Temporal Dynamics and Evolution of SARS-CoV-2 Demonstrate the Necessity of Ongoing Viral Genome Sequencing in Ontario, Canada

Sjaarda, Calvin; Guthrie, Jennifer L.; Mubareka, Samira; Simpson, Jared T.; Hamelin, Bettina; Wong, Henry; Mortimer, Leanne; Slinger, Robert; McArthur, Andrew G.; Desjardins, Marc; McGeer, Allison; Mazzulli, Tony; Douchant, Katya; Brabant-Kirwan, Danielle; Fattouh, Ramzi; Campigotto, Aaron; Patel, Samir N.; Fittipaldi, Nahuel; Colautti, Robert I.; Sheth, Prameet M.

doi:10.1128/msphere.00011-21

Cited by 8 publications

(5 citation statements)

References 40 publications

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“…While higher than other predictions 4 , this frequency is comparable to similar observations in poliovirus, which also utilizes an RdRp for replication but lacks an associated proofreading activity 8,11,26 . The error frequency estimations were previously based on the presence of a proofreading 3'-to-5' exoribonuclease (ExoN, nsp14) in SARS-CoV-2 that is distinct from the viral RdRp 27 . The same proofreading activity has been implicated in promoting template switching 28 , which we show here is error-prone.…”

Section: Discussionmentioning

confidence: 99%

RNA polymerase inaccuracy underlies SARS-CoV-2 variants and vaccine heterogeneity

Herman

Bradley

Gordon

et al. 2022

Preprint

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Both the SARS-CoV-2 virus and its mRNA vaccines depend on RNA polymerases (RNAP)1,2; however, these enzymes are inherently error-prone and can introduce variants into the RNA3. To understand SARS-CoV-2 evolution and vaccine efficacy, it is critical to identify the extent and distribution of errors introduced by the RNAPs involved in each process. Current methods lack the sensitivity and specificity to measure de novo RNA variants in low input samples like viral isolates3. Here, we determine the frequency and nature of RNA errors in both SARS-CoV-2 and its vaccine using a targeted Accurate RNA Consensus sequencing method (tARC-seq). We found that the viral RNA-dependent RNAP (RdRp) makes ~1 error every 10,000 nucleotides – higher than previous estimates4. We also observed that RNA variants are not randomly distributed across the genome but are associated with certain genomic features and genes, such as S (Spike). tARC-seq captured a number of large insertions, deletions and complex mutations that can be modeled through non-programmed RdRp template switching. This template switching feature of RdRp explains many key genetic changes observed during the evolution of different lineages worldwide, including Omicron. Further sequencing of the Pfizer-BioNTech COVID-19 vaccine revealed an RNA variant frequency of ~1 in 5,000, meaning most of the vaccine transcripts produced in vitro by T7 phage RNAP harbor a variant. These results demonstrate the extraordinary genetic diversity of viral populations and the heterogeneous nature of an mRNA vaccine fueled by RNAP inaccuracy. Along with functional studies and pandemic data, tARC-seq variant spectra can inform models to predict how SARS-CoV-2 may evolve. Finally, our results may help improve future vaccine development and study design as mRNA therapies continue to gain traction.

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Section: Discussionmentioning

confidence: 99%

RNA polymerase inaccuracy underlies SARS-CoV-2 variants and vaccine heterogeneity

Herman

Bradley

Gordon

et al. 2022

Preprint

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“…Data for 24,244 complete (>29,000 base pairs), high coverage (<1% N’s), and nonduplicate SARS-CoV-2 genomic sequences in FASTA format sampled from January 1, 2020, to December 31, 2021, were retrieved from the GISAID database on January 1, 2022 [ 20 ]. Metadata associated with each genomic sequence, including sampling date and GISAID clade assignment [ 37 ], were also retrieved from the GISAID database.…”

Section: Methodsmentioning

confidence: 99%

“…Previous SARS-CoV-2 genomic studies have characterized the landscape of mutation types and allele frequencies around the world, including but not limited to the United States [ 14 ], Qatar [ 15 ], the United Kingdom [ 16 ], Uruguay [ 17 ], and Canada [ 18 ]. Public health policies implemented in different countries to reduce COVID-19 transmission may in part influence the emergence of novel SARS-CoV-2 genetic variants [ 19 ] and mutation rates that can lead to the evolution of resistance to vaccines [ 20 ]. For instance, genomic epidemiology of the first 2 waves of SARS-CoV-2 in Canada revealed that the number of sublineages imported to Canada reduced by over 10-fold when restrictions of foreign nationals were implemented in March 2020.…”

Section: Introductionmentioning

confidence: 99%

Mutational Patterns Observed in SARS-CoV-2 Genomes Sampled From Successive Epochs Delimited by Major Public Health Events in Ontario, Canada: Genomic Surveillance Study

Chen¹,

Randhawa²,

Soltysiak³

et al. 2022

JMIR Bioinform Biotech

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Background The emergence of SARS-CoV-2 variants with mutations associated with increased transmissibility and virulence is a public health concern in Ontario, Canada. Characterizing how the mutational patterns of the SARS-CoV-2 genome have changed over time can shed light on the driving factors, including selection for increased fitness and host immune response, that may contribute to the emergence of novel variants. Moreover, the study of SARS-CoV-2 in the microcosm of Ontario, Canada can reveal how different province-specific public health policies over time may be associated with observed mutational patterns as a model system. Objective This study aimed to perform a comprehensive analysis of single base substitution (SBS) types, counts, and genomic locations observed in SARS-CoV-2 genomic sequences sampled in Ontario, Canada. Comparisons of mutational patterns were conducted between sequences sampled during 4 different epochs delimited by major public health events to track the evolution of the SARS-CoV-2 mutational landscape over 2 years. Methods In total, 24,244 SARS-CoV-2 genomic sequences and associated metadata sampled in Ontario, Canada from January 1, 2020, to December 31, 2021, were retrieved from the Global Initiative on Sharing All Influenza Data database. Sequences were assigned to 4 epochs delimited by major public health events based on the sampling date. SBSs from each SARS-CoV-2 sequence were identified relative to the MN996528.1 reference genome. Catalogues of SBS types and counts were generated to estimate the impact of selection in each open reading frame, and identify mutation clusters. The estimation of mutational fitness over time was performed using the Augur pipeline. Results The biases in SBS types and proportions observed support previous reports of host antiviral defense activity involving the SARS-CoV-2 genome. There was an increase in U>C substitutions associated with adenosine deaminase acting on RNA (ADAR) activity uniquely observed during Epoch 4. The burden of novel SBSs observed in SARS-CoV-2 genomic sequences was the greatest in Epoch 2 (median 5), followed by Epoch 3 (median 4). Clusters of SBSs were observed in the spike protein open reading frame, ORF1a, and ORF3a. The high proportion of nonsynonymous SBSs and increasing dN/dS metric (ratio of nonsynonymous to synonymous mutations in a given open reading frame) to above 1 in Epoch 4 indicate positive selection of the spike protein open reading frame. Conclusions Quantitative analysis of the mutational patterns of the SARS-CoV-2 genome in the microcosm of Ontario, Canada within early consecutive epochs of the pandemic tracked the mutational dynamics in the context of public health events that instigate significant shifts in selection and mutagenesis. Continued genomic surveillance of emergent variants will be useful for the design of public health policies in response to the evolving COVID-19 pandemic.

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“…The good thing about the Mpox vaccination is we can easily achieve herd immunity. Since MPXV has a double-stranded DNA, its genomic material is more stable than RNA viruses (e.g., SARS-CoV-2 and influenza A virus), making the mutation rate slow; thus, making our vaccines effective against infection and achieving herd immunity (25). The second goal includes public health policy modifications, which will increase health communication and education funds on Mpox, availability of diagnostic tests and vaccines, and workforce for wider surveillance.…”

Section: Infection Prevention and Control Practices Against Mpoxmentioning

confidence: 99%

Assessing the Mpox and Infection Prevention and Control Knowledge of Personal Service Establishments' Operators in Metro Vancouver Regional District of British Columbia

Valeroso,

Chen

2023

ephj

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Mpox virus, formerly known as the Monkeypox virus, is a re-emerging pathogen that causes the infectious disease Mpox. Mpox was designated as a public health emergency of international concern by the World Health Organization due to its rapid spread outside West and Central Africa. Personal service establishments (PSEs) could be a setting for exposure to Mpox because some of their services involve direct contact with their patrons. The aim of this research was to investigate the infection prevention and control (IPAC) and Mpox knowledge levels among PSE operators and to determine the associations between IPAC knowledge, Mpox knowledge, years of experience, and point-of-service risk assessment

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Temporal Dynamics and Evolution of SARS-CoV-2 Demonstrate the Necessity of Ongoing Viral Genome Sequencing in Ontario, Canada

Cited by 8 publications

References 40 publications

RNA polymerase inaccuracy underlies SARS-CoV-2 variants and vaccine heterogeneity

RNA polymerase inaccuracy underlies SARS-CoV-2 variants and vaccine heterogeneity

Mutational Patterns Observed in SARS-CoV-2 Genomes Sampled From Successive Epochs Delimited by Major Public Health Events in Ontario, Canada: Genomic Surveillance Study

Assessing the Mpox and Infection Prevention and Control Knowledge of Personal Service Establishments' Operators in Metro Vancouver Regional District of British Columbia

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