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. 3). 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. Lancet 383, 541548 (2013). =0.00075 and one with a mean of 0.00024 and s.d. Virus Evol. Its genome is closest to that of severe acute respiratory syndrome-related coronaviruses from horseshoe bats, and its receptor-binding domain is closest to that of pangolin viruses. performed recombination and phylogenetic analysis and annotated virus names with geographical and sampling dates. Wu, F. et al. The origins we present in Fig. 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. Probable Pangolin Origin of SARS-CoV-2 Associated with the COVID-19 As a proxy, it would be possible to model the long-term purifying selection dynamics as a major source of time-dependent rates43,44,52, but this is beyond the scope of the current study. 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. Bioinformatics 30, 13121313 (2014). Means and 95% HPD intervals are 0.080 [0.0580.101] and 0.530 [0.3040.780] for the patristic distances between SARS-CoV-2 and RaTG13 (green) and 0.143 [0.1090.180] and 0.154 [0.0930.231] for the patristic distances between SARS-CoV-2 and Pangolin 2019 (orange). Med. Nature 538, 193200 (2016). Nature 558, 180182 (2018). 725422-ReservoirDOCS). Python 379 102 pangoLEARN Public Store of the trained model for pangolin to access. RegionB is 5,525nt long. 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. 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. Below, we report divergence time estimates based on the HCoV-OC43-centred rate prior for NRR1, NRR2 and NRA3 and summarize corresponding estimates for the MERS-CoV-centred rate priors in Extended Data Fig. 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. SARS-CoV-2 and RaTG13 are also exceptions because they were sampled from Hubei and Yunnan, respectively. 1, vev016 (2015). 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 . We use three bioinformatic approaches to remove the effects of recombination, and we combine these approaches to identify putative non-recombinant regions that can be used for reliable phylogenetic reconstruction and dating. Smuggled pangolins were carrying viruses closely related to the one sweeping the world, say scientists. Nat Microbiol 5, 14081417 (2020). Sequences are colour-coded by province according to the map. GARD identified eight breakpoints that were also within 50nt of those identified by 3SEQ. J. Virol. Kosakovsky Pond, S. L., Posada, D., Gravenor, M. B., Woelk, C. H. & Frost, S. D. W. Automated phylogenetic detection of recombination using a genetic algorithm. Green boxplots show the TMRCA estimate for the RaTG13/SARS-CoV-2 lineage and its most closely related pangolin lineage (Guangdong 2019). Evol. Specifically, using a formal Bayesian approach42 (see Methods), we estimate a fast evolutionary rate (0.00169 substitutions per siteyr1, 95% highest posterior density (HPD) interval (0.00131,0.00205)) for SARS viruses sampled over a limited timescale (1year), a slower rate (0.00078 (0.00063,0.00092) substitutions per siteyr1) for MERS-CoV on a timescale of about 4years and the slowest rate (0.00024 (0.00019,0.00029) substitutions per siteyr1) for HCoV-OC43 over almost five decades. Because the SARS-CoV-2 S protein has been implicated in past recombination events or possibly convergent evolution12, we specifically investigated several subregions of the Sproteinthe N-terminal domain of S1, the C-terminal domain of S1, the variable-loop region of the C-terminal domain, and S2. Decimal years are shown on the x axis for the 1.2 years of SARS sampling in c. d, Mean evolutionary rate estimates plotted against sampling time range for the same three datasets (represented by the same colour as the data points in their respective RtT divergence plots), as well as for the comparable NRA3 using the two different priors for the rate in the Bayesian inference (red points). 26, 450452 (2020). 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). Due to the absence of temporal signal in the sarbecovirus datasets, we used informative prior distributions on the evolutionary rate to estimate divergence dates. Regions AC were further examined for mosaic signals by 3SEQ, and all showed signs of mosaicism. Biol. Rev. Preprint at https://doi.org/10.1101/2020.02.10.942748 (2020). 3 Priors and posteriors for evolutionary rate of SARS-CoV-2. However, on closer inspection, the relative divergences in the phylogenetic tree (Fig. It is clear from our analysis that viruses closely related to SARS-CoV-2 have been circulating in horseshoe bats for many decades. The rate of genome generation is unprecedented, yet there is currently no coherent nor accepted scheme for naming the expanding . 6, eabb9153 (2020). 2a. Nature 579, 265269 (2020). Except for specifying that sequences are linear, all settings were kept to their defaults. Our most conservative approach attempted to ensure that putative NRRs had no mosaic or phylogenetic incongruence signals. Based on the identified breakpoints in each genome, only the major non-recombinant region is kept in each genome while other regions are masked. These datasets were subjected to the same recombination masking approach as NRA3 and were characterized by a strong temporal signal (Fig. The Artic Network receives funding from the Wellcome Trust through project no. Extensive diversity of coronaviruses in bats from China. CAS BEAGLE 3: improved performance, scaling, and usability for a high-performance computing library for statistical phylogenetics. For the HCoV-OC43, MERS-CoV and SARS datasets we specified flexible skygrid coalescent tree priors. 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. Use the Previous and Next buttons to navigate the slides or the slide controller buttons at the end to navigate through each slide. Phylogenies of subregions of NRR1 depict an appreciable degree of spatial structuring of the bat sarbecovirus population across different regions (Fig. Impact of SARS-CoV-2 Gamma lineage introduction and COVID-19 - Nature We thank all authors who have kindly deposited and shared genome data on GISAID. 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. Pango lineage designation and assignment using SARS-CoV-2 - PubMed Nat. & Holmes, E. C. A genomic perspective on the origin and emergence of SARS-CoV-2. 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. CAS Hon, C. 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. & Boni, M. F. Improved algorithmic complexity for the 3SEQ recombination detection algorithm. Why Can't We Just Call BA.2 Omicron? - The Atlantic As of December 2, 2021, SJdRP, a medium-sized city in the Northwest region of So Paulo state, Brazil (Fig. 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. 1, vev003 (2015). Trafficked pangolins can carry coronaviruses closely related to 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. CNN . He, B. et al. These differences reflect the fact that rate estimates can vary considerably with the timescale of measurement, a frequently observed phenomenon in viruses known as time-dependent evolutionary rates41,43,44. Lancet 395, 565574 (2020). T.T.-Y.L. M.F.B. J. Virol. Evol. These rate priors are subsequently used in the Bayesian inference of posterior rates for NRR1, NRR2, and NRA3 as indicated by the solid arrows. COVID-19: A Catastrophe or Opportunity for Pangolin Conservation? - Nature Evol. The sizes of the black internal node circles are proportional to the posterior node support. Biol. While there is involvement of other mammalian speciesspecifically pangolins for SARS-CoV-2as a plausible conduit for transmission to humans, there is no evidence that pangolins are facilitating adaptation to humans. Biol. Coronavirus Software Tools - Illumina, Inc. The fact that these estimates lie between the rates for MERS-CoV and HCoV-OC43 is consistent with the intermediate sampling time range of about 18years (Fig. and X.J. Aside from RaTG13, Pangolin-CoV is the most closely related CoV to SARS-CoV-2. PubMed Coronavirus: Pangolins found to carry related strains - BBC News eLife 7, e31257 (2018). stand-alone pangolin work flows or Illumina DRAGEN COVID Lineage App (v3.5.5) following the default parameters. 110. 1c). 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. Biol. 2). 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)). 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. 17, 15781579 (1999). GitHub - cov-lineages/pangolin: Software package for assigning SARS-CoV-2 genome sequences to global lineages. Virus Evol. 25, 3548 (2017). The red and blue boxplots represent the divergence time estimates for SARS-CoV-2 (red) and the 2002-2003 SARS-CoV (blue) from their most closely related bat virus, with the light- and dark-colored versions based on the HCoV-OC43 and MERS-CoV centered priors, respectively. Pangolins may have incubated the novel coronavirus, gene study shows 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 . Bioinformatics 28, 32483256 (2012). RegionB showed no PI signals within the region, except one including sequence SC2018 (Sichuan), and thus this sequence was also removed from the set. Aiewsakun, P. & Katzourakis, A. Time-dependent rate phenomenon in viruses. We showed that severe acute respiratory syndrome coronavirus 2 is probably a novel recombinant virus. 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). volume5,pages 14081417 (2020)Cite this article. Zhou, P. et al. Viral metagenomics revealed Sendai virus and coronavirus infection of Malayan pangolins (Manis javanica). All four of these breakpoints were also identified with the tree-based recombination detection method GARD35. USA 113, 30483053 (2016). PLoS Pathog. 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. Sliding window analysis of changes in the patterns of sequence similarity between human SARS-CoV-2, and pangolin and bat coronaviruses as described further in Fig. PubMed Adv. In Extended Data Fig. Don't blame pangolins, coronavirus family tree tracing could prove key is funded by the MRC (no.