In our analyses of the sarbecovirus datasets, we incorporated the uncertainty of the sampling dates when exact dates were not available. 874850). 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. Trends Microbiol. Xiao, K. et al. Overview of the SARS-CoV-2 genotypes circulating in Latin America Sign up for the Nature Briefing newsletter what matters in science, free to your inbox daily. Nature 579, 270273 (2020). 5). Li, Q. et al. 26, 450452 (2020). Virus Evol. Software package for assigning SARS-CoV-2 genome sequences to global lineages. 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. 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 pangolin coronaviruses show lower similarity to SARS-CoV-2 than bat coronavirus RaTG13 across the whole genome, but higher similarity in the spike receptor binding domain, although the similarity at either scale remains too low to implicate . 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. J. Infect. Using the most conservative approach to identification of a non-recombinant genomic region (NRR1), SARS-CoV-2 forms a sister lineage with RaTG13, with genetically related cousin lineages of coronavirus sampled in pangolins in Guangdong and Guangxi provinces (Fig. 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. Due to the absence of temporal signal in the sarbecovirus datasets, we used informative prior distributions on the evolutionary rate to estimate divergence dates. Holmes, E. C., Rambaut, A. ac, Root-to-tip (RtT) divergence as a function of sampling time for the three coronavirus evolutionary histories unfolding over different timescales (HCoV-OC43 (n=37; a) MERS (n=35; b) and SARS (n=69; c)). 725422-ReservoirDOCS). 3) to examine the sensitivity of date estimates to this prior specification. Patino-Galindo, J. 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). 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. There is a 90% DNA match between SARS CoV 2 and a coronavirus in pangolins. 6, eabb9153 (2020). 32, 268274 (2014). The proximal origin of SARS-CoV-2 | Nature Medicine SARS-CoV-2 is an appropriate name for the new coronavirus. T.L. Virology 507, 110 (2017). 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). 3). For weather, science, and COVID-19 . This is not surprising for diverse viral populations with relatively deep evolutionary histories. 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. 68, 10521061 (2019). 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. Google Scholar. 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. Developed by the Centre for Genomic Pathogen Surveillance. Yuan, J. et al. Menachery, V. D. et al. Global epidemiology of bat coronaviruses. (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. Liu, P. et al. cov-lineages/pangolin - GitHub In the variable-loop region, RaTG13 diverges considerably with the TMRCA, now outside that of SARS-CoV-2 and the Pangolin Guangdong 2019 ancestor, suggesting that RaTG13 has acquired this region from a more divergent and undetected bat lineage. COVID-19 lineage names can be confusing to navigate; there are many aliases and if you want to catch them all to examine further in data analyses it helps to Allen O'Brien on LinkedIn: #r #rstudio #rstats #pangolin #covid19 #datascience #epidemiology Curr. 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. Relevant bootstrap values are shown on branches, and grey-shaded regions show sequences exhibiting phylogenetic incongruence along the genome. 3). 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. Sarbecovirus, HCoV-OC43 and SARS-CoV data were assembled from GenBank to be as complete as possible, with sampling year as an inclusion criterion. 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 RegionC showed no PI signals within it. Evol. Conducting analogous analyses of codon usage bias as Ji et al. Nguyen, L.-T., Schmidt, H. A., Von Haeseler, A. 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. PLoS Pathog. Region A has been shortened to A (5,017nt) based on potential recombination signals within the region. The relatively fast evolutionary rate means that it is most appropriate to estimate shallow nodes in the sarbecovirus evolutionary history. 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). Stamatakis, A. RAxML-VI-HPC: maximum likelihood-based phylogenetic analyses with thousands of taxa and mixed models. Coronavirus: Pangolins found to carry related strains - BBC News Pangolins may have incubated the novel coronavirus, gene study shows Gorbalenya, A. E. et al. We thank all authors who have kindly deposited and shared genome data on GISAID. COVID-19: Time to exonerate the pangolin from the transmission of SARS We extracted a similar number (n=35) of genomes from a MERS-CoV dataset analysed by Dudas et al.59 using the phylogenetic diversity analyser tool60 (v.0.5). Why Can't We Just Call BA.2 Omicron? - The Atlantic 82, 18191826 (2008). Virus Evol. Pangolin was developed to implement the dynamic nomenclature of SARS-CoV-2 lineages, known as the Pango nomenclature. 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. B.W.P. 1 Phylogenetic relationships in the C-terminal domain (CTD). 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 Are pangolins the intermediate host of the 2019 novel coronavirus (SARS-CoV-2)? Since the release of Version 2.0 in July 2020, however, it has used the 'pangoLEARN' machine-learning-based assignment algorithm to assign lineages to new SARS-CoV-2 genomes. Sci. 31922087). Wang, H., Pipes, L. & Nielsen, R. Synonymous mutations and the molecular evolution of SARS-Cov-2 origins. Mol. Nat. 4), but also by markedly different evolutionary rates. Pango lineage designation and assignment using SARS-CoV-2 - PubMed Using the most conservative approach (NRR1), the divergence time estimate for SARS-CoV-2 and RaTG13 is 1969 (95% HPD: 19302000), while that between SARS-CoV and its most closely related bat sequence is 1962 (95% HPD: 19321988); see Fig. Hu, B. et al. Host ecology determines the dispersal patterns of a plant virus. 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. 16, e1008421 (2020). 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. M.F.B., P.L. In Extended Data Fig. 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). 30, 21962203 (2020). 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. The sizes of the black internal node circles are proportional to the posterior node support. 36, 17931803 (2019). Many Git commands accept both tag and branch names, so creating this branch may cause unexpected behavior. 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. Python 379 102 pangoLEARN Public Store of the trained model for pangolin to access. Microbiol. The web application was developed by the Centre for Genomic Pathogen Surveillance. https://doi.org/10.1038/s41564-020-0771-4, DOI: https://doi.org/10.1038/s41564-020-0771-4. In case of DRAGEN COVID Lineage tool, the minimum accepted alignment score was set to 22 and results with scores <22 were discarded. Abstract. Note that breakpoints can be shared between sequences if they are descendants of the same recombination events. 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. Eight other BFRs <500nt were identified, and the regions were named BFRAJ in order of length. Viral metagenomics revealed Sendai virus and coronavirus infection of Malayan pangolins (Manis javanica). 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. Bruen, T. C., Philippe, H. & Bryant, D. A simple and robust statistical test for detecting the presence of recombination. Use of Genomics to Track Coronavirus Disease Outbreaks, New Zealand Except for specifying that sequences are linear, all settings were kept to their defaults. 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. "This is an extremely interesting . 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. Viruses 11, 174 (2019). In March, when covid cases began spiking around India, Bani Jolly went hunting for answers in the virus's genetic code. PubMed Central 35, 247251 (2018). the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in After removal of A1 and A4, we named the new region A. CAS Evolutionary origins of the SARS-CoV-2 sarbecovirus lineage responsible for the COVID-19 pandemic. J. Med Virol. 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 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. Coronavirus Software Tools - Illumina, Inc. It is available as a command line tool and a web application. Boxes show 95% HPD credible intervals. Li, X. et al. 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. 90, 71847195 (2016). 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. Preprint at https://doi.org/10.1101/2020.02.10.942748 (2020). Combining regions A, B and C and removing the five named sequences gives us putative NRR1, as an alignment of 63sequences. Extended Data Fig. Genetics 172, 26652681 (2006). 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). 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. Complete genome sequence data were downloaded from GenBank and ViPR; accession numbers of all 68sequences are available in Supplementary Table 4. In December 2019, a cluster of pneumonia cases epidemiologically linked to an open-air live animal market in the city of Wuhan (Hubei Province), China1,2 led local health officials to issue an epidemiological alert to the Chinese Center for Disease Control and Prevention and the World Health Organizations (WHO) China Country Office. Divergence time estimates based on the three regions/alignments where the effects of recombination have been removed. and D.L.R. A., Lytras, S., Singer, J. Boni, M. F., Posada, D. & Feldman, M. W. An exact nonparametric method for inferring mosaic structure in sequence triplets. USA 113, 30483053 (2016). Pangolin-CoV is 91.02% and 90.55% identical to SARS-CoV-2 and BatCoV RaTG13, respectively, at the whole-genome level. The command line tool is open source software available under the GNU General Public License v3.0. Zhou, P. et al. It is RaTG13 that is more divergent in the variable-loop region (Extended Data Fig. Use the Previous and Next buttons to navigate the slides or the slide controller buttons at the end to navigate through each slide. The extent of sarbecovirus recombination history can be illustrated by five phylogenetic trees inferred from BFRs or concatenated adjacent BFRs (Fig. He, B. et al. Bayesian evaluation of temporal signal in measurably evolving populations. 5). and T.A.C. Med. Boxplots show interquartile ranges, white lines are medians and box whiskers show the full range of posterior distribution. The virus then. with an alignment on which an initial recombination analysis was done. If the latter still identified non-negligible recombination signal, we removed additional genomes that were identified as major contributors to the remaining signal. The origins we present in Fig. CAS Discovery and genetic analysis of novel coronaviruses in least horseshoe bats in southwestern China. Avian influenza a virus (H7N7) epidemic in The Netherlands in 2003: course of the epidemic and effectiveness of control measures. Boni, M. F., Zhou, Y., Taubenberger, J. K. & Holmes, E. C. Homologous recombination is very rare or absent in human influenza A virus. performed codon usage analysis. Uncertainty measures are shown in Extended Data Fig. Preprint at https://doi.org/10.1101/2020.04.20.052019 (2020). Microbiol. 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. Green boxplots show the TMRCA estimate for the RaTG13/SARS-CoV-2 lineage and its most closely related pangolin lineage (Guangdong 2019). Share . 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. 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. 190, 20882095 (2004). 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. Of the countries that have contributed SARS-CoV-2 data, 30% had genomes of this lineage. J. Virol. Softw. 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. 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 . Our most conservative approach attempted to ensure that putative NRRs had no mosaic or phylogenetic incongruence signals. Intraspecies diversity of SARS-like coronaviruses in Rhinolophus sinicus and its implications for the origin of SARS coronaviruses in humans. The S1 protein of Pangolin-CoV is much more closely related to SARS-CoV-2 than to RaTG13. Identifying SARS-CoV-2-related coronaviruses in Malayan pangolins. Bayesian phylogenetic and phylodynamic data integration using BEAST 1.10. Nature 558, 180182 (2018). To avoid artefacts due to recombination, we focused on NRR1 and NRR2 and the recombination-masked alignment NRA3 to infer time-measured evolutionary histories. We demonstrate that the sarbecoviruses circulating in horseshoe bats have complex recombination histories as reported by others15,20,21,22,23,24,25,26. Regions AC were further examined for mosaic signals by 3SEQ, and all showed signs of mosaicism. Viruses 11, 979 (2019). Evol. As illustrated by the dashed arrows, these two posteriors motivate our specification of prior distributions with standard deviations inflated 10-fold (light color). 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. MERS-CoV data were subsampled to match sample sizes with SARS-CoV and HCoV-OC43. stand-alone pangolin work flows or Illumina DRAGEN COVID Lineage App (v3.5.5) following the default parameters. 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. 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. RegionB showed no PI signals within the region, except one including sequence SC2018 (Sichuan), and thus this sequence was also removed from the set. All custom code used in the manuscript is available at https://github.com/plemey/SARSCoV2origins. Lancet 395, 565574 (2020). Nat Microbiol 5, 14081417 (2020). 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.

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