In regionA, we removed subregion A1 (ntpositions 3,8724,716 within regionA) and subregion A4 (nt1,6422,113) because both showed PI signals with other subregions of regionA. All custom code used in the manuscript is available at https://github.com/plemey/SARSCoV2origins. In this study, we report the case of a child with severe combined immu presenting a prolonged severe acute respiratory syndrome coronavirus 2 infection. 31922087). Nat. Discovery and genetic analysis of novel coronaviruses in least horseshoe bats in southwestern China. PI signals were identified (with bootstrap support >80%) for seven of these eight breakpoints: positions 1,684, 3,046, 9,237, 11,885, 21,753, 22,773 and 24,628. Divergence time estimates based on the three regions/alignments where the effects of recombination have been removed. 5. . Stegeman, A. et al. Coronavirus Disease 2019 (COVID-19) Situation Report 51 (World Health Organization, 2020). 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. Here, we analyse the evolutionary history of SARS-CoV-2 using available genomic data on sarbecoviruses. J. Virol. 25, 3548 (2017). 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. 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. 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. Calibration of priors can be performed using other coronaviruses (SARS-CoV, MERS-CoV and HCoV-OC43), but estimated rates vary with the timescale of sample collection. Cell 181, 223227 (2020). Early detection via genomics was not possible during Southeast Asias initial outbreaks of avian influenza H5N1 (1997 and 20032004) or the first SARS outbreak (20022003). Our third approach involved identifying breakpoints and masking minor recombinant regions (with gaps, which are treated as unobserved characters in probabilistic phylogenetic approaches). Unfortunately, a response that would achieve containment was not possible. Global epidemiology of bat coronaviruses. PLoS Pathog. These are in general agreement with estimates using NRR2 and NRA3, which result in divergence times of 1982 (19482009) and 1948 (18791999), respectively, for SARS-CoV-2, and estimates of 1952 (19061989) and 1970 (19321996), respectively, for the divergence time of SARS-CoV from its closest known bat relative. For the HCoV-OC43, MERS-CoV and SARS datasets we specified flexible skygrid coalescent tree priors. T.L. We considered (1) the possibility that BFRs could be combined into larger non-recombinant regions and (2) the possibility of further recombination within each BFR. First, we took an approach that relies on identification of mosaic regions (via 3SEQ14 v.1.7) that are also supported by PI signals19. 5 Comparisons of GC content across taxa. Lu, R. et al. Sarbecovirus, HCoV-OC43 and SARS-CoV data were assembled from GenBank to be as complete as possible, with sampling year as an inclusion criterion. 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. 3). 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. 3) to examine the sensitivity of date estimates to this prior specification. However, inconsistency in the nomenclature limits uniformity in its epidemiological understanding. Viruses 11, 174 (2019). 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. While there is evidence of positive selection in the sarbecovirus lineage leading to RaTG13/SARS-CoV-2 (ref. 4), but also by markedly different evolutionary rates. Proc. Sequencing from Malayan pangolins collected during anti-smuggling operations in southern China detected coronavirus lineages related to SARS-CoV-2. If the latter still identified non-negligible recombination signal, we removed additional genomes that were identified as major contributors to the remaining signal. 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. performed recombination analysis for non-recombining regions1 and 2, breakpoint analysis and phylogenetic inference on recombinant segments. & Muhire, B. RDP4: Detection and analysis of recombination patterns in virus genomes. The estimated divergence times for the pangolin virus most closely related to the SARS-CoV-2/RaTG13 lineage range from 1851 (17301958) to 1877 (17461986), indicating that these pangolin lineages were acquired from bat viruses divergent to those that gave rise to SARS-CoV-2. Evol. Evol. However, formal testing using marginal likelihood estimation41 does provide some evidence of a temporal signal, albeit with limited log Bayes factor support of 3 (NRR1), 10 (NRR2) and 3 (NRA3); see Supplementary Table 1. SARS-CoV-2 is an appropriate name for the new coronavirus. B.W.P. 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. Lond. Bayesian phylogenetic and phylodynamic data integration using BEAST 1.10. Yres, D. L. et al. # 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 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)). Centre for Genomic Pathogen Surveillance. Biol. 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. Except for specifying that sequences are linear, all settings were kept to their defaults. In our second stage, we wanted to construct non-recombinant regions where our approach to breakpoint identification was as conservative as possible. Bioinformatics 28, 32483256 (2012). A single 3SEQ run on the genome alignment resulted in 67 out of 68sequences supporting some recombination in the past, with multiple candidate breakpoint ranges listed for each putative recombinant. 21, 255265 (2004). The time-calibrated phylogeny represents a maximum clade credibility tree inferred for NRR1. 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. Genetic lineages of SARS-CoV-2 have been emerging and circulating around the world since the beginning of the COVID-19 pandemic. Membrebe, J. V., Suchard, M. A., Rambaut, A., Baele, G. & Lemey, P. Bayesian inference of evolutionary histories under time-dependent substitution rates. BEAGLE 3: improved performance, scaling, and usability for a high-performance computing library for statistical phylogenetics. . D.L.R. These authors contributed equally: Maciej F. Boni, Philippe Lemey. The coverage threshold and consensus sequence generation threshold were set to 20 and 90 respectively. =0.00025. & Bedford, T. MERS-CoV spillover at the camelhuman interface. Bioinformatics 22, 26882690 (2006). Based on the identified breakpoints in each genome, only the major non-recombinant region is kept in each genome while other regions are masked. Five example sequences with incongruent phylogenetic positions in the two trees are indicated by dashed lines. 2). 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. Python 379 102 pangoLEARN Public Store of the trained model for pangolin to access. A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence. The boxplots show divergence time estimates (posterior medians) for SARS-CoV-2 (red) and the 20022003 SARS-CoV virus (blue) from their most closely related bat virus. It allows a user to assign a SARS-CoV-2 genome sequence the most likely lineage (Pango lineage) to SARS-CoV-2 query sequences. Sequence similarity. 6, eabb9153 (2020). 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). To employ phylogenetic dating methods, recombinant regions of a 68-genome sarbecovirus alignment were removed with three independent methods. the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Concatenated region ABC is NRR1. 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. Biazzo et al. A., Lytras, S., Singer, J. This new approach classifies the newly sequenced genome against all the diverse lineages present instead of a representative select sequences. Google Scholar. Genetics 172, 26652681 (2006). Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor. Proc. 2a. Preprint at https://doi.org/10.1101/2020.05.28.122366 (2020). Pangolin relies on a novel algorithm called pangoLEARN. Mol. Aiewsakun, P. & Katzourakis, A. Time-dependent rate phenomenon in viruses. Nature 579, 265269 (2020). 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. Its origin and direct ancestral viruses have not been . Trends Microbiol. We used TreeAnnotator to summarize posterior tree distributions and annotated the estimated values to a maximum clade credibility tree, which was visualized using FigTree.
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