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). Gorbalenya, A. E. et al. 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). RegionB is 5,525nt long. 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 . The estimated divergence times for the pangolin virus most closely related to the SARS-CoV-2/RaTG13 lineage range from 1851 (1730-1958) to 1877 (1746-1986), indicating that these pangolin . The Pango dynamic nomenclature is a popular system for classifying and naming genetically-distinct lineages of SARS-CoV-2, including variants of concern, and is based on the analysis of complete or near-complete virus genomes. 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. 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. 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 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). 5). Posada, D., Crandall, K. A. Katoh, K., Asimenos, G. & Toh, H. in Bioinformatics for DNA Sequence Analysis (ed. Extended Data Fig. & Boni, M. F. Improved algorithmic complexity for the 3SEQ recombination detection algorithm. 4), that region and shorter BFRs were not included in combined putative non-recombinant regions. In this approach, we considered a breakpoint as supported only if it had three types of statistical support: from (1) mosaic signals identified by 3SEQ, (2) PI signals identified by building trees around 3SEQs breakpoints and (3) the GARD algorithm35, which identifies breakpoints by identifying PI signals across proposed breakpoints. Biol. Phylogenetic Assignment of Named Global Outbreak Lineages Another similarity between SARS-CoV and SARS-CoV-2 is their divergence time (4070years ago) from currently known extant bat virus lineages (Fig. 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. Regions AC were further examined for mosaic signals by 3SEQ, and all showed signs of mosaicism. Proc. Evol. 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. Nat. 1c). Zhou, H. et al. However, on closer inspection, the relative divergences in the phylogenetic tree (Fig. Several of the recombinant sequences in these trees show that recombination events do occur across geographically divergent clades. CNN . and P.L.) & Muhire, B. RDP4: Detection and analysis of recombination patterns in virus genomes. First, we took an approach that relies on identification of mosaic regions (via 3SEQ14 v.1.7) that are also supported by PI signals19. Indeed, the rates reported by these studies are in line with the short-term SARS rates that we estimate (Fig. is funded by The National Natural Science Foundation of China Excellent Young Scientists Fund (Hong Kong and Macau; no. Among the 68sequences in the aligned sarbecovirus sequence set, 67 show evidence of mosaicism (all DunnSidak-corrected P<4104 and 3SEQ14), indicating involvement in homologous recombination either directly with identifiable parentals or in their deeper shared evolutionary historythat is, due to shared ancestral recombination events. Did Pangolin Trafficking Cause the Coronavirus Pandemic? Extended Data Fig. B.W.P. Google Scholar. 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. Novel Coronavirus (2019-nCoV) Situation Report 1, 21 January 2020 (World Health Organization, 2020). 13, e1006698 (2017). Schierup, M. H. & Hein, J. Recombination and the molecular clock. Green boxplots show the TMRCA estimate for the RaTG13/SARS-CoV-2 lineage and its most closely related pangolin lineage (Guangdong 2019). Since experts have suggested that pangolins may be the reservoir species for COVID-19, the scaly anteater has been catapulted into headlines, news reports, and conversationsand some are calling COVID-19 "the revenge of the . The rate of genome generation is unprecedented, yet there is currently no coherent nor accepted scheme for naming the expanding . Intraspecies diversity of SARS-like coronaviruses in Rhinolophus sinicus and its implications for the origin of SARS coronaviruses in humans. Share . 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. All custom code used in the manuscript is available at https://github.com/plemey/SARSCoV2origins. 3) to examine the sensitivity of date estimates to this prior specification. Su, S. et al. 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). 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. Evol. Wang, H., Pipes, L. & Nielsen, R. Synonymous mutations and the molecular evolution of SARS-Cov-2 origins. Pangolin relies on a novel algorithm called pangoLEARN. Meet the people who warn the world about new covid variants 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. Suchard, M. A. et al. 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). Phylogenies of subregions of NRR1 depict an appreciable degree of spatial structuring of the bat sarbecovirus population across different regions (Fig. Even before the COVID-19 pandemic, pangolins have been making headlines. Aside from RaTG13, Pangolin-CoV is the most closely related CoV to SARS-CoV-2. These means are based on the mean rates estimated for MERS-CoV and HCoV-OC43, respectively, while the standard deviations are set ten times higher than empirical values to allow greater prior uncertainty and avoid strong bias (Extended Data Fig. Nat Microbiol 5, 14081417 (2020). Graham, R. L. & Baric, R. S. Recombination, reservoirs, and the modular spike: mechanisms of coronavirus cross-species transmission. Sequencing from Malayan pangolins collected during anti-smuggling operations in southern China detected coronavirus lineages related to SARS-CoV-2. Coronavirus Disease 2019 (COVID-19) Situation Report 51 (World Health Organization, 2020). 190, 20882095 (2004). matics program called Pangolin was developed. 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. J. Virol. Divergence dates between SARS-CoV-2 and the bat sarbecovirus reservoir were estimated as 1948 (95% highest posterior density (HPD): 18791999), 1969 (95% HPD: 19302000) and 1982 (95% HPD: 19482009), indicating that the lineage giving rise to SARS-CoV-2 has been circulating unnoticed in bats for decades. Using these breakpoints, the longest putative non-recombining segment (nt1,88521,753) is 9.9kb long, and we call this region NRR2. Is the COVID-19 Outbreak the 'Revenge of the Pangolin'? | PETA These authors contributed equally: Maciej F. Boni, Philippe Lemey. We thank A. Chan and A. Irving for helpful comments on the manuscript. 382, 11991207 (2020). Conservatively, we combined the three BFRs >2kb identified above into non-recombining region1 (NRR1). This boundary appears to be rarely crossed. A counting renaissance: combining stochastic mapping and empirical Bayes to quickly detect amino acid sites under positive selection. Biol. While there is evidence of positive selection in the sarbecovirus lineage leading to RaTG13/SARS-CoV-2 (ref. 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). . Phylogenetic classification of the whole-genome sequences of SARS-CoV-2 Lie, P., Chen, W. & Chen, J.-P. Researchers in the UK had just set the scientific world . The S1 protein of Pangolin-CoV is much more closely related to SARS-CoV-2 than to RaTG13. R. Soc. 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. Li, X. et al. [12] 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. 24, 490502 (2016). Of importance for future spillover events is the appreciation that SARS-CoV-2 has emerged from the same horseshoe bat subgenus that harbours SARS-like coronaviruses. 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 . Virus Evol. Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. Phylogenetic trees and exact breakpoints for all ten BFRs are shown in Supplementary Figs. Holmes, E. C., Rambaut, A. Nature 538, 193200 (2016). Except for specifying that sequences are linear, all settings were kept to their defaults. Mol. J. Virol. 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. 4, vey016 (2018). 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. Hon, C. et al. Wong, A. C. P., Li, X., Lau, S. K. P. & Woo, P. C. Y. 82, 18191826 (2008). Lam, H. M., Ratmann, O. 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. 5, 536544 (2020). Ji, W., Wang, W., Zhao, X., Zai, J. Mol. Webster, R. G., Bean, W. J., Gorman, O. T., Chambers, T. M. & Kawaoka, Y. Evolution and ecology of influenza A viruses. Pangolin-CoV is 91.02% and 90.55% identical to SARS-CoV-2 and BatCoV RaTG13, respectively, at the whole-genome level. Are you sure you want to create this branch? 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. Holmes, E. C., Dudas, G., Rambaut, A. Centre for Genomic Pathogen Surveillance. Emergence of SARS-CoV-2 through recombination and strong purifying selection. SARS-like WIV1-CoV poised for human emergence. Med. A dynamic nomenclature proposal for SARS-CoV-2 lineages to assist CAS Python 379 102 pangoLEARN Public Store of the trained model for pangolin to access. Smuggled pangolins were carrying viruses closely related to the one sweeping the world, say scientists. . Don't blame pangolins, coronavirus family tree tracing could prove key