Stamatakis, A. RAxML version 8: a tool for phylogenetic analysis and post-analysis of large phylogenies. PubMed acknowledges support by the Research FoundationFlanders (Fonds voor Wetenschappelijk OnderzoekVlaanderen (nos. 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. Biol. PubMed Sequencing from Malayan pangolins collected during anti-smuggling operations in southern China detected coronavirus lineages related to SARS-CoV-2. Zhou, H. et al. The SARS-CoV divergence times are somewhat earlier than dates previously estimated15 because previous estimates were obtained using a collection of SARS-CoV genomes from human and civet hosts (as well as a few closely related bat genomes), which implies that evolutionary rates were predominantly informed by the short-term SARS outbreak scale and probably biased upwards. https://doi.org/10.1093/molbev/msaa163 (2020). 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. 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. Google Scholar. ISSN 2058-5276 (online). This produced non-recombining alignment NRA3, which included 63 of the 68genomes. Nat. Wu, Y. et al. 5). Avian influenza a virus (H7N7) epidemic in The Netherlands in 2003: course of the epidemic and effectiveness of control measures. Rambaut, A., Lam, T. T., Carvalho, L. M. & Pybus, O. G. Exploring the temporal structure of heterochronous sequences using TempEst (formerly Path-O-Gen). Trends Microbiol. 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. To estimate non-synonymous over synonymous rate ratios for the concatenated coding genes, we used the empirical Bayes Renaissance countingprocedure67. In March, when covid cases began spiking around India, Bani Jolly went hunting for answers in the virus's genetic code. 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. Extended Data Fig. 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. 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. We thank A. Chan and A. Irving for helpful comments on the manuscript. 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. Posterior rate distributions for MERS-CoV (far left) and HCoV-OC43 (far right) using BEAST on n=27 sequences spread over 4 years (MERS-CoV) and n=27 sequences spread over 49 years (HCoV-OC43). 16, e1008421 (2020). and X.J. Wu, F. et al. Duchene, S., Holmes, E. C. & Ho, S. Y. W. Analyses of evolutionary dynamics in viruses are hindered by a time-dependent bias in rate estimates. 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. 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 Google Scholar. 25, 3548 (2017). PLoS Pathog. By 2009, however, rapid genomic analysis had become a routine component of outbreak response. Current sampling of pangolins does not implicate them as an intermediate host. If the latter still identified non-negligible recombination signal, we removed additional genomes that were identified as major contributors to the remaining signal. Zhou, P. et al. There are outstanding evolutionary questions on the recent emergence of human coronavirus SARS-CoV-2 including the role of reservoir species, the role of recombination and its time of divergence from animal viruses. Methods Ecol. Stamatakis, A. RAxML-VI-HPC: maximum likelihood-based phylogenetic analyses with thousands of taxa and mixed models. CAS 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. is funded by the MRC (no. A pneumonia outbreak associated with a new coronavirus of probable bat origin. 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 . In outbreaks of zoonotic pathogens, identification of the infection source is crucial because this may allow health authorities to separate human populations from the wildlife or domestic animal reservoirs posing the zoonotic risk9,10. 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. RegionsB and C span nt3,6259,150 and 9,26111,795, respectively. A third approach attempted to minimize the number of regions removed while also minimizing signals of mosaicism and homoplasy. 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. Using a third consensus-based approach for identifying recombinant regions in individual sequenceswith six different recombination detection methods in RDP5 (ref. Yu, H. et al. Coronavirus Disease 2019 (COVID-19) Situation Report 51 (World Health Organization, 2020). Epidemiology, genetic recombination, and pathogenesis of coronaviruses. 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. Bioinformatics 30, 13121313 (2014). 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. 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. These rate priors are subsequently used in the Bayesian inference of posterior rates for NRR1, NRR2, and NRA3 as indicated by the solid arrows. 82, 48074811 (2008). 3). 3). 3). Proc. Google Scholar. GitHub - cov-lineages/pangolin: Software package for assigning SARS-CoV-2 genome sequences to global lineages. 382, 11991207 (2020). 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. Grey tips correspond to bat viruses, green to pangolin, blue to SARS-CoV and red to SARS-CoV-2. Genetics 172, 26652681 (2006). 23, 18911901 (2006). wrote the first draft of the manuscript, and all authors contributed to manuscript editing. Hon, C. et al. R. Soc. 5). Holmes, E. C. The Evolution and Emergence of RNA Viruses (Oxford Univ. A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence. 725422-ReservoirDOCS). 36)gives a putative recombination-free alignment that we call non-recombinant alignment3 (NRA3) (see Methods). 36) (RDP, GENECONV, MaxChi, Bootscan, SisScan and 3SEQ) and considered recombination signals detected by more than two methods for breakpoint identification. All custom code used in the manuscript is available at https://github.com/plemey/SARSCoV2origins. Stegeman, A. et al. 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. 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. Nature 583, 282285 (2020). Lemey, P., Minin, V. N., Bielejec, F., Pond, S. L. K. & Suchard, M. A. & Holmes, E. C. A genomic perspective on the origin and emergence of SARS-CoV-2. J. Virol. 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. Five example sequences with incongruent phylogenetic positions in the two trees are indicated by dashed lines. Posterior means with 95% HPDs are shown in Supplementary Information Table 2. Identification of diverse alphacoronaviruses and genomic characterization of a novel severe acute respiratory syndrome-like coronavirus from bats in China. A deep dive into the genetics of the novel coronavirus shows it seems to have spent some time infecting both bats and pangolins before it jumped into humans, researchers said . Maclean, O. PubMedGoogle Scholar. Evolutionary rate estimation can be profoundly affected by the presence of recombination50. 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. A distinct name is needed for the new coronavirus. 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. Researchers have found that SARS-CoV-2 in humans shares about 90.3% of its genome sequence with a coronavirus found in pangolins (Cyranoski, 2020). 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. 4, vey016 (2018). We showed that severe acute respiratory syndrome coronavirus 2 is probably a novel recombinant virus. These authors contributed equally: Maciej F. Boni, Philippe Lemey. A tag already exists with the provided branch name. 21, 15081514 (2015). Viruses 11, 979 (2019). After removal of A1 and A4, we named the new region A. 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. Means and 95% HPD intervals are 0.080 [0.0580.101] and 0.530 [0.3040.780] for the patristic distances between SARS-CoV-2 and RaTG13 (green) and 0.143 [0.1090.180] and 0.154 [0.0930.231] for the patristic distances between SARS-CoV-2 and Pangolin 2019 (orange). 6, 8391 (2015). 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. 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. =0.00075 and one with a mean of 0.00024 and s.d. 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. According to GISAID . 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. The extent of sarbecovirus recombination history can be illustrated by five phylogenetic trees inferred from BFRs or concatenated adjacent BFRs (Fig. Ji, W., Wang, W., Zhao, X., Zai, J. The coverage threshold and consensus sequence generation threshold were set to 20 and 90 respectively. Open reading frames are shown above the breakpoint plot, with the variable-loop region indicated in the Sprotein. stand-alone pangolin work flows or Illumina DRAGEN COVID Lineage App (v3.5.5) following the default parameters. 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. 2a. Given that these pangolin viruses are ancestral to the progenitor of the RaTG13/SARS-CoV-2 lineage, it is more likely that they are also acquiring viruses from bats. Mol. J. Med Virol. 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. 1 Phylogenetic relationships in the C-terminal domain (CTD). Conservatively, we combined the three BFRs >2kb identified above into non-recombining region1 (NRR1). performed recombination and phylogenetic analysis and annotated virus names with geographical and sampling dates. Evolutionary origins of the SARS-CoV-2 sarbecovirus lineage responsible for the COVID-19 pandemic. Transparent bands of interquartile range width and with the same colours are superimposed to highlight the overlap between estimates.
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