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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. Nature 579, 270273 (2020). 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. & Andersen, K. G. The evolution of Ebola virus: insights from the 20132016 epidemic. Complete genome sequence data were downloaded from GenBank and ViPR; accession numbers of all 68sequences are available in Supplementary Table 4. 5. This boundary appears to be rarely crossed. All three approaches to removal of recombinant genomic segments point to a single ancestral lineage for SARS-CoV-2 and RaTG13. BEAST inferences made use of the BEAGLE v.3 library68 for efficient likelihood computations. It allows a user to assign a SARS-CoV-2 genome sequence the most likely lineage (Pango lineage) to SARS-CoV-2 query sequences. 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. Article acknowledges support by the Research FoundationFlanders (Fonds voor Wetenschappelijk OnderzoekVlaanderen (nos. 1c). PubMedGoogle Scholar. 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. Genetic lineages of SARS-CoV-2 have been emerging and circulating around the world since the beginning of the COVID-19 pandemic. 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. Xiao, K. et al. b, Similarity plot between SARS-CoV-2 and several selected sequences including RaTG13 (black), SARS-CoV (pink) and two pangolin sequences (orange). Our third approach involved identifying breakpoints and masking minor recombinant regions (with gaps, which are treated as unobserved characters in probabilistic phylogenetic approaches). Extended Data Fig. Identifying SARS-CoV-2-related coronaviruses in Malayan pangolins. Virological.org http://virological.org/t/ncovs-relationship-to-bat-coronaviruses-recombination-signals-no-snakes-no-evidence-the-2019-ncov-lineage-is-recombinant/331 (2020). Humans' selfish, speciesist treatment of these animals could be the very reason why the novel coronavirus exists. Lam, T. T. et al. 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 . 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. Conservatively, we combined the three BFRs >2kb identified above into non-recombining region1 (NRR1). 84, 31343146 (2010). The relatively fast evolutionary rate means that it is most appropriate to estimate shallow nodes in the sarbecovirus evolutionary history. Temporal signal was tested using a recently developed marginal likelihood estimation procedure41 (Supplementary Table 1). 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. Because the estimated rates and divergence dates were highly similar in the three datasets analysed, we conclude that our estimates are robust to the method of identifying a genomes NRRs. Indeed, the rates reported by these studies are in line with the short-term SARS rates that we estimate (Fig. (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. Note that six of these sequences fall under the terms of use of the GISAID platform. The inset represents divergence time estimates based on NRR1, NRR2 and NRA3. Stamatakis, A. RAxML version 8: a tool for phylogenetic analysis and post-analysis of large phylogenies. 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. 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. Collectively our analyses point to bats being the primary reservoir for the SARS-CoV-2 lineage. 3) to examine the sensitivity of date estimates to this prior specification. The authors declare no competing interests. J. Virol. 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. Aiewsakun, P. & Katzourakis, A. Time-dependent rate phenomenon in viruses. Google Scholar. 1 Phylogenetic relationships in the C-terminal domain (CTD). Syst. Boxes show 95% HPD credible intervals. Evol. 190, 20882095 (2004). Boni, M. F., Zhou, Y., Taubenberger, J. K. & Holmes, E. C. Homologous recombination is very rare or absent in human influenza A virus. 25, 3548 (2017). This new approach classifies the newly sequenced genome against all the diverse lineages present instead of a representative select sequences. Microbiol. Emerg. T.L. eLife 7, e31257 (2018). 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. stand-alone pangolin work flows or Illumina DRAGEN COVID Lineage App (v3.5.5) following the default parameters. Here, we analyse the evolutionary history of SARS-CoV-2 using available genomic data on sarbecoviruses. 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 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. 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 . 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. Preprint at https://doi.org/10.1101/2020.04.20.052019 (2020). and X.J. Using a third consensus-based approach for identifying recombinant regions in individual sequenceswith six different recombination detection methods in RDP5 (ref. Boni, M.F., Lemey, P., Jiang, X. et al. PubMed Central 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. 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. This statement informs us of the possibility that a virus has spilled over from a very rare and shy reptile-looking mammal . Rambaut, A., Lam, T. T., Carvalho, L. M. & Pybus, O. G. Exploring the temporal structure of heterochronous sequences using TempEst (formerly Path-O-Gen). 26, 450452 (2020). 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). Viruses 11, 174 (2019). Biol. It is RaTG13 that is more divergent in the variable-loop region (Extended Data Fig. Frontiers | Novel Highly Divergent SARS-CoV-2 Lineage With the Spike Further information on research design is available in the Nature Research Reporting Summary linked to this article. J. Virol. 3). We thank A. Chan and A. Irving for helpful comments on the manuscript. The proximal origin of SARS-CoV-2 | Nature Medicine Emergence of SARS-CoV-2 through recombination and strong purifying selection. 30, 21962203 (2020). Based on the identified breakpoints in each genome, only the major non-recombinant region is kept in each genome while other regions are masked. 5 Comparisons of GC content across taxa. Posterior distributions were approximated through Markov chain Monte Carlo sampling, which were run sufficiently long to ensure effective sampling sizes >100. The difficulty in inferring reliable evolutionary histories for coronaviruses is that their high recombination rate48,49 violates the assumption of standard phylogenetic approaches because different parts of the genome have different histories. USA 113, 30483053 (2016). The idea is that pangolins carrying the virus, SARS-CoV-2, came into contact with humans. and JavaScript. The plots are based on maximum likelihood tree reconstructions with a root position that maximises the residual mean squared for the regression of root-to-tip divergence and sampling time. # File containing the ID of the samples, the Sequence of the haplotype, the Continent, the country, the Region, the Data, the Lineage of Pangolin and Nextstrain clade, and the haplotype number # In this order # Could be obtained from the database PLoS Pathog. Because coronaviruses are known to be highly recombinant, we used three different approaches to identify non-recombinant regions for use in our Bayesian time-calibrated phylogenetic inference. Combining regions A, B and C and removing the five named sequences gives us putative NRR1, as an alignment of 63sequences. 4 TMRCAs for SARS-CoV and SARS-CoV-2. Sci. Nat Microbiol 5, 14081417 (2020). To estimate non-synonymous over synonymous rate ratios for the concatenated coding genes, we used the empirical Bayes Renaissance countingprocedure67. It is clear from our analysis that viruses closely related to SARS-CoV-2 have been circulating in horseshoe bats for many decades. Katoh, K., Asimenos, G. & Toh, H. in Bioinformatics for DNA Sequence Analysis (ed. 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. Mol. The Bat, the Pangolin and the City: A Tale of COVID-19 PubMed Evolutionary origins of the SARS-CoV-2 sarbecovirus lineage responsible for the COVID-19 pandemic. 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. Evol. Future trajectory of SARS-CoV-2: Constant spillover back and forth Identifying the origins of an emerging pathogen can be critical during the early stages of an outbreak, because it may allow for containment measures to be precisely targeted at a stage when the number of daily new infections is still low. 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. 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. First, we took an approach that relies on identification of mosaic regions (via 3SEQ14 v.1.7) that are also supported by PI signals19. MC_UU_1201412). 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. SARS-like WIV1-CoV poised for human emergence. Coronavirus origins: genome analysis suggests two viruses may have combined 13, e1006698 (2017). J. Virol. Anderson, K. G., Rambaut, A., Lipkin, W. I., Holmes, E. C. & Garry, R. F. The proximal origin of SARS-CoV-2. Publishers note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Discovery and genetic analysis of novel coronaviruses in least horseshoe bats in southwestern China. 24, 490502 (2016). & Boni, M. F. Improved algorithmic complexity for the 3SEQ recombination detection algorithm. =0.00075 and one with a mean of 0.00024 and s.d. & Bedford, T. MERS-CoV spillover at the camelhuman interface. Coronavirus Disease 2019 (COVID-19) Situation Report 51 (World Health Organization, 2020). Coronavirus: Pangolins found to carry related strains. The virus then. Sibling lineages to RaTG13/SARS-CoV-2 include a pangolin sequence sampled in Guangdong Province in March 2019 and a clade of pangolin sequences from Guangxi Province sampled in 2017. 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. Lancet 395, 949950 (2020). 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 . PLoS Pathog. Of the countries that have contributed SARS-CoV-2 data, 30% had genomes of this lineage. July 26, 2021. "This is an extremely interesting . 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. 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). GitHub - cov-lineages/pangolin: Software package for assigning SARS-CoV-2 genome sequences to global lineages. is funded by The National Natural Science Foundation of China Excellent Young Scientists Fund (Hong Kong and Macau; no. The Artic Network receives funding from the Wellcome Trust through project no. Get the most important science stories of the day, free in your inbox. master 4 branches 94 tags Code AngieHinrichs Add entries for pangolin-data/-assignment 1.18.1.1 ( #512) ad16752 4 days ago 990 commits .github/ workflows Update pangolin.yml 7 months ago docs docs need guide tree now 3 years ago pangolin S. China corresponds to Guangxi, Yunnan, Guizhou and Guangdong provinces. P.L. A., Lytras, S., Singer, J. We used TreeAnnotator to summarize posterior tree distributions and annotated the estimated values to a maximum clade credibility tree, which was visualized using FigTree. This commit does not belong to any branch on this repository, and may belong to a fork outside of the repository. 53), this is inferred to have occurred before the divergence of RaTG13 and SARS-CoV-2 and thus should not influence our inferences. But some theories suggest that pangolins may be the source of the novel coronavirus. 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. Identifying SARS-CoV-2-related coronaviruses in Malayan pangolins 1, vev016 (2015). PubMed Central Phylogenetic Assignment of Named Global Outbreak Lineages 2 Lack of root-to-tip temporal signal in SARS-CoV-2. 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 & Muhire, B. RDP4: Detection and analysis of recombination patterns in virus genomes. Due to the absence of temporal signal in the sarbecovirus datasets, we used informative prior distributions on the evolutionary rate to estimate divergence dates. Evidence of the recombinant origin of a bat severe acute respiratory syndrome (SARS)-like coronavirus and its implications on the direct ancestor of SARS coronavirus. Time-measured phylogenetic reconstruction was performed using a Bayesian approach implemented in BEAST42 v.1.10.4. Genetics 176, 10351047 (2007). . Extended Data Fig. 874850). 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. Mol. 87, 62706282 (2013). Patino-Galindo, J. Evol. Bioinformatics 22, 26882690 (2006). is funded by the MRC (no. Wong, A. C. P., Li, X., Lau, S. K. P. & Woo, P. C. Y. A new coronavirus associated with human respiratory disease in China. Curr. Mol. 23, 18911901 (2006). https://doi.org/10.1038/s41564-020-0771-4, DOI: https://doi.org/10.1038/s41564-020-0771-4. A pneumonia outbreak associated with a new coronavirus of probable bat origin. These authors contributed equally: Maciej F. Boni, Philippe Lemey. He, B. et al. Coronavirus: Pangolins found to carry related strains - BBC News & Holmes, E. C. A genomic perspective on the origin and emergence of SARS-CoV-2. 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.