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SARS-CoV-2 Mutant Spectra at Different Depth Levels Reveal an Overwhelming Abundance of Low Frequency Mutations

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Department of Clinical Microbiology, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Av. Reyes Católicos 2, 28040 Madrid, Spain
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Department of Molecular and Cell Biology, Centro Nacional de Biotecnología (CNB-CSIC), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, 28049 Madrid, Spain
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Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, 28049 Madrid, Spain
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Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
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Structural Biology Department, Institut de Biología Molecular de Barcelona CSIC, 08028 Barcelona, Spain
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Department of Genetics & Genomics, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Av. Reyes Católicos 2, 28040 Madrid, Spain
7
Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain
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Bioinformatics Unit, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), 28040 Madrid, Spain
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Biotechvana, “Scientific Park”, Universidad de Valencia, 46980 Valencia, Spain
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Unidad de Genómica, “Scientific Park of Madrid”, Campus de Cantoblanco, 28049 Madrid, Spain
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Departamento de Biología Molecular, Universidad Autónoma de Madrid, Campus de Cantoblanco, 28049 Madrid, Spain
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Departamento de Sistemas Informáticos, Escuela Técnica Superior de Ingeniería de Sistemas Informáticos (ETSISI), Universidad Politécnica de Madrid, 28031 Madrid, Spain
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Departamento de Bioquímica y Biología Molecular, Universidad Complutense de Madrid, 28005 Madrid, Spain
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Unidad de Virología Molecular, Laboratorio de Referencia e Investigación en Retrovirus, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, 28222 Madrid, Spain
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Instituto de Parasitología y Biomedicina ‘López-Neyra’ (CSIC), Parque Tecnológico Ciencias de la Salud, Armilla, 18016 Granada, Spain
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Allergy Unit, Hospital Infanta Elena, Valdemoro, 28342 Madrid, Spain
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Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Av. Reyes Católicos 2, 28040 Madrid, Spain
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Faculty of Medicine, Universidad Francisco de Vitoria, 28223 Madrid, Spain
*
Authors to whom correspondence should be addressed.
Academic Editor: Anna Honko
Pathogens 2022, 11(6), 662; https://doi.org/10.3390/pathogens11060662
Received: 29 April 2022 / Revised: 2 June 2022 / Accepted: 6 June 2022 / Published: 8 June 2022
(This article belongs to the Collection SARS-CoV-2 Infection and COVID-19 Disease)
Populations of RNA viruses are composed of complex and dynamic mixtures of variant genomes that are termed mutant spectra or mutant clouds. This applies also to SARS-CoV-2, and mutations that are detected at low frequency in an infected individual can be dominant (represented in the consensus sequence) in subsequent variants of interest or variants of concern. Here we briefly review the main conclusions of our work on mutant spectrum characterization of hepatitis C virus (HCV) and SARS-CoV-2 at the nucleotide and amino acid levels and address the following two new questions derived from previous results: (i) how is the SARS-CoV-2 mutant and deletion spectrum composition in diagnostic samples, when examined at progressively lower cut-off mutant frequency values in ultra-deep sequencing; (ii) how the frequency distribution of minority amino acid substitutions in SARS-CoV-2 compares with that of HCV sampled also from infected patients. The main conclusions are the following: (i) the number of different mutations found at low frequency in SARS-CoV-2 mutant spectra increases dramatically (50- to 100-fold) as the cut-off frequency for mutation detection is lowered from 0.5% to 0.1%, and (ii) that, contrary to HCV, SARS-CoV-2 mutant spectra exhibit a deficit of intermediate frequency amino acid substitutions. The possible origin and implications of mutant spectrum differences among RNA viruses are discussed. View Full-Text
Keywords: RNA virus; COVID-19; ultra-deep sequencing; viral quasispecies; mutation; deletion; nsp12 (polymerase); spike RNA virus; COVID-19; ultra-deep sequencing; viral quasispecies; mutation; deletion; nsp12 (polymerase); spike
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MDPI and ACS Style

Martínez-González, B.; Soria, M.E.; Vázquez-Sirvent, L.; Ferrer-Orta, C.; Lobo-Vega, R.; Mínguez, P.; de la Fuente, L.; Llorens, C.; Soriano, B.; Ramos-Ruíz, R.; Cortón, M.; López-Rodríguez, R.; García-Crespo, C.; Somovilla, P.; Durán-Pastor, A.; Gallego, I.; de Ávila, A.I.; Delgado, S.; Morán, F.; López-Galíndez, C.; Gómez, J.; Enjuanes, L.; Salar-Vidal, L.; Esteban-Muñoz, M.; Esteban, J.; Fernández-Roblas, R.; Gadea, I.; Ayuso, C.; Ruíz-Hornillos, J.; Verdaguer, N.; Domingo, E.; Perales, C. SARS-CoV-2 Mutant Spectra at Different Depth Levels Reveal an Overwhelming Abundance of Low Frequency Mutations. Pathogens 2022, 11, 662. https://doi.org/10.3390/pathogens11060662

AMA Style

Martínez-González B, Soria ME, Vázquez-Sirvent L, Ferrer-Orta C, Lobo-Vega R, Mínguez P, de la Fuente L, Llorens C, Soriano B, Ramos-Ruíz R, Cortón M, López-Rodríguez R, García-Crespo C, Somovilla P, Durán-Pastor A, Gallego I, de Ávila AI, Delgado S, Morán F, López-Galíndez C, Gómez J, Enjuanes L, Salar-Vidal L, Esteban-Muñoz M, Esteban J, Fernández-Roblas R, Gadea I, Ayuso C, Ruíz-Hornillos J, Verdaguer N, Domingo E, Perales C. SARS-CoV-2 Mutant Spectra at Different Depth Levels Reveal an Overwhelming Abundance of Low Frequency Mutations. Pathogens. 2022; 11(6):662. https://doi.org/10.3390/pathogens11060662

Chicago/Turabian Style

Martínez-González, Brenda, María Eugenia Soria, Lucía Vázquez-Sirvent, Cristina Ferrer-Orta, Rebeca Lobo-Vega, Pablo Mínguez, Lorena de la Fuente, Carlos Llorens, Beatriz Soriano, Ricardo Ramos-Ruíz, Marta Cortón, Rosario López-Rodríguez, Carlos García-Crespo, Pilar Somovilla, Antoni Durán-Pastor, Isabel Gallego, Ana Isabel de Ávila, Soledad Delgado, Federico Morán, Cecilio López-Galíndez, Jordi Gómez, Luis Enjuanes, Llanos Salar-Vidal, Mario Esteban-Muñoz, Jaime Esteban, Ricardo Fernández-Roblas, Ignacio Gadea, Carmen Ayuso, Javier Ruíz-Hornillos, Nuria Verdaguer, Esteban Domingo, and Celia Perales. 2022. "SARS-CoV-2 Mutant Spectra at Different Depth Levels Reveal an Overwhelming Abundance of Low Frequency Mutations" Pathogens 11, no. 6: 662. https://doi.org/10.3390/pathogens11060662

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