The idea is that pangolins carrying the virus, SARS-CoV-2, came into contact with humans. Virus Evol. Natl Acad. Virological.org http://virological.org/t/ncov-2019-codon-usage-and-reservoir-not-snakes-v2/339 (2020). 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. and T.A.C. 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. 725422-ReservoirDOCS). Virus Evol. Over relatively shallow timescales, such differences can primarily be explained by varying selective pressure, with mildly deleterious variants being eliminated more strongly by purifying selection over longer timescales44,45,46. Biol. Our most conservative approach attempted to ensure that putative NRRs had no mosaic or phylogenetic incongruence signals. In March, when covid cases began spiking around India, Bani Jolly went hunting for answers in the virus's genetic code. 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. Biol. NTD, N-terminal domain; CTD, C-terminal domain. All authors contributed to analyses and interpretations. https://doi.org/10.1093/molbev/msaa163 (2020). 24, 490502 (2016). 5). A., Filip, I., AlQuraishi, M. & Rabadan, R. Recombination and lineage-specific mutations led to the emergence of SARS-CoV-2. We compare both MERS-CoV- and HCoV-OC43-centred prior distributions (Extended Data Fig. Are pangolins the intermediate host of the 2019 novel coronavirus (SARS-CoV-2)? Evol. Combining regions A, B and C and removing the five named sequences gives us putative NRR1, as an alignment of 63sequences. b, Similarity plot between SARS-CoV-2 and several selected sequences including RaTG13 (black), SARS-CoV (pink) and two pangolin sequences (orange). A counting renaissance: combining stochastic mapping and empirical Bayes to quickly detect amino acid sites under positive selection. D.L.R. MERS-CoV data were subsampled to match sample sizes with SARS-CoV and HCoV-OC43. Grey tips correspond to bat viruses, green to pangolin, blue to SARS-CoV and red to SARS-CoV-2. 2). 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. 5). Microbiol. M.F.B., P.L. Maciej F. Boni, Philippe Lemey, Andrew Rambaut or David L. Robertson. It allows a user to assign a SARS-CoV-2 genome sequence the most likely lineage (Pango lineage) to SARS-CoV-2 query sequences. 17, 15781579 (1999). PubMed 4. wrote the first draft of the manuscript, and all authors contributed to manuscript editing. 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). A novel bat coronavirus closely related to SARS-CoV-2 contains natural insertions at the S1/S2 cleavage site of the Spike protein. To estimate non-synonymous over synonymous rate ratios for the concatenated coding genes, we used the empirical Bayes Renaissance countingprocedure67. Extensive diversity of coronaviruses in bats from China. Evol. BEAGLE 3: improved performance, scaling, and usability for a high-performance computing library for statistical phylogenetics. performed recombination analysis for non-recombining alignment3, calibration of rate of evolution and phylogenetic reconstruction and dating. CNN . Menachery, V. D. et al. 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. The inset represents divergence time estimates based on NRR1, NRR2 and NRA3. Get the most important science stories of the day, free in your inbox. 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. This leaves the insertion of polybasic. Bruen, T. C., Philippe, H. & Bryant, D. A simple and robust statistical test for detecting the presence of recombination. Bioinformatics 22, 26882690 (2006). Biol. Biol. Evol. Several of the recombinant sequences in these trees show that recombination events do occur across geographically divergent clades. While there is evidence of positive selection in the sarbecovirus lineage leading to RaTG13/SARS-CoV-2 (ref. CAS 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. Virology 507, 110 (2017). Published. Root-to-tip divergence as a function of sampling time for non-recombinant regions NRR1 and NRR2 and recombination-masked alignment set NRA3. It is clear from our analysis that viruses closely related to SARS-CoV-2 have been circulating in horseshoe bats for many decades. CAS 1, vev016 (2015). eLife 7, e31257 (2018). Duchene, S., Holmes, E. C. & Ho, S. Y. W. Analyses of evolutionary dynamics in viruses are hindered by a time-dependent bias in rate estimates. Pangolin relies on a novel algorithm called pangoLEARN. 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. Sorting these breakpoint-free regions (BFRs) by length results in two segments >5kb: an ORF1a subregion spanning nucleotides (nt) 3,6259,150 and the first half of ORF1b spanning nt13,29119,628 (sequence numbering given in Source Data, https://github.com/plemey/SARSCoV2origins). Regions AC were further examined for mosaic signals by 3SEQ, and all showed signs of mosaicism. The presence in pangolins of an RBD very similar to that of SARS-CoV-2 means that we can infer this was also probably in the virus that jumped to humans. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. J. Virol. Robertson, D. nCoVs relationship to bat coronaviruses & recombination signals (no snakes) no evidence the 2019-nCoV lineage is recombinant. 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. 36)gives a putative recombination-free alignment that we call non-recombinant alignment3 (NRA3) (see Methods). 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. J. Virol. CAS We thank A. Chan and A. Irving for helpful comments on the manuscript. We used TreeAnnotator to summarize posterior tree distributions and annotated the estimated values to a maximum clade credibility tree, which was visualized using FigTree. Trova, S. et al. 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. Note that six of these sequences fall under the terms of use of the GISAID platform. Despite the high frequency of recombination among bat viruses, the block-like nature of the recombination patterns across the genome permits retrieval of a clean subalignment for phylogenetic analysis. Preprint at https://doi.org/10.1101/2020.05.28.122366 (2020). Mol. Slider with three articles shown per slide. The command line tool is open source software available under the GNU General Public License v3.0. To employ phylogenetic dating methods, recombinant regions of a 68-genome sarbecovirus alignment were removed with three independent methods. Extended Data Fig. PureBasic 53 13 constellations Public Python 42 17 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. 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. The shaded region corresponds to the Sprotein. 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. Su, S. et al. 4), that region and shorter BFRs were not included in combined putative non-recombinant regions. Epidemiology, genetic recombination, and pathogenesis of coronaviruses. Dudas, G., Carvalho, L. M., Rambaut, A. Pangolin-CoV is 91.02% and 90.55% identical to SARS-CoV-2 and BatCoV RaTG13, respectively, at the whole-genome level. PubMed Central 874850). 3). If the latter still identified non-negligible recombination signal, we removed additional genomes that were identified as major contributors to the remaining signal. S. China corresponds to Guangxi, Yunnan, Guizhou and Guangdong provinces. Menachery, V. D. et al.

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