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. It is RaTG13 that is more divergent in the variable-loop region (Extended Data Fig. Biazzo 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. The time-calibrated phylogeny represents a maximum clade credibility tree inferred for NRR1. J. Virol. 2). 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. 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. Menachery, V. D. et al. 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. c, Maximum likelihood phylogenetic trees rooted on a 2007 virus sampled in Kenya (BtKy72; root truncated from images), shown for five BFRs of the sarbecovirus alignment. . The Artic Network receives funding from the Wellcome Trust through project no. Divergence time estimates based on the three regions/alignments where the effects of recombination have been removed. Boni, M. F., de Jong, M. D., van Doorn, H. R. & Holmes, E. C. Guidelines for identifying homologous recombination events in influenza A virus. In the meantime, to ensure continued support, we are displaying the site without styles 95% credible interval bars are shown for all internal node ages. Avian influenza a virus (H7N7) epidemic in The Netherlands in 2003: course of the epidemic and effectiveness of control measures. Evol. 2). Dudas, G., Carvalho, L. M., Rambaut, A. Lie, P., Chen, W. & Chen, J.-P. Trova, S. et al. As illustrated by the dashed arrows, these two posteriors motivate our specification of prior distributions with standard deviations inflated 10-fold (light color). 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 . 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. Sci. 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. Proc. Schierup, M. H. & Hein, J. Recombination and the molecular clock. Nevertheless, the viral population is largely spatially structured according to provinces in the south and southeast on one lineage, and provinces in the centre, east and northeast on another (Fig. 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. Nature 503, 535538 (2013). the development of viral diversity. PubMed CAS These shy, quirky but cute mammals are one of the most heavily trafficked yet least understood animals in the world. This is not surprising for diverse viral populations with relatively deep evolutionary histories. 87, 62706282 (2013). 36, 7597 (2002). J. Med. 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. 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. Microbiol. The sizes of the black internal node circles are proportional to the posterior node support. (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). PANGOLIN lineage database (15, 16) was used to analyze the frequency of lineages among countries. Discovery and genetic analysis of novel coronaviruses in least horseshoe bats in southwestern China. Published. J. Virol. Using these breakpoints, the longest putative non-recombining segment (nt1,88521,753) is 9.9kb long, and we call this region NRR2. performed recombination analysis for non-recombining alignment3, calibration of rate of evolution and phylogenetic reconstruction and dating. Aiewsakun, P. & Katzourakis, A. Time-dependent rate phenomenon in viruses. 5). 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. =0.00025. 82, 18191826 (2008). 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. 874850). The genetic distances between SARS-CoV-2 and RaTG13 (bottom) demonstrate that their relationship is consistent across all regions except for the variable loop. Syst. Lu, R. et al. We demonstrate that the sarbecoviruses circulating in horseshoe bats have complex recombination histories as reported by others15,20,21,22,23,24,25,26. We used TreeAnnotator to summarize posterior tree distributions and annotated the estimated values to a maximum clade credibility tree, which was visualized using FigTree. 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. is funded by The National Natural Science Foundation of China Excellent Young Scientists Fund (Hong Kong and Macau; no. Unlike other viruses that have emerged in the past two decades, coronaviruses are highly recombinogenic14,15,16. 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. R. Soc. A pneumonia outbreak associated with a new coronavirus of probable bat origin. For coronaviruses, however, recombination means that small genomic subregions can have independent origins, identifiable if sufficient sampling has been done in the animal reservoirs that support the endemic circulation, co-infection and recombination that appear to be common. Med. J. Gen. Virol. With horseshoe bats currently the most plausible origin of SARS-CoV-2, it is important to consider that sarbecoviruses circulate in a variety of horseshoe bat species with widely overlapping species ranges57. 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. A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence. Mol. 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. 23, 18911901 (2006). Using a third consensus-based approach for identifying recombinant regions in individual sequenceswith six different recombination detection methods in RDP5 (ref. According to GISAID . 84, 31343146 (2010). and D.L.R. 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. 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). 68, 10521061 (2019). 5 Comparisons of GC content across taxa. Zhou, P. et al. D.L.R. 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. For weather, science, and COVID-19 . & Bedford, T. MERS-CoV spillover at the camelhuman interface. First, we took an approach that relies on identification of mosaic regions (via 3SEQ14 v.1.7) that are also supported by PI signals19. These authors contributed equally: Maciej F. Boni, Philippe Lemey. Here, we analyse the evolutionary history of SARS-CoV-2 using available genomic data on sarbecoviruses. Evol. Robertson, D. nCoVs relationship to bat coronaviruses & recombination signals (no snakes) no evidence the 2019-nCoV lineage is recombinant. B., Weaver, S. & Sergei, L. Evidence of significant natural selection in the evolution of SARS-CoV-2 in bats, not 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. In our second stage, we wanted to construct non-recombinant regions where our approach to breakpoint identification was as conservative as possible. A tag already exists with the provided branch name. The key to successful surveillance is knowing which viruses to look for and prioritizing those that can readily infect humans47. We thank T. Bedford for providing M.F.B. Provided by the Springer Nature SharedIt content-sharing initiative, Molecular and Cellular Biochemistry (2023), Nature Microbiology (Nat Microbiol) The construction of NRR1 is the most conservative as it is least likely to contain any remaining recombination signals. 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. Extended Data Fig. Transparent bands of interquartile range width and with the same colours are superimposed to highlight the overlap between estimates. This boundary appears to be rarely crossed. The rate of genome generation is unprecedented, yet there is currently no coherent nor accepted scheme for naming the expanding . 35, 247251 (2018). It allows a user to assign a SARS-CoV-2 genome sequence the most likely lineage (Pango lineage) to SARS-CoV-2 query sequences. Developed by the Centre for Genomic Pathogen Surveillance. 5). A.R. Five example sequences with incongruent phylogenetic positions in the two trees are indicated by dashed lines. USA 113, 30483053 (2016). 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). There is a 90% DNA match between SARS CoV 2 and a coronavirus in pangolins. Evol. Specifically, we used a combination of six methods implemented in v.5.5 of RDP5 (ref. Ji, W., Wang, W., Zhao, X., Zai, J. It is available as a command line tool and a web application. 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. The idea is that pangolins carrying the virus, SARS-CoV-2, came into contact with humans. Nat. performed codon usage analysis. M.F.B. 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. Preprint at https://doi.org/10.1101/2020.05.28.122366 (2020). GARD identified eight breakpoints that were also within 50nt of those identified by 3SEQ. One study suggests that over a century ago, one lineage of coronavirus circulating in bats gave rise to SARS-CoV-2, RaTG13 and a Pangolin coronavirus known as Pangolin-2019, Live Science . 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. He, B. et al. Med. 1. In March, when covid cases began spiking around India, Bani Jolly went hunting for answers in the virus's genetic code. The inset represents divergence time estimates based on NRR1, NRR2 and NRA3. 3 Priors and posteriors for evolutionary rate of SARS-CoV-2. 21, 255265 (2004). While there is evidence of positive selection in the sarbecovirus lineage leading to RaTG13/SARS-CoV-2 (ref. Specifically, using a formal Bayesian approach42 (see Methods), we estimate a fast evolutionary rate (0.00169 substitutions per siteyr1, 95% highest posterior density (HPD) interval (0.00131,0.00205)) for SARS viruses sampled over a limited timescale (1year), a slower rate (0.00078 (0.00063,0.00092) substitutions per siteyr1) for MERS-CoV on a timescale of about 4years and the slowest rate (0.00024 (0.00019,0.00029) substitutions per siteyr1) for HCoV-OC43 over almost five decades. To obtain 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. In case of DRAGEN COVID Lineage tool, the minimum accepted alignment score was set to 22 and results with scores <22 were discarded. However, for several reasons, nucleotide sequences may be generated that cover only the spike gene of SARS-CoV-2. We showed that severe acute respiratory syndrome coronavirus 2 is probably a novel recombinant virus. B 281, 20140732 (2014). SARS-CoV-2 and RaTG13 are also exceptions because they were sampled from Hubei and Yunnan, respectively. Another similarity between SARS-CoV and SARS-CoV-2 is their divergence time (4070years ago) from currently known extant bat virus lineages (Fig. Identification of diverse alphacoronaviruses and genomic characterization of a novel severe acute respiratory syndrome-like coronavirus from bats in China. 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. 3) to examine the sensitivity of date estimates to this prior specification. 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 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. All three approaches to removal of recombinant genomic segments point to a single ancestral lineage for SARS-CoV-2 and RaTG13. SARS-like WIV1-CoV poised for human emergence. The S1 protein of Pangolin-CoV is much more closely related to SARS-CoV-2 than to RaTG13. 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. But some theories suggest that pangolins may be the source of the novel coronavirus. 4 TMRCAs for SARS-CoV and SARS-CoV-2. b, Similarity plot between SARS-CoV-2 and several selected sequences including RaTG13 (black), SARS-CoV (pink) and two pangolin sequences (orange). 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. 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).
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