5. Our most conservative approach attempted to ensure that putative NRRs had no mosaic or phylogenetic incongruence signals. EPI_ISL_410721) and Beijing Institute of Microbiology and Epidemiology (W.-C. Cao, T.T.-Y.L., N. Jia, Y.-W. Zhang, J.-F. Jiang and B.-G. Jiang, nos. There is a 90% DNA match between SARS CoV 2 and a coronavirus in pangolins. Software package for assigning SARS-CoV-2 genome sequences to global lineages. Temporal signal was tested using a recently developed marginal likelihood estimation procedure41 (Supplementary Table 1). Possible Bat Origin of Severe Acute Respiratory Syndrome Coronavirus 2 Boni, M.F., Lemey, P., Jiang, X. et al. obtained the genome sequences of 10 SARS-CoV-2 virus strains through nanopore sequencing of nasopharyngeal swabs in Malta and analyzed the assembled genome with pangolin software, and the results showed that these virus strains were assigned to B.1 lineage, indicating that SARS-CoV-2 was widely spread in Europe (Biazzo et al., 2021). 16, e1008421 (2020). 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). 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. Removal of five sequences that appear to be recombinants and two small subregions of BFRA was necessary to ensure that there were no phylogenetic incongruence signals among or within the three BFRs. J. Virol. Evol. 1, vev003 (2015). 36, 17931803 (2019). The time-calibrated phylogeny represents a maximum clade credibility tree inferred for NRR1. 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. Phylogenetic Assignment of Named Global Outbreak Lineages 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. GitHub - cov-lineages/pangolin: Software package for assigning SARS-CoV-2 genome sequences to global lineages. 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. Don't blame pangolins, coronavirus family tree tracing could prove key All four of these breakpoints were also identified with the tree-based recombination detection method GARD35. 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. This study provides an integration of existing classifications and describes evolutionary trends of the SARS-CoV . Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor. The canine viral genome was excluded from the Bayesian phylogenetic analyses because temporal signal analyses (see below) indicated that it was an outlier. & Holmes, E. C. A genomic perspective on the origin and emergence of SARS-CoV-2. CAS New COVID-19 Variant Alert: Everything We Know About the IHU Variant In addition, sequences NC_014470 (Bulgaria 2008), CoVZXC21, CoVZC45 and DQ412042 (Hubei-Yichang) needed to be removed to maintain a clean non-recombinant signal in A. Eden, J.-S., Tanaka, M. M., Boni, M. F., Rawlinson, W. D. & White, P. A. Recombination within the pandemic norovirus GII.4 lineage. Nature 579, 270273 (2020). Nguyen, L.-T., Schmidt, H. A., Von Haeseler, A. 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. Zhou, H. et al. 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. and X.J. Across a large region of the virus genome, corresponding approximately to ORF1b, it did not cluster with any of the known bat coronaviruses indicating that recombination probably played a role in the evolutionary history of these viruses5,7. Evol. 32, 268274 (2014). Another similarity between SARS-CoV and SARS-CoV-2 is their divergence time (4070years ago) from currently known extant bat virus lineages (Fig. We infer time-measured evolutionary histories using a Bayesian phylogenetic approach while incorporating rate priors based on mean MERS-CoV and HCoV-OC43 rates and with standard deviations that allow for more uncertainty than the empirical estimates for both viruses (see Methods). Aiewsakun, P. & Katzourakis, A. Time-dependent rate phenomenon in viruses. 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. . 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. Divergence time estimates based on the HCoV-OC43-centred rate prior for the separate BFRs (Supplementary Table 3) show consistency in TMRCA estimates across the genome. Based on the identified breakpoints in each genome, only the major non-recombinant region is kept in each genome while other regions are masked. 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. We compare both MERS-CoV- and HCoV-OC43-centred prior distributions (Extended Data Fig. A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence. PubMed Central RegionsB and C span nt3,6259,150 and 9,26111,795, respectively. 190, 20882095 (2004). The construction of NRR1 is the most conservative as it is least likely to contain any remaining recombination signals. https://doi.org/10.1093/molbev/msaa163 (2020). Add entries for pangolin-data/-assignment 1.18.1.1 (, Really add a document on testing strategy. 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. 5, 536544 (2020). (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). Get the most important science stories of the day, free in your inbox. 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. with an alignment on which an initial recombination analysis was done. This boundary appears to be rarely crossed. 68, 10521061 (2019). PI signals were identified (with bootstrap support >80%) for seven of these eight breakpoints: positions 1,684, 3,046, 9,237, 11,885, 21,753, 22,773 and 24,628. 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. 5. https://doi.org/10.1038/s41564-020-0771-4, DOI: https://doi.org/10.1038/s41564-020-0771-4. By 2009, however, rapid genomic analysis had become a routine component of outbreak response. Lam, T. T. et al. J. Virol. The most parsimonious explanation for these shared ACE2-specific residues is that they were present in the common ancestors of SARS-CoV-2, RaTG13 and Pangolin Guangdong 2019, and were lost through recombination in the lineage leading to RaTG13. Bruen, T. C., Philippe, H. & Bryant, D. A simple and robust statistical test for detecting the presence of recombination. Using a third consensus-based approach for identifying recombinant regions in individual sequenceswith six different recombination detection methods in RDP5 (ref. 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. B 281, 20140732 (2014). collected SARS-CoV data and assisted in analyses of SARS-CoV and SARS-CoV-2 data. Nature 579, 265269 (2020). Softw. PubMed Bioinformatics 30, 13121313 (2014). (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. Eight other BFRs <500nt were identified, and the regions were named BFRAJ in order of length. P.L. 2, vew007 (2016). is funded by The National Natural Science Foundation of China Excellent Young Scientists Fund (Hong Kong and Macau; no. Humans' selfish, speciesist treatment of these animals could be the very reason why the novel coronavirus exists. & Minh, B. Q. IQ-TREE: a fast and effective stochastic algorithm for estimating maximum-likelihood phylogenies. July 26, 2021. Developed by the Centre for Genomic Pathogen Surveillance. Extended Data Fig. Sequences are colour-coded by province according to the map. 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). Its origin and direct ancestral viruses have not been . Genetic lineages of SARS-CoV-2 have been emerging and circulating around the world since the beginning of the COVID-19 pandemic. Indeed, the rates reported by these studies are in line with the short-term SARS rates that we estimate (Fig. After removal of A1 and A4, we named the new region A. 2a. 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. Su, S. et al. Viral metagenomics revealed Sendai virus and coronavirus infection of Malayan pangolins (Manis javanica). PubMedGoogle Scholar. 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. The research leading to these results received funding (to A.R. BEAST inferences made use of the BEAGLE v.3 library68 for efficient likelihood computations. 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. 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. Emerg. You are using a browser version with limited support for CSS. T.L. Liu, P. et al. Suchard, M. A. et al. We thank T. Bedford for providing M.F.B. 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. 382, 11991207 (2020). 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). In light of these time-dependent evolutionary rate dynamics, a slower rate is appropriate for calibration of the sarbecovirus evolutionary history. Extended Data Fig. matics program called Pangolin was developed. Why Can't We Just Call BA.2 Omicron? - The Atlantic Zhou, P. et al. Nature 503, 535538 (2013). 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. A distinct name is needed for the new coronavirus. Prolonged SARS-CoV-2 Infection and Intra-Patient Viral Evolu : The Novel Coronavirus (2019-nCoV) Situation Report 1, 21 January 2020 (World Health Organization, 2020). D.L.R. Evidence of the recombinant origin of a bat severe acute respiratory syndrome (SARS)-like coronavirus and its implications on the direct ancestor of SARS coronavirus. Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. 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. 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. Posterior means (horizontal bars) of patristic distances between SARS-CoV-2 and its closest bat and pangolin sequences, for the spike proteins variable loop region and CTD region excluding the variable loop. Mol. RegionB is 5,525nt long. Slider with three articles shown per slide. 92, 433440 (2020). 27) receptors and its RBD being genetically closer to a pangolin virus than to RaTG13 (refs. Trends Microbiol. Trova, S. et al. Dis. 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). J. Virol. 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. Extended Data Fig. Allen O'Brien on LinkedIn: #r #rstudio #rstats #pangolin #covid19 # J. Gen. Virol. 4 TMRCAs for SARS-CoV and SARS-CoV-2. Due to the absence of temporal signal in the sarbecovirus datasets, we used informative prior distributions on the evolutionary rate to estimate divergence dates. These rate priors are subsequently used in the Bayesian inference of posterior rates for NRR1, NRR2, and NRA3 as indicated by the solid arrows. 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. 84, 31343146 (2010). Adv. These are in general agreement with estimates using NRR2 and NRA3, which result in divergence times of 1982 (19482009) and 1948 (18791999), respectively, for SARS-CoV-2, and estimates of 1952 (19061989) and 1970 (19321996), respectively, for the divergence time of SARS-CoV from its closest known bat relative. The idea is that pangolins carrying the virus, SARS-CoV-2, came into contact with humans. 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. 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)). Stegeman, A. et al. Virus Evol. Using these breakpoints, the longest putative non-recombining segment (nt1,88521,753) is 9.9kb long, and we call this region NRR2. Biol. Biol. 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. Sci. Nature 583, 282285 (2020). Internet Explorer). J. Virol. 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. Concurrent evidence also proposed pangolins as a potential intermediate species for SARS-CoV-2 emergence and suggested them as a potential reservoir species11,12,13. Frontiers | Novel Highly Divergent SARS-CoV-2 Lineage With the Spike PubMed performed recombination and phylogenetic analysis and annotated virus names with geographical and sampling dates. 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. Dudas, G., Carvalho, L. M., Rambaut, A. Stamatakis, A. RAxML version 8: a tool for phylogenetic analysis and post-analysis of large phylogenies. 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. The web application was developed by the Centre for Genomic Pathogen Surveillance. When viewing the last 7kb of the genome, a clade of viruses from northern China appears to cluster with sequences from southern Chinese provinces but, when inspecting trees from different parts of ORF1ab, the N. China clade is phylogenetically separated from the S. China clade. Evol. Boni, M. F., Zhou, Y., Taubenberger, J. K. & Holmes, E. C. Homologous recombination is very rare or absent in human influenza A virus. 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. 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. 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. 82, 18191826 (2008). Bioinformatics 28, 32483256 (2012). Because these subclades had different phylogenetic relationships in regionD (Supplementary Fig. The inset represents divergence time estimates based on NRR1, NRR2 and NRA3. "This is an extremely interesting . 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. Boni, M. F., de Jong, M. D., van Doorn, H. R. & Holmes, E. C. Guidelines for identifying homologous recombination events in influenza A virus.
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