Aiewsakun, P. & Katzourakis, A. Time-dependent rate phenomenon in viruses. 1) and thus likely to be the product of recombination, acquiring a divergent variable loop from a hitherto unsampled bat sarbecovirus28. Dis. 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. Methods Ecol. Host ecology determines the dispersal patterns of a plant virus. Genetics 176, 10351047 (2007). 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. 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. obtained the genome sequences of 10 SARS-CoV-2 virus strains through nanopore sequencing of nasopharyngeal swabs in Malta and analyzed the assembled genome with pangolin software, and the results showed that these virus strains were assigned to B.1 lineage, indicating that SARS-CoV-2 was widely spread in Europe (Biazzo et al., 2021). Despite the SARS-CoV-2 lineages acquisition of residues in its Spike (S) proteins receptor-binding domain (RBD) permitting the use of human ACE2 (ref. 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. Nature 579, 265269 (2020). Humans' selfish, speciesist treatment of these animals could be the very reason why the novel coronavirus exists. Holmes, E. C., Rambaut, A. Boni, M. F., Zhou, Y., Taubenberger, J. K. & Holmes, E. C. Homologous recombination is very rare or absent in human influenza A virus. Sci. A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence. D.L.R. Across a large region of the virus genome, corresponding approximately to ORF1b, it did not cluster with any of the known bat coronaviruses indicating that recombination probably played a role in the evolutionary history of these viruses5,7. Emergence of SARS-CoV-2 through recombination and strong purifying selection. 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. These authors contributed equally: Maciej F. Boni, Philippe Lemey. 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. Evolutionary rate estimation can be profoundly affected by the presence of recombination50. 4, vey016 (2018). This underscores the need for a global network of real-time human disease surveillance systems, such as that which identified the unusual cluster of pneumonia in Wuhan in December 2019, with the capacity to rapidly deploy genomic tools and functional studies for pathogen identification and characterization. Conducting analogous analyses of codon usage bias as Ji et al. This boundary appears to be rarely crossed. Ge, X. et al. 2). 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. A third approach attempted to minimize the number of regions removed while also minimizing signals of mosaicism and homoplasy. 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. 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. 6, e14 (2017). from the European Research Council under the European Unions Horizon 2020 research and innovation programme (grant agreement no. 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. Virus Evol. 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 . Time-measured phylogenetic reconstruction was performed using a Bayesian approach implemented in BEAST42 v.1.10.4. The canine viral genome was excluded from the Bayesian phylogenetic analyses because temporal signal analyses (see below) indicated that it was an outlier. Developed by the Centre for Genomic Pathogen Surveillance. 1 Phylogenetic relationships in the C-terminal domain (CTD). 16, e1008421 (2020). Use the Previous and Next buttons to navigate the slides or the slide controller buttons at the end to navigate through each slide. 1c). & Bedford, T. MERS-CoV spillover at the camelhuman interface. Bayesian evolutionary rate and divergence date estimates were shown to be consistent for these three approaches and for two different prior specifications of evolutionary rates based on HCoV-OC43 and MERS-CoV. 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. 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. 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. 1c). However, on closer inspection, the relative divergences in the phylogenetic tree (Fig. 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. Rev. B 281, 20140732 (2014). J. Infect. Using both prior distributions, this results in six highly similar posterior rate estimates for NRR1, NRR2 and NRA3, centred around 0.00055 substitutions per siteyr1. First, we took an approach that relies on identification of mosaic regions (via 3SEQ14 v.1.7) that are also supported by PI signals19. Coronavirus: Pangolins found to carry related strains. Mol. Using these breakpoints, the longest putative non-recombining segment (nt1,88521,753) is 9.9kb long, and we call this region NRR2. We infer time-measured evolutionary histories using a Bayesian phylogenetic approach while incorporating rate priors based on mean MERS-CoV and HCoV-OC43 rates and with standard deviations that allow for more uncertainty than the empirical estimates for both viruses (see Methods). A pneumonia outbreak associated with a new coronavirus of probable bat origin. A., Filip, I., AlQuraishi, M. & Rabadan, R. Recombination and lineage-specific mutations led to the emergence of SARS-CoV-2. Relevant bootstrap values are shown on branches, and grey-shaded regions show sequences exhibiting phylogenetic incongruence along the genome. 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. 3). In addition, sequences NC_014470 (Bulgaria 2008), CoVZXC21, CoVZC45 and DQ412042 (Hubei-Yichang) needed to be removed to maintain a clean non-recombinant signal in A. Several of the recombinant sequences in these trees show that recombination events do occur across geographically divergent clades. Annu Rev. Mol. All three approaches to removal of recombinant genomic segments point to a single ancestral lineage for SARS-CoV-2 and RaTG13. These residues are also in the Pangolin Guangdong 2019 sequence. 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. 4. Google Scholar. All custom code used in the manuscript is available at https://github.com/plemey/SARSCoV2origins. Grey tips correspond to bat viruses, green to pangolin, blue to SARS-CoV and red to SARS-CoV-2. CNN . Evol. 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 Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor. Lam, T. T. et al. Biol. Uncertainty measures are shown in Extended Data Fig. The genetic distances between SARS-CoV-2 and RaTG13 (bottom) demonstrate that their relationship is consistent across all regions except for the variable loop. 2). Maclean, O. PubMedGoogle Scholar. The coronavirus genome that these researchers had assembled, from pangolin lung-tissue samples, contained some gene regions that were ninety-nine per cent similar to equivalent parts of the SARS . 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. To gauge the length of time this lineage has circulated in bats, we estimate the time to the most recent common ancestor (TMRCA) of SARS-CoV-2 and RaTG13. Boni, M. F., Posada, D. & Feldman, M. W. An exact nonparametric method for inferring mosaic structure in sequence triplets. Virus Evol. Extensive diversity of coronaviruses in bats from China. 32, 268274 (2014). We thank A. Chan and A. Irving for helpful comments on the manuscript. The relatively fast evolutionary rate means that it is most appropriate to estimate shallow nodes in the sarbecovirus evolutionary history. 4). 4 we compare these divergence time estimates to those obtained using the MERS-CoV-centred rate priors for NRR1, NRR2 and NRA3. 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. Due to the absence of temporal signal in the sarbecovirus datasets, we used informative prior distributions on the evolutionary rate to estimate divergence dates. 88, 70707082 (2014). b, Similarity plot between SARS-CoV-2 and several selected sequences including RaTG13 (black), SARS-CoV (pink) and two pangolin sequences (orange). & Holmes, E. C. A genomic perspective on the origin and emergence of SARS-CoV-2. Originally, PANGOLIN used a maximum-likelihood-based assignment algorithm to assign query SARS-CoV-2 the most likely lineage sequence. (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. We thank T. Bedford for providing M.F.B. https://doi.org/10.1093/molbev/msaa163 (2020). This commit does not belong to any branch on this repository, and may belong to a fork outside of the repository. Virus Evol. 56, 152179 (1992). . Boni, M.F., Lemey, P., Jiang, X. et al. If stopping an outbreak in its early stages is not possibleas was the case for the COVID-19 epidemic in Hubeiidentification of origins and point sources is nevertheless important for containment purposes in other provinces and prevention of future outbreaks. Viruses 11, 979 (2019). Eden, J.-S., Tanaka, M. M., Boni, M. F., Rawlinson, W. D. & White, P. A. Recombination within the pandemic norovirus GII.4 lineage. Correspondence to Unlike other viruses that have emerged in the past two decades, coronaviruses are highly recombinogenic14,15,16. 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). Slider with three articles shown per slide. PubMed Central We showed that severe acute respiratory syndrome coronavirus 2 is probably a novel recombinant virus. Collectively our analyses point to bats being the primary reservoir for the SARS-CoV-2 lineage. 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 most parsimonious explanation for these shared ACE2-specific residues is that they were present in the common ancestors of SARS-CoV-2, RaTG13 and Pangolin Guangdong 2019, and were lost through recombination in the lineage leading to RaTG13. Because these subclades had different phylogenetic relationships in regionD (Supplementary Fig. For coronaviruses, however, recombination means that small genomic subregions can have independent origins, identifiable if sufficient sampling has been done in the animal reservoirs that support the endemic circulation, co-infection and recombination that appear to be common. Split diversity in constrained conservation prioritization using integer linear programming. 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. 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. Unfortunately, a response that would achieve containment was not possible. Are you sure you want to create this branch? Temporal signal was tested using a recently developed marginal likelihood estimation procedure41 (Supplementary Table 1). Sequences were aligned by MAFTT58 v.7.310, with a final alignment length of 30,927, and used in the analyses below. 1a-c ), has the third-highest number of confirmed COVID-19 cases in the state of So. Biol. 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 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. 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. Subsequently a bat sarbecovirusRaTG13, sampled from a Rhinolophus affinis horseshoe bat in 2013 in Yunnan Provincewas reported that clusters with SARS-CoV-2 in almost all genomic regions with approximately 96% genome sequence identity2. 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). The genetic distances between SARS-CoV-2 and Pangolin Guangdong 2019 are consistent across all regions except the N-terminal domain, implying that a recombination event between these two sequences in this region is unlikely. Concurrent evidence also proposed pangolins as a potential intermediate species for SARS-CoV-2 emergence and suggested them as a potential reservoir species11,12,13. Genetic lineages of SARS-CoV-2 have been emerging and circulating around the world since the beginning of the COVID-19 pandemic. In case of DRAGEN COVID Lineage tool, the minimum accepted alignment score was set to 22 and results with scores <22 were discarded. 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 . 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. We compiled a dataset including 27human coronavirus OC43 virus genomes and ten related animal virus genomes (six bovine, three white-tailed deer and one canine virus). Combining regions A, B and C and removing the five named sequences gives us putative NRR1, as an alignment of 63sequences. Nat. Evolutionary origins of the SARS-CoV-2 sarbecovirus lineage responsible for the COVID-19 pandemic. 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. The command line tool is open source software available under the GNU General Public License v3.0. Article 1, vev016 (2015). Cell 181, 223227 (2020). Evol. All authors contributed to analyses and interpretations. Genet. Effect of closure of live poultry markets on poultry-to-person transmission of avian influenza A H7N9 virus: an ecological study. Yuan, J. et al. The virus then. While pangolins could be acting as intermediate hosts for bat viruses to get into humansthey develop severe respiratory disease38 and commonly come into contact with people through traffickingthere is no evidence that pangolin infection is a requirement for bat viruses to cross into humans. Schierup, M. H. & Hein, J. Recombination and the molecular clock. Boxplots show interquartile ranges, white lines are medians and box whiskers show the full range of posterior distribution. 30, 21962203 (2020). Accurate estimation of ages for deeper nodes would require adequate accommodation of time-dependent rate variation. PLoS ONE 5, e10434 (2010). Epidemiology, genetic recombination, and pathogenesis of coronaviruses. 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. To begin characterizing any ancestral relationships for SARS-CoV-2, NRRs of the genome must be identified so that reliable phylogenetic reconstruction and dating can be performed. Mol. Pink, green and orange bars show BFRs, with regionA (nt 13,29119,628) showing two trimmed segments yielding regionA (nt13,29114,932, 15,40517,162, 18,00919,628).
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