SARS-CoV-2 Quasispecies provides insight into its genetic dynamics during infection
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Abstract
A novel coronavirus disease (COVID-19) caused by SARS-CoV-2 has been pandemic worldwide. The genetic dynamics of quasispecies afford RNA viruses a great fitness on cell tropism and host range. However, no quasispecies data of SARS-CoV-2 have been reported yet. To explore quasispecies haplotypes and its transmission characteristics, we carried out single-molecule real-time (SMRT) sequencing of the full-length of SARS-CoV-2 spike gene within 14 RNA samples from 2 infection clusters, covering first-to third-generation infected-patients. We observed a special quasispecies structure of SARS-CoV-2 (modeled as ‘One-King’): one dominant haplotype (mean abundance ~70.15%) followed by numerous minor haplotypes (mean abundance < 0.10%). We not only discovered a novel dominant haplotype of F 1040 but also realized that minor quasispecies were also worthy of attention. Notably, some minor haplotypes (like F 1040 and currently pandemic one G 614 ) could potentially reveal adaptive and converse into the dominant one. However, minor haplotypes exhibited a high transmission bottleneck (~6% could be stably transmitted), and the new adaptive/dominant haplotypes were likely originated from genetic variations within a host rather than transmission. The evolutionary rate was estimated as 2.68-3.86 × 10 −3 per site per year, which was larger than the estimation at consensus genome level. The ‘One-King’ model and conversion event expanded our understanding of the genetic dynamics of SARS-CoV-2, and explained the incomprehensible phenomenon at the consensus genome level, such as limited cumulative mutations and low evolutionary rate. Moreover, our findings suggested the epidemic strains may be multi-host origin and future traceability would face huge difficulties.
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SciScore for 10.1101/2020.08.20.258376: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: All the samples were from our previous study 35, which was approved by the ethics committee of CPHMC (document no. 2020-002-01-KY, 2020-003-01-KY) and conducted in accordance with Declaration of Helsinki principles.
Consent: Written informed consent was obtained from each subject.Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable The first case FG1 (a 70-year-old male) was a local resident in Wuhan, and came to Chongqing to visit his younger sister’s family (FG2, FG2’s husband: FG3, FG2’s son: FG4, FG2’s grandson: FG5) in Jan 15 of 2020 by taking a train and then they lived together from that day. Table 2: …
SciScore for 10.1101/2020.08.20.258376: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: All the samples were from our previous study 35, which was approved by the ethics committee of CPHMC (document no. 2020-002-01-KY, 2020-003-01-KY) and conducted in accordance with Declaration of Helsinki principles.
Consent: Written informed consent was obtained from each subject.Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable The first case FG1 (a 70-year-old male) was a local resident in Wuhan, and came to Chongqing to visit his younger sister’s family (FG2, FG2’s husband: FG3, FG2’s son: FG4, FG2’s grandson: FG5) in Jan 15 of 2020 by taking a train and then they lived together from that day. Table 2: Resources
Software and Algorithms Sentences Resources Through direct contact, two family members of SG2 were also infected and revealed viral RNA positive on 19 Jan, including SG2’s wife SG4 and SG4’s mother SG3. SG2’ssuggested: NoneAfter size selection, full-length DNA of S gene was quantified using The Qubit 2.0 Fluorometer and Qubit dsDNA HS Assay Kit (Thermofisher No. Q32851). Thermofisher No.suggested: NoneSeven samples could be obtained the next-generation sequencing reads from metagenomic sequencing, which was used to access the amplification bias by BWA software 36 ( BWAsuggested: (BWA, RRID:SCR_010910)Meanwhile, SNV information were extracted using PERL scripts based on the BLAST results. BLASTsuggested: (BLASTX, RRID:SCR_001653)Results from OddPub: Thank you for sharing your data.
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Our study had some limitations. Firstly, due to technical limitations, it was currently difficult to obtain a haplotype with full-length of genome (~29Kb), and the spike gene (~4Kb) may be partially reflected the genome-wide quasispecies information. Secondly, insufficient number of samples made it difficult to observe the dynamics in a relatively large scope such as the intermediate transition state. Thirdly, the current study only focuses on SNVs, and other mutation types such as insertions, deletions, and structural variations need to be further studied. The ‘One-King’ structure of SARS-CoV-2 quasispecies reflected a novel quasispecies genetic fitness mechanism. Behind the dominant haplotype, there were countless minor fitness haplotypes that could be survived as dominant one in different hosts. Although these haplotypes may be suppressed and unable overcome the transmission bottleneck, the advantage mutations within them could be high-frequently obtained by virus mutations. Future molecular epidemiologic investigations, clinical interventions and vaccine designs need to consider the potential advantage SARS-CoV-2 quasispecies and its related mutations, which are missed by routine single concensus genotype 34 (Supplementary Tables 3 and 4).
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.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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