The evolutionary history of ACE2 usage within the coronavirus subgenus Sarbecovirus
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Abstract
SARS-CoV-1 and SARS-CoV-2 are not phylogenetically closely related; however, both use the ACE2 receptor in humans for cell entry. This is not a universal sarbecovirus trait; for example, many known sarbecoviruses related to SARS-CoV-1 have two deletions in the receptor binding domain of the spike protein that render them incapable of using human ACE2. Here, we report three sequences of a novel sarbecovirus from Rwanda and Uganda which are phylogenetically intermediate to SARS-CoV-1 and SARS-CoV-2 and demonstrate via in vitro studies that they are also unable to utilize human ACE2. Furthermore, we show that the observed pattern of ACE2 usage among sarbecoviruses is best explained by recombination not of SARS-CoV-2, but of SARS-CoV-1 and its relatives. We show that the lineage that includes SARS-CoV-2 is most likely the ancestral ACE2-using lineage, and that recombination with at least one virus from this group conferred ACE2 usage to the lineage including SARS-CoV-1 at some time in the past. We argue that alternative scenarios such as convergent evolution are much less parsimonious; we show that biogeography and patterns of host tropism support the plausibility of a recombination scenario; and we propose a competitive release hypothesis to explain how this recombination event could have occurred and why it is evolutionarily advantageous. The findings provide important insights into the natural history of ACE2 usage for both SARS-CoV-1 and SARS-CoV-2, and a greater understanding of the evolutionary mechanisms that shape zoonotic potential of coronaviruses. This study also underscores the need for increased surveillance for sarbecoviruses in southwestern China, where most ACE2-using viruses have been found to date, as well as other regions such as Africa, where these viruses have only recently been discovered.
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SciScore for 10.1101/2020.07.07.190546: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Experimental Models: Cell Lines Sentences Resources Cell culture and transfection: BHK and 293T cells were obtained from the American Type Culture Collection and maintained in Dulbecco’s modified Eagle’s medium (DMEM; Sigma–Aldrich) supplemented with 10% fetal bovine serum (FBS), penicillin/streptomycin and L-glutamine. 293Tsuggested: NoneBHK cells were seeded and transfected the next day with 100ng of plasmid encoding hACE2 or an empty vector using polyethylenimine (Polysciences). BHKsuggested: NoneSoftware and Algorithms Sentences Resources Samples were subsequently deep sequenced using the Illumina HiSeq platform and reads were … SciScore for 10.1101/2020.07.07.190546: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Experimental Models: Cell Lines Sentences Resources Cell culture and transfection: BHK and 293T cells were obtained from the American Type Culture Collection and maintained in Dulbecco’s modified Eagle’s medium (DMEM; Sigma–Aldrich) supplemented with 10% fetal bovine serum (FBS), penicillin/streptomycin and L-glutamine. 293Tsuggested: NoneBHK cells were seeded and transfected the next day with 100ng of plasmid encoding hACE2 or an empty vector using polyethylenimine (Polysciences). BHKsuggested: NoneSoftware and Algorithms Sentences Resources Samples were subsequently deep sequenced using the Illumina HiSeq platform and reads were bioinformatically de novo assembled using MEGAHIT v1.2.8 [73] after quality control steps and subtraction of host reads using Bowtie2 v2.3.5. MEGAHITsuggested: (MEGAHIT, RRID:SCR_018551)Bowtie2suggested: (Bowtie 2, RRID:SCR_016368)The RdRp gene (nucleotides 13,431 to 16,222 based on SARS-CoV-2 sequence EPI_ISL_402125 from GISAID) and RBD region (nucleotides 22,506 to 23,174 based on the same SARS-CoV-2 reference genome) were extracted and aligned using Muscle v10.2.6. Musclesuggested: (MUSCLE, RRID:SCR_011812)Phylogenetic reconstruction was performed using BEAST v2.6.3 [75] with partitioned codon positions, a GTR+Γ substitution model for each of the three codon positions, a constant size coalescent process prior, and a strict molecular clock model. BEASTsuggested: (BEAST, RRID:SCR_010228)Log files were examined using Tracer v1.7.1 to confirm that the model converged and that the effective sample size (ESS) for each parameter was at least 100. Tracersuggested: (Tracer, RRID:SCR_019121)Use of Beagle 2.1.2 was chosen to increase computational speed. Beaglesuggested: (BEAGLE, RRID:SCR_001789)Maximum clade credibility trees were built using TreeAnnotator and visualized with FigTree with branches scaled by distance. FigTreesuggested: (FigTree, RRID:SCR_008515)Results from OddPub: Thank you for sharing your data.
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
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