and P.L.) To estimate non-synonymous over synonymous rate ratios for the concatenated coding genes, we used the empirical Bayes Renaissance countingprocedure67. PubMed Central 6, e14 (2017). Are pangolins the intermediate host of the 2019 novel coronavirus (SARS-CoV-2)? We compare both MERS-CoV- and HCoV-OC43-centred prior distributions (Extended Data Fig. A new coronavirus associated with human respiratory disease in China. You signed in with another tab or window. The sizes of the black internal node circles are proportional to the posterior node support. 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. 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. Due to the absence of temporal signal in the sarbecovirus datasets, we used informative prior distributions on the evolutionary rate to estimate divergence dates. Discovery of a rich gene pool of bat SARS-related coronaviruses provides new insights into the origin of SARS coronavirus. He, B. et al. 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. performed recombination analysis for non-recombining regions1 and 2, breakpoint analysis and phylogenetic inference on recombinant segments. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent for the current coronavirus disease (COVID-19) pandemic that has affected more than 35 million people and caused . This study provides an integration of existing classifications and describes evolutionary trends of the SARS-CoV . 1, vev003 (2015). Early detection via genomics was not possible during Southeast Asias initial outbreaks of avian influenza H5N1 (1997 and 20032004) or the first SARS outbreak (20022003). Ge, X. et al. Biol. 27) receptors and its RBD being genetically closer to a pangolin virus than to RaTG13 (refs. Yu, H. et al. Further information on research design is available in the Nature Research Reporting Summary linked to this article. Figure 1 (top) shows the distribution of all identified breakpoints (using 3SEQs exhaustive triplet search) by the number of candidate recombinant sequences supporting them. Viruses 11, 979 (2019). Lam, H. M., Ratmann, O. Stamatakis, A. RAxML-VI-HPC: maximum likelihood-based phylogenetic analyses with thousands of taxa and mixed models. Provided by the Springer Nature SharedIt content-sharing initiative, Molecular and Cellular Biochemistry (2023), Nature Microbiology (Nat Microbiol) 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. 2 Lack of root-to-tip temporal signal in SARS-CoV-2. 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. These shy, quirky but cute mammals are one of the most heavily trafficked yet least understood animals in the world. Many Git commands accept both tag and branch names, so creating this branch may cause unexpected behavior. Evolutionary origins of the SARS-CoV-2 sarbecovirus lineage responsible for the COVID-19 pandemic. PLoS Pathog. 35, 247251 (2018). 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. 94, e0012720 (2020). Anderson, K. G. nCoV-2019 codon usage and reservoir (not snakes v2). Rev. The key to successful surveillance is knowing which viruses to look for and prioritizing those that can readily infect humans47. Zhang, Y.-Z. 36, 7597 (2002). 84, 31343146 (2010). Extended Data Fig. the development of viral diversity. 5. Posterior means with 95% HPDs are shown in Supplementary Information Table 2. Python 379 102 pangoLEARN Public Store of the trained model for pangolin to access. 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. Liu, P. et al. 6, 8391 (2015). In early January, the aetiological agent of the pneumonia cases was found to be a coronavirus3, subsequently named SARS-CoV-2 by an International Committee on Taxonomy of Viruses (ICTV) Study Group4 and also named hCoV-19 by Wu et al.5. PubMed The first available sequence data6 placed this novel human pathogen in the Sarbecovirus subgenus of Coronaviridae7, the same subgenus as the SARS virus that caused a global outbreak of >8,000 cases in 20022003. 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. Wang, H., Pipes, L. & Nielsen, R. Synonymous mutations and the molecular evolution of SARS-Cov-2 origins. 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 thank all authors who have kindly deposited and shared genome data on GISAID. The plots are based on maximum likelihood tree reconstructions with a root position that maximises the residual mean squared for the regression of root-to-tip divergence and sampling time. The time-calibrated phylogeny represents a maximum clade credibility tree inferred for NRR1. As a proxy, it would be possible to model the long-term purifying selection dynamics as a major source of time-dependent rates43,44,52, but this is beyond the scope of the current study. 90, 71847195 (2016). Boni, M. F., de Jong, M. D., van Doorn, H. R. & Holmes, E. C. Guidelines for identifying homologous recombination events in influenza A virus. Uncertainty measures are shown in Extended Data Fig. Google Scholar. 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. Scientists defined the pangolin lineage of this variant to be B.1.1.523 and it was originally recognized as a variant under monitoring on July 14, 2021. PLoS Pathog. Aside from RaTG13, Pangolin-CoV is the most closely related CoV to SARS-CoV-2. 88, 70707082 (2014). Using both prior distributions, this results in six highly similar posterior rate estimates for NRR1, NRR2 and NRA3, centred around 0.00055 substitutions per siteyr1. The red and blue boxplots represent the divergence time estimates for SARS-CoV-2 (red) and the 2002-2003 SARS-CoV (blue) from their most closely related bat virus, with the light- and dark-colored versions based on the HCoV-OC43 and MERS-CoV centered priors, respectively. Med. . 26, 450452 (2020). Accurate estimation of ages for deeper nodes would require adequate accommodation of time-dependent rate variation. However, inconsistency in the nomenclature limits uniformity in its epidemiological understanding. 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. Pangolin was developed to implement the dynamic nomenclature of SARS-CoV-2 lineages, known as the Pango nomenclature. Avian influenza a virus (H7N7) epidemic in The Netherlands in 2003: course of the epidemic and effectiveness of control measures. These authors contributed equally: Maciej F. Boni, Philippe Lemey. Mol. 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). Preprint at https://doi.org/10.1101/2020.04.20.052019 (2020). Emerg. Published. 24, 490502 (2016). In our analyses of the sarbecovirus datasets, we incorporated the uncertainty of the sampling dates when exact dates were not available. Nature 583, 282285 (2020). We thank originating laboratories at South China Agricultural University (Y. Shen, L. Xiao and W. Chen; no. 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. This new approach classifies the newly sequenced genome against all the diverse lineages present instead of a representative select sequences. 91, 10581062 (2010). In such cases, even moderate rate variation among long, deep phylogenetic branches will substantially impact expected root-to-tip divergences over a sampling time range that represents only a small fraction of the evolutionary history40. Researchers in the UK had just set the scientific world . Preprint at https://doi.org/10.1101/2020.05.28.122366 (2020). a, Breakpoints identified by 3SEQ illustrated by percentage of sequences (out of 68) that support a particular breakpoint position. 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. Genetic lineages of SARS-CoV-2 have been emerging and circulating around the world since the beginning of the COVID-19 pandemic. 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. Pangolin-CoV is 91.02% and 90.55% identical to SARS-CoV-2 and BatCoV RaTG13, respectively, at the whole-genome level. 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. A.R. Maclean, O. Without better sampling, however, it is impossible to estimate whether or how many of these additional lineages exist. Another similarity between SARS-CoV and SARS-CoV-2 is their divergence time (4070years ago) from currently known extant bat virus lineages (Fig. 1c). T.L. RegionC showed no PI signals within it. 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). PubMed Biol. Evol. We used TreeAnnotator to summarize posterior tree distributions and annotated the estimated values to a maximum clade credibility tree, which was visualized using FigTree. Boni, M. F., Zhou, Y., Taubenberger, J. K. & Holmes, E. C. Homologous recombination is very rare or absent in human influenza A virus. 874850). 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. Coronavirus: Pangolins found to carry related strains. Robertson, D. nCoVs relationship to bat coronaviruses & recombination signals (no snakes) no evidence the 2019-nCoV lineage is recombinant. Sarbecovirus, HCoV-OC43 and SARS-CoV data were assembled from GenBank to be as complete as possible, with sampling year as an inclusion criterion. PubMed The new paper finds that the genetic sequences of several strains of coronavirus found in pangolins were between 88.5 percent and 92.4 percent similar to those of the novel coronavirus. 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. 3). P.L. Except for specifying that sequences are linear, all settings were kept to their defaults. Our third approach involved identifying breakpoints and masking minor recombinant regions (with gaps, which are treated as unobserved characters in probabilistic phylogenetic approaches). SARS-CoV-2 itself is not a recombinant of any sarbecoviruses detected to date, and its receptor-binding motif, important for specificity to human ACE2 receptors, appears to be an ancestral trait shared with bat viruses and not one acquired recently via recombination. & Muhire, B. RDP4: Detection and analysis of recombination patterns in virus genomes. It performs: K-mer based detection Map/align, variant calling Consensus sequence generation Lineage/clade analysis using Pangolin and NextClade Access the DRAGEN COVID Lineage App on BaseSpace Sequence Hub Mol. 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. 36)gives a putative recombination-free alignment that we call non-recombinant alignment3 (NRA3) (see Methods). 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.
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