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). Open reading frames are shown above the breakpoint plot, with the variable-loop region indicated in the Sprotein. 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). J. Virol. Emergence of SARS-CoV-2 through recombination and strong purifying selection. =0.00075 and one with a mean of 0.00024 and s.d. Liu, P. et al. 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. For weather, science, and COVID-19 . 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. Several of the recombinant sequences in these trees show that recombination events do occur across geographically divergent clades. The Artic Network receives funding from the Wellcome Trust through project no. Microbiol. Viral metagenomics revealed Sendai virus and coronavirus infection of Malayan pangolins (Manis javanica). 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 Genet. The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Relevant bootstrap values are shown on branches, and grey-shaded regions show sequences exhibiting phylogenetic incongruence along the genome. Phylogenetic trees and exact breakpoints for all ten BFRs are shown in Supplementary Figs. GitHub - cov-lineages/pangolin: Software package for assigning SARS-CoV-2 genome sequences to global lineages. Stamatakis, A. RAxML version 8: a tool for phylogenetic analysis and post-analysis of large phylogenies. and T.A.C. Google Scholar. Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. The command line tool is open source software available under the GNU General Public License v3.0. This new approach classifies the newly sequenced genome against all the diverse lineages present instead of a representative select sequences. 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 . 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. 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. 36, 17931803 (2019). PubMedGoogle Scholar. 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 . 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. 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. PubMed Central 13, e1006698 (2017). Lu, R. et al. This boundary appears to be rarely crossed. RegionB is 5,525nt long. The construction of NRR1 is the most conservative as it is least likely to contain any remaining recombination signals. Sign up for the Nature Briefing newsletter what matters in science, free to your inbox daily. 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. Maclean, O. 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. 5 (NRR1) are conservative in the sense that NRR1 is more likely to be non-recombinant than NRR2 or NRA3. Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor. 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 Originally, PANGOLIN used a maximum-likelihood-based assignment algorithm to assign query SARS-CoV-2 the most likely lineage sequence. Sequencing from Malayan pangolins collected during anti-smuggling operations in southern China detected coronavirus lineages related to SARS-CoV-2. Eight other BFRs <500nt were identified, and the regions were named BFRAJ in order of length. Evol. Evol. Viruses 11, 979 (2019). Bryant, D. & Moulton, V. Neighbor-Net: an agglomerative method for the construction of phylogenetic networks. Provided by the Springer Nature SharedIt content-sharing initiative, Molecular and Cellular Biochemistry (2023), Nature Microbiology (Nat Microbiol) Lie, P., Chen, W. & Chen, J.-P. 1c). Boni, M. F., Posada, D. & Feldman, M. W. An exact nonparametric method for inferring mosaic structure in sequence triplets. Google Scholar. 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. Nature 503, 535538 (2013). NTD, N-terminal domain; CTD, C-terminal domain. Alexandre Hassanin, Vuong Tan Tu, Gabor Csorba, Nicola F. Mller, Kathryn E. Kistler & Trevor Bedford, Jack M. Crook, Ivana Murphy, Diana Bell, Simon Pollett, Matthew A. Conte, Irina Maljkovic Berry, Yatish Turakhia, Bryan Thornlow, Russell Corbett-Detig, Nature Microbiology Biol. 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. 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. July 26, 2021. We showed that severe acute respiratory syndrome coronavirus 2 is probably a novel recombinant virus. R. Soc. volume5,pages 14081417 (2020)Cite this article. Maciej F. Boni, Philippe Lemey, Andrew Rambaut or David L. Robertson. 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. These residues are also in the Pangolin Guangdong 2019 sequence. 68, 10521061 (2019). eLife 7, e31257 (2018). PubMed Central 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. 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). Identifying SARS-CoV-2-related coronaviruses in Malayan pangolins. Proc. Bruen, T. C., Philippe, H. & Bryant, D. A simple and robust statistical test for detecting the presence of recombination. 6, 8391 (2015). Emerg. 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. 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. We compiled a dataset including 27human coronavirus OC43 virus genomes and ten related animal virus genomes (six bovine, three white-tailed deer and one canine virus). 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 ). 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. This commit does not belong to any branch on this repository, and may belong to a fork outside of the repository. Slider with three articles shown per slide. "This is an extremely interesting . Intraspecies diversity of SARS-like coronaviruses in Rhinolophus sinicus and its implications for the origin of SARS coronaviruses in humans. The shaded region corresponds to the Sprotein. 56, 152179 (1992). Due to the absence of temporal signal in the sarbecovirus datasets, we used informative prior distributions on the evolutionary rate to estimate divergence dates. Concatenated region ABC is NRR1. A third approach attempted to minimize the number of regions removed while also minimizing signals of mosaicism and homoplasy. SARS-CoV-2 is an appropriate name for the new coronavirus. Boxplots show interquartile ranges, white lines are medians and box whiskers show the full range of posterior distribution. 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. is funded by the MRC (no. A new coronavirus associated with human respiratory disease in China. 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. Trends Microbiol. Another similarity between SARS-CoV and SARS-CoV-2 is their divergence time (4070years ago) from currently known extant bat virus lineages (Fig. Wang, H., Pipes, L. & Nielsen, R. Synonymous mutations and the molecular evolution of SARS-Cov-2 origins. Even before the COVID-19 pandemic, pangolins have been making headlines. Holmes, E. C., Dudas, G., Rambaut, A. The canine viral genome was excluded from the Bayesian phylogenetic analyses because temporal signal analyses (see below) indicated that it was an outlier. Martin, D. P., Murrell, B., Golden, M., Khoosal, A. However, on closer inspection, the relative divergences in the phylogenetic tree (Fig. 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. Mol. In this study, we report the case of a child with severe combined immu presenting a prolonged severe acute respiratory syndrome coronavirus 2 infection. Wong, A. C. P., Li, X., Lau, S. K. P. & Woo, P. C. Y. 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. The key to successful surveillance is knowing which viruses to look for and prioritizing those that can readily infect humans47. 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). Cell 181, 223227 (2020). https://doi.org/10.1093/molbev/msaa163 (2020). 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. Conservatively, we combined the three BFRs >2kb identified above into non-recombining region1 (NRR1). Nucleotide positions for phylogenetic inference are 147695, 9621,686 (first tree), 3,6259,150 (second tree, also BFR B), 9,26111,795 (third tree, also BFR C), 12,44319,638 (fourth tree) and 23,63124,633, 24,79525,847, 27,70228,843 and 29,57430,650 (fifth tree). 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. Virus Evol. & Muhire, B. RDP4: Detection and analysis of recombination patterns in virus genomes. 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. RegionsB and C span nt3,6259,150 and 9,26111,795, respectively. Indeed, the rates reported by these studies are in line with the short-term SARS rates that we estimate (Fig. Holmes, E. C., Rambaut, A. 3). 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. From this perspective, it may be useful to perform surveillance for more closely related viruses to SARS-CoV-2 along the gradient from Yunnan to Hubei. Centre for Genomic Pathogen Surveillance. In Extended Data Fig. 4 TMRCAs for SARS-CoV and SARS-CoV-2. Li, Q. et al. Stamatakis, A. RAxML-VI-HPC: maximum likelihood-based phylogenetic analyses with thousands of taxa and mixed models. According to GISAID . 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. Because 3SEQ is the most statistically powerful of the mosaic methods61, we used it to identify the best-supported breakpoint history for each potential child (recombinant) sequence in the dataset. A distinct name is needed for the new coronavirus. Menachery, V. D. et al. 36)gives a putative recombination-free alignment that we call non-recombinant alignment3 (NRA3) (see Methods). Evol. 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. Li, X. et al. 1a-c ), has the third-highest number of confirmed COVID-19 cases in the state of So. However, for several reasons, nucleotide sequences may be generated that cover only the spike gene of SARS-CoV-2. 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. Anderson, K. G., Rambaut, A., Lipkin, W. I., Holmes, E. C. & Garry, R. F. The proximal origin of SARS-CoV-2. 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. 23, 18911901 (2006). The genetic distances between SARS-CoV-2 and RaTG13 (bottom) demonstrate that their relationship is consistent across all regions except for the variable loop. The extent of sarbecovirus recombination history can be illustrated by five phylogenetic trees inferred from BFRs or concatenated adjacent BFRs (Fig. P.L. 04:20. SARS-CoV-2 and RaTG13 are also exceptions because they were sampled from Hubei and Yunnan, respectively. 5. collected SARS-CoV data and assisted in analyses of SARS-CoV and SARS-CoV-2 data. 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. (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). 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. 1) and thus likely to be the product of recombination, acquiring a divergent variable loop from a hitherto unsampled bat sarbecovirus28. Coronavirus Disease 2019 (COVID-19) Situation Report 51 (World Health Organization, 2020). 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. 725422-ReservoirDOCS). the development of viral diversity. 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. Virus Evol. While there is evidence of positive selection in the sarbecovirus lineage leading to RaTG13/SARS-CoV-2 (ref. We say that this approach is conservative because sequences and subregions generating recombination signals have been removed, and BFRs were concatenated only when no PI signals could be detected between them. 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. 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. 24, 490502 (2016). 25, 3548 (2017). Suchard, M. A. et al. Genetic lineages of SARS-CoV-2 have been emerging and circulating around the world since the beginning of the COVID-19 pandemic. The consistency of the posterior rates for the different prior means also implies that the data do contribute to the evolutionary rate estimate, despite the fact that a temporal signal was visually not apparent (Extended Data Fig. 82, 18191826 (2008). A novel bat coronavirus closely related to SARS-CoV-2 contains natural insertions at the S1/S2 cleavage site of the Spike protein. Gorbalenya, A. E. et al. Microbes Infect. 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. RegionC showed no PI signals within it. 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 . These authors contributed equally: Maciej F. Boni, Philippe Lemey. 5). In our analyses of the sarbecovirus datasets, we incorporated the uncertainty of the sampling dates when exact dates were not available. Note that six of these sequences fall under the terms of use of the GISAID platform. PubMed We named the length-sorted BFRs as: BFRA (ntpositions 13,29119,628, length=6,338nt), BFRB (ntpositions 3,6259,150, length=5,526nt), BFRC (ntpositions 9,26111,795, length=2,535nt), BFRD (ntpositions 27,70228,843, length=1,142nt) and six further regions (EJ). Lancet 383, 541548 (2013). 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. J. Virol. 1 Phylogenetic relationships in the C-terminal domain (CTD). 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. Aside from RaTG13, Pangolin-CoV is the most closely related CoV to SARS-CoV-2. Pangolin relies on a novel algorithm called pangoLEARN. All sequence data analysed in this manuscript are available at https://github.com/plemey/SARSCoV2origins. 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. Preprint at https://doi.org/10.1101/2020.04.20.052019 (2020). Trends Microbiol. Are you sure you want to create this branch? Green boxplots show the TMRCA estimate for the RaTG13/SARS-CoV-2 lineage and its most closely related pangolin lineage (Guangdong 2019). 27) receptors and its RBD being genetically closer to a pangolin virus than to RaTG13 (refs. 3) clusters with viruses from provinces in the centre, east and northeast of China. These differences reflect the fact that rate estimates can vary considerably with the timescale of measurement, a frequently observed phenomenon in viruses known as time-dependent evolutionary rates41,43,44. Region A has been shortened to A (5,017nt) based on potential recombination signals within the region. Med. D.L.R. Wu, Y. et al. 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. 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.

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