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Longitudinal analysis of SARS-CoV-2 spike and RNA-dependent RNA polymerase protein sequences reveals the emergence and geographic distribution of diverse mutations.
Infect Genet Evol. 2022 01; 97:105153.IG

Abstract

Amid the ongoing COVID-19 pandemic, it has become increasingly important to monitor the mutations that arise in the SARS-CoV-2 virus, to prepare public health strategies and guide the further development of vaccines and therapeutics. The spike (S) protein and the proteins comprising the RNA-Dependent RNA Polymerase (RdRP) are key vaccine and drug targets, respectively, making mutation surveillance of these proteins of great importance. Full protein sequences were downloaded from the GISAID database, aligned, and the variants identified. 437,006 unique viral genomes were analyzed. Polymorphisms in the protein sequence were investigated and examined longitudinally to identify sequence and strain variants appearing between January 5th, 2020 and January 16th, 2021. A structural analysis was also performed to investigate mutations in the receptor binding domain and the N-terminal domain of the spike protein. Within the spike protein, there were 766 unique mutations observed in the N-terminal domain and 360 in the receptor binding domain. Four residues that directly contact ACE2 were mutated in more than 100 sequences, including positions K417, Y453, S494, and N501. Within the furin cleavage site of the spike protein, a high degree of conservation was observed, but the P681H mutation was observed in 10.47% of sequences analyzed. Within the RNA dependent RNA polymerase complex proteins, 327 unique mutations were observed in Nsp8, 166 unique mutations were observed in Nsp7, and 1157 unique mutations were observed in Nsp12. Only 4 sequences analyzed contained mutations in the 9 residues that directly interact with the therapeutic Remdesivir, suggesting limited mutations in drug interacting residues. The identification of new variants emphasizes the need for further study on the effects of the mutations and the implications of increased prevalence, particularly for vaccine or therapeutic efficacy.

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Authors+Show Affiliations

Showers WM
University of Colorado Anschutz Medical Campus, 13001 East 17th Place, Aurora, CO, USA; Center for Genes, Environment, and Health, National Jewish Health, Smith Building, Room A651, 1400 Jackson Street, Denver, CO, USA. Electronic address: william.showers@cuanschutz.edu.
Leach SM
University of Colorado Anschutz Medical Campus, 13001 East 17th Place, Aurora, CO, USA; Center for Genes, Environment, and Health, National Jewish Health, Smith Building, Room A651, 1400 Jackson Street, Denver, CO, USA.
Kechris K
University of Colorado Anschutz Medical Campus, 13001 East 17th Place, Aurora, CO, USA.
Strong M
University of Colorado Anschutz Medical Campus, 13001 East 17th Place, Aurora, CO, USA; Center for Genes, Environment, and Health, National Jewish Health, Smith Building, Room A651, 1400 Jackson Street, Denver, CO, USA.

MeSH

Adenosine MonophosphateAfricaAlanineAmino Acid SubstitutionAngiotensin-Converting Enzyme 2Antiviral AgentsAsiaBinding SitesCOVID-19Coronavirus RNA-Dependent RNA PolymeraseDatabases, FactualEpidemiological MonitoringEuropeEvolution, MolecularFurinGene ExpressionGenome, ViralHumansMolecular Docking SimulationMutationProtein BindingProtein Conformation, alpha-HelicalProtein Conformation, beta-StrandProtein Interaction Domains and MotifsSARS-CoV-2Spike Glycoprotein, CoronavirusUnited StatesViral Nonstructural ProteinsCOVID-19 Drug Treatment

Pub Type(s)

Journal Article

Language

eng

PubMed ID

34801754

Citation

Showers, William M., et al. "Longitudinal Analysis of SARS-CoV-2 Spike and RNA-dependent RNA Polymerase Protein Sequences Reveals the Emergence and Geographic Distribution of Diverse Mutations." Infection, Genetics and Evolution : Journal of Molecular Epidemiology and Evolutionary Genetics in Infectious Diseases, vol. 97, 2022, p. 105153.
Showers WM, Leach SM, Kechris K, et al. Longitudinal analysis of SARS-CoV-2 spike and RNA-dependent RNA polymerase protein sequences reveals the emergence and geographic distribution of diverse mutations. Infect Genet Evol. 2022;97:105153.
Showers, W. M., Leach, S. M., Kechris, K., & Strong, M. (2022). Longitudinal analysis of SARS-CoV-2 spike and RNA-dependent RNA polymerase protein sequences reveals the emergence and geographic distribution of diverse mutations. Infection, Genetics and Evolution : Journal of Molecular Epidemiology and Evolutionary Genetics in Infectious Diseases, 97, 105153. https://doi.org/10.1016/j.meegid.2021.105153
Showers WM, et al. Longitudinal Analysis of SARS-CoV-2 Spike and RNA-dependent RNA Polymerase Protein Sequences Reveals the Emergence and Geographic Distribution of Diverse Mutations. Infect Genet Evol. 2022;97:105153. PubMed PMID: 34801754.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Longitudinal analysis of SARS-CoV-2 spike and RNA-dependent RNA polymerase protein sequences reveals the emergence and geographic distribution of diverse mutations. AU - Showers,William M, AU - Leach,Sonia M, AU - Kechris,Katerina, AU - Strong,Michael, Y1 - 2021/11/18/ PY - 2021/04/30/received PY - 2021/11/05/revised PY - 2021/11/16/accepted PY - 2021/11/22/pubmed PY - 2022/1/28/medline PY - 2021/11/21/entrez KW - Bioinformatics KW - Computational genomics KW - Pathogen surveillance KW - SARS-CoV-2 SP - 105153 EP - 105153 JF - Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases JO - Infect Genet Evol VL - 97 N2 - Amid the ongoing COVID-19 pandemic, it has become increasingly important to monitor the mutations that arise in the SARS-CoV-2 virus, to prepare public health strategies and guide the further development of vaccines and therapeutics. The spike (S) protein and the proteins comprising the RNA-Dependent RNA Polymerase (RdRP) are key vaccine and drug targets, respectively, making mutation surveillance of these proteins of great importance. Full protein sequences were downloaded from the GISAID database, aligned, and the variants identified. 437,006 unique viral genomes were analyzed. Polymorphisms in the protein sequence were investigated and examined longitudinally to identify sequence and strain variants appearing between January 5th, 2020 and January 16th, 2021. A structural analysis was also performed to investigate mutations in the receptor binding domain and the N-terminal domain of the spike protein. Within the spike protein, there were 766 unique mutations observed in the N-terminal domain and 360 in the receptor binding domain. Four residues that directly contact ACE2 were mutated in more than 100 sequences, including positions K417, Y453, S494, and N501. Within the furin cleavage site of the spike protein, a high degree of conservation was observed, but the P681H mutation was observed in 10.47% of sequences analyzed. Within the RNA dependent RNA polymerase complex proteins, 327 unique mutations were observed in Nsp8, 166 unique mutations were observed in Nsp7, and 1157 unique mutations were observed in Nsp12. Only 4 sequences analyzed contained mutations in the 9 residues that directly interact with the therapeutic Remdesivir, suggesting limited mutations in drug interacting residues. The identification of new variants emphasizes the need for further study on the effects of the mutations and the implications of increased prevalence, particularly for vaccine or therapeutic efficacy. SN - 1567-7257 UR - https://www.unboundmedicine.com/medline/citation/34801754/Longitudinal_analysis_of_SARS_CoV_2_spike_and_RNA_dependent_RNA_polymerase_protein_sequences_reveals_the_emergence_and_geographic_distribution_of_diverse_mutations_ DB - PRIME DP - Unbound Medicine ER -