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. The coverage threshold and consensus sequence generation threshold were set to 20 and 90 respectively. CoV-lineages GitHub SARS-CoV-2 genetic lineages in the United States are routinely monitored through epidemiological investigations, virus genetic sequence-based surveillance, and laboratory studies. Host ecology determines the dispersal patterns of a plant virus. Virus Evol. 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. Zhang, Y.-Z. While there is evidence of positive selection in the sarbecovirus lineage leading to RaTG13/SARS-CoV-2 (ref. Transparent bands of interquartile range width and with the same colours are superimposed to highlight the overlap between estimates. We call this approach breakpoint-conservative, but note that this has the opposite effect to the construction of NRR1 in that this approach is the most likely to allow breakpoints to remain inside putative non-recombining regions. 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. 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. 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. 4). Why Can't We Just Call BA.2 Omicron? - The Atlantic For the current pandemic, the novel pathogen identification component of outbreak response delivered on its promise, with viral identification and rapid genomic analysis providing a genome sequence and confirmation, within weeks, that the December 2019 outbreak first detected in Wuhan, China was caused by a coronavirus3. 1c). Coronavirus: Pangolins found to carry related strains. SARS-CoV-2 and RaTG13 are also exceptions because they were sampled from Hubei and Yunnan, respectively. In March, when covid cases began spiking around India, Bani Jolly went hunting for answers in the virus's genetic code. Li, X. et al. Wong, A. C. P., Li, X., Lau, S. K. P. & Woo, P. C. Y. Extended Data Fig. 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). The authors declare no competing interests. 6, eabb9153 (2020). Sign up for the Nature Briefing newsletter what matters in science, free to your inbox daily. Originally, PANGOLIN used a maximum-likelihood-based assignment algorithm to assign query SARS-CoV-2 the most likely lineage sequence. 874850). Boxes show 95% HPD credible intervals. To obtain Press, H.) 3964 (Springer, 2009). 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. Prolonged SARS-CoV-2 Infection and Intra-Patient Viral Evolu : The PubMed Grey tips correspond to bat viruses, green to pangolin, blue to SARS-CoV and red to SARS-CoV-2. 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. MERS-CoV data were subsampled to match sample sizes with SARS-CoV and HCoV-OC43. The relatively fast evolutionary rate means that it is most appropriate to estimate shallow nodes in the sarbecovirus evolutionary history. Membrebe, J. V., Suchard, M. A., Rambaut, A., Baele, G. & Lemey, P. Bayesian inference of evolutionary histories under time-dependent substitution rates. 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. 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 A phylogenetic treeusing RAxML v8.2.8 (ref. Katoh, K., Asimenos, G. & Toh, H. in Bioinformatics for DNA Sequence Analysis (ed. Mol. All custom code used in the manuscript is available at https://github.com/plemey/SARSCoV2origins. It is RaTG13 that is more divergent in the variable-loop region (Extended Data Fig. Relevant bootstrap values are shown on branches, and grey-shaded regions show sequences exhibiting phylogenetic incongruence along the genome. Lam, H. M., Ratmann, O. Stegeman, A. et al. A tag already exists with the provided branch name. 1, vev003 (2015). 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. 6, 8391 (2015). The proximal origin of SARS-CoV-2 | Nature Medicine Nature 583, 282285 (2020). 110. Are pangolins the intermediate host of the 2019 novel coronavirus (SARS-CoV-2)? For the HCoV-OC43, MERS-CoV and SARS datasets we specified flexible skygrid coalescent tree priors. 3). performed codon usage analysis. D.L.R. Green boxplots show the TMRCA estimate for the RaTG13/SARS-CoV-2 lineage and its most closely related pangolin lineage (Guangdong 2019). 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. Biol. J. Med. Possible Bat Origin of Severe Acute Respiratory Syndrome Coronavirus 2 Preprint at https://doi.org/10.1101/2020.02.10.942748 (2020). Posada, D., Crandall, K. A. Dis. 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 . The estimated divergence times for the pangolin virus most closely related to the SARS-CoV-2/RaTG13 lineage range from 1851 (17301958) to 1877 (17461986), indicating that these pangolin lineages were acquired from bat viruses divergent to those that gave rise to SARS-CoV-2. Nature 583, 286289 (2020). cov-lineages/pangolin - GitHub Intraspecies diversity of SARS-like coronaviruses in Rhinolophus sinicus and its implications for the origin of SARS coronaviruses in humans. Evol. the development of viral diversity. . J. Virol. 190, 20882095 (2004). PubMedGoogle Scholar. Bioinformatics 22, 26882690 (2006). Intragenomic rearrangements involving 5-untranslated region segments in SARS-CoV-2, other betacoronaviruses, and alphacoronaviruses, Crystal structure of the CoV-Y domain of SARS-CoV-2 nonstructural protein 3, Association of underlying comorbidities and progression of COVID-19 infection amongst 2586 patients hospitalised in the National Capital Region of India: a retrospective cohort study, Molecular characterization of horse nettle virus A, a new member of subgroup B of the genus Nepovirus, Molecular phylogeny of coronaviruses and host receptors among domestic and close-contact animals reveals subgenome-level conservation, crossover, and divergence. Sci. Accurate estimation of ages for deeper nodes would require adequate accommodation of time-dependent rate variation. Patino-Galindo, J. 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. The Bat, the Pangolin and the City: A Tale of COVID-19 Note that six of these sequences fall under the terms of use of the GISAID platform. Nat. covid19_mostefai2021_paper/01_CreateObjects.r at master HussinLab Biol. Mol. Microbiol. Bruen, T. C., Philippe, H. & Bryant, D. A simple and robust statistical test for detecting the presence of recombination. CAS Current Overview on Disease and Health Research Vol. 6 A second breakpoint-conservative approach was conservative with respect to breakpoint identification, but this means that it is accepting of false-negative outcomes in breakpoint inference, resulting in less certainty that a putative NRR truly contains no breakpoints. Download a free copy. Internet Explorer). PubMed Central Temporal signal was tested using a recently developed marginal likelihood estimation procedure41 (Supplementary Table 1). This new approach classifies the newly sequenced genome against all the diverse lineages present instead of a representative select sequences. =0.00025. 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. 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. 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. Hon, C. et al. 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 . 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. Maciej F. Boni, Philippe Lemey, Andrew Rambaut or David L. Robertson. Correspondence to In this study, we report the case of a child with severe combined immu presenting a prolonged severe acute respiratory syndrome coronavirus 2 infection. Google Scholar. J. Gen. Virol. These datasets were subjected to the same recombination masking approach as NRA3 and were characterized by a strong temporal signal (Fig. Zhou, P. et al. In the meantime, to ensure continued support, we are displaying the site without styles Google Scholar. The genetic distances between SARS-CoV-2 and RaTG13 (bottom) demonstrate that their relationship is consistent across all regions except for the variable loop. If the latter still identified non-negligible recombination signal, we removed additional genomes that were identified as major contributors to the remaining signal. Press, 2009). Extended Data Fig. 5 (NRR1) are conservative in the sense that NRR1 is more likely to be non-recombinant than NRR2 or NRA3. Nature 558, 180182 (2018). B.W.P. 6, e14 (2017). CAS Curr. The lineage B.1 has been the major basal and widespread lineage from the initial SARS-CoV-2 spread and it became the more prevalent lineage in Colombia ( 13 ), while the B.1.111 lineage, first detected in the USA from a sample collected on March 7, 2020 and subsequently in Colombia on March 13, 2020 is currently circulating and mainly represented 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. Open reading frames are shown above the breakpoint plot, with the variable-loop region indicated in the Sprotein. 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. Wang, L. et al. The web application was developed by the Centre for Genomic Pathogen Surveillance. 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. Virus Evol. Pangolins: What are they and why are they linked to Covid-19? - Inverse Preprint at https://doi.org/10.1101/2020.04.20.052019 (2020). PubMed 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). Trends Microbiol. 26, 450452 (2020). Webster, R. G., Bean, W. J., Gorman, O. T., Chambers, T. M. & Kawaoka, Y. Evolution and ecology of influenza A viruses. 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. Influenza viruses reassort17 but they do not undergo homologous recombination within RNA segments18,19, meaning that origins questions for influenza outbreaks can always be reduced to origins questions for each of influenzas eight RNA segments. Chernomor, O. et al. and T.A.C. Viruses 11, 979 (2019). Smuggled pangolins were carrying viruses closely related to the one sweeping the world, say scientists. Menachery, V. D. et al. 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 ). & Boni, M. F. Improved algorithmic complexity for the 3SEQ recombination detection algorithm. 3 Priors and posteriors for evolutionary rate of SARS-CoV-2. Evol. 21, 255265 (2004). Sequences were aligned by MAFTT58 v.7.310, with a final alignment length of 30,927, and used in the analyses below. 3). Consistent with this, we estimate a concomitantly decreasing non-synonymous-to-synonymous substitution rate ratio over longer evolutionary timescales: 1.41 (1.20,1.68), 0.35 (0.30,0.41) and 0.133 (0.129,0.136) for SARS, MERS-CoV and HCoV-OC43, respectively. 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. . Provided by the Springer Nature SharedIt content-sharing initiative, Molecular and Cellular Biochemistry (2023), Nature Microbiology (Nat Microbiol) When the genomic data included both coding and non-coding regions we used a single GTR+ substitution model; for concatenated coding genes we partitioned the alignment by codon position and specified an independent GTR+ model for each partition with a separate gamma model to accommodate inter-site rate variation. Biol. Evolutionary origins of the SARS-CoV-2 sarbecovirus lineage responsible for the COVID-19 pandemic. We showed that severe acute respiratory syndrome coronavirus 2 is probably a novel recombinant virus. Its origin and direct ancestral viruses have not been . performed recombination analysis for non-recombining regions1 and 2, breakpoint analysis and phylogenetic inference on recombinant segments. 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). Lin, X. et al. Global epidemiology of bat coronaviruses. Phylogenies of subregions of NRR1 depict an appreciable degree of spatial structuring of the bat sarbecovirus population across different regions (Fig. 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. A novel bat coronavirus closely related to SARS-CoV-2 contains natural insertions at the S1/S2 cleavage site of the Spike protein. The assumption of long-term purifying selection would imply that coronaviruses are in endemic equilibrium with their natural host species, horseshoe bats, to which they are presumably well adapted. This boundary appears to be rarely crossed. However, inconsistency in the nomenclature limits uniformity in its epidemiological understanding. Eden, J.-S., Tanaka, M. M., Boni, M. F., Rawlinson, W. D. & White, P. A. Recombination within the pandemic norovirus GII.4 lineage. Due to the absence of temporal signal in the sarbecovirus datasets, we used informative prior distributions on the evolutionary rate to estimate divergence dates. Li, Q. et al. Preprint at https://doi.org/10.1101/2020.05.28.122366 (2020). Zhou et al.2 concluded from the genetic proximity of SARS-CoV-2 to RaTG13 that a bat origin for the current COVID-19 outbreak is probable. 1 Phylogenetic relationships in the C-terminal domain (CTD). Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. b, Similarity plot between SARS-CoV-2 and several selected sequences including RaTG13 (black), SARS-CoV (pink) and two pangolin sequences (orange). A distinct name is needed for the new coronavirus. Regions AC were further examined for mosaic signals by 3SEQ, and all showed signs of mosaicism. All sequence data analysed in this manuscript are available at https://github.com/plemey/SARSCoV2origins. 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)). 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)). Holmes, E. C., Dudas, G., Rambaut, A. Which animal did the novel coronavirus come from? | Live Science performed recombination and phylogenetic analysis and annotated virus names with geographical and sampling dates. The histogram allows for the identification of non-recombining regions (NRRs) by revealing regions with no breakpoints. 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.