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SARS-CoV-2 Point Mutation and Deletion Spectra, and Their Association with Different Disease Outcome

Brenda Martínez-González, María Eugenia Soria, Lucía Vázquez-Sirvent, Cristina Ferrer-Orta, Rebeca Lobo-Vega, Pablo Mínguez, Lorena de la Fuente, Carlos Llorens, Beatriz Soriano, View ORCID ProfileRicardo Ramos, Marta Cortón, Rosario López-Rodríguez, Carlos García-Crespo, Isabel Gallego, Ana Isabel de Ávila, Jordi Gómez, View ORCID ProfileLuis Enjuanes, Llanos Salar-Vidal, View ORCID ProfileJaime Esteban, Ricardo Fernandez-Roblas, Ignacio Gadea, Carmen Ayuso, Javier Ruíz-Hornillos, View ORCID ProfileNuria Verdaguer, View ORCID ProfileEsteban Domingo, View ORCID ProfileCelia Perales
doi: https://doi.org/10.1101/2022.01.10.475768
Brenda Martínez-González
1Department 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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María Eugenia Soria
1Department 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
2Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, 28049 Madrid, Spain
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Lucía Vázquez-Sirvent
1Department 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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Cristina Ferrer-Orta
3Structural Biology Department, Institut de Biología Molecular de Barcelona CSIC, 08028 Barcelona, Spain
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Rebeca Lobo-Vega
1Department 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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Pablo Mínguez
4Department 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
5Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain
6Bioinformatics Unit, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid 28040, Spain
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Lorena de la Fuente
4Department 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
5Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain
6Bioinformatics Unit, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid 28040, Spain
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Carlos Llorens
7Biotechvana, “Scientific Park”, Universidad de Valencia, 46980 Valencia, Spain
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Beatriz Soriano
7Biotechvana, “Scientific Park”, Universidad de Valencia, 46980 Valencia, Spain
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Ricardo Ramos
8Unidad de Genómica, “Scientific Park of Madrid”, Campus de Cantoblanco, 28049 Madrid, Spain
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Marta Cortón
4Department 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
5Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain
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Rosario López-Rodríguez
4Department 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
5Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain
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Carlos García-Crespo
2Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, 28049 Madrid, Spain
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Isabel Gallego
2Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, 28049 Madrid, Spain
9Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
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Ana Isabel de Ávila
2Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, 28049 Madrid, Spain
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Jordi Gómez
9Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
10Instituto de Parasitología y Biomedicina ‘López-Neyra’ (CSIC), Parque Tecnológico Ciencias de la Salud, Armilla, 18016 Granada, Spain
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Luis Enjuanes
11Department 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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Llanos Salar-Vidal
1Department 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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Jaime Esteban
1Department 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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Ricardo Fernandez-Roblas
1Department 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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Ignacio Gadea
1Department 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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Carmen Ayuso
4Department 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
5Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain
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Javier Ruíz-Hornillos
12Allergy Unit, Hospital Infanta Elena, Valdemoro, Madrid, Spain
13Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Av. Reyes Católicos 2, 28040 Madrid, Spain
14Faculty of Medicine, Universidad Francisco de Vitoria, Madrid, Spain
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Nuria Verdaguer
3Structural Biology Department, Institut de Biología Molecular de Barcelona CSIC, 08028 Barcelona, Spain
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Esteban Domingo
2Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, 28049 Madrid, Spain
9Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
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  • For correspondence: cperales@cbm.csic.es edomingo@cbm.csic.es
Celia Perales
1Department 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
9Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
11Department 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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  • ORCID record for Celia Perales
  • For correspondence: cperales@cbm.csic.es edomingo@cbm.csic.es
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ABSTRACT

Mutant spectra of RNA viruses are important to understand viral pathogenesis, and response to selective pressures. There is a need to characterize the complexity of mutant spectra in coronaviruses sampled from infected patients. In particular, the possible relationship between SARS-CoV-2 mutant spectrum complexity and disease associations has not been established. In the present study, we report an ultra-deep sequencing (UDS) analysis of the mutant spectrum of amplicons from the nsp12 (polymerase)- and spike (S)-coding regions of thirty nasopharyngeal isolates (diagnostic samples) of SARS-CoV-2 of the first COVID-19 pandemic wave (Madrid, Spain, April 2020) classified according to the severity of ensuing COVID-19. Low frequency mutations and deletions, counted relative to the consensus sequence of the corresponding isolate, were overwhelmingly abundant. We show that the average number of different point mutations, mutations per haplotype and several diversity indices was significantly higher in SARS-CoV-2 isolated from patients who developed mild disease than in those associated with moderate or severe disease (exitus). No such bias was observed with RNA deletions. Location of amino acid substitutions in the three dimensional structures of nsp12 (polymerase) and S suggest significant structural or functional effects. Thus, patients who develop mild symptoms may be a richer source of genetic variants of SARS-CoV-2 than patients with moderate or severe COVID-19.

IMPORTANCE The study shows that mutant spectra of SARS-CoV-2 from diagnostic samples differ in point mutation abundance and complexity, and that significantly larger values were observed in virus from patients who developed mild COVID-19 symptoms. Mutant spectrum complexity is not a uniform trait among isolates. The nature and location of low frequency amino acid substitutions present in mutant spectra anticipate great potential for phenotypic diversification of SARS-CoV-2.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted January 12, 2022.
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SARS-CoV-2 Point Mutation and Deletion Spectra, and Their Association with Different Disease Outcome
Brenda Martínez-González, María Eugenia Soria, Lucía Vázquez-Sirvent, Cristina Ferrer-Orta, Rebeca Lobo-Vega, Pablo Mínguez, Lorena de la Fuente, Carlos Llorens, Beatriz Soriano, Ricardo Ramos, Marta Cortón, Rosario López-Rodríguez, Carlos García-Crespo, Isabel Gallego, Ana Isabel de Ávila, Jordi Gómez, Luis Enjuanes, Llanos Salar-Vidal, Jaime Esteban, Ricardo Fernandez-Roblas, Ignacio Gadea, Carmen Ayuso, Javier Ruíz-Hornillos, Nuria Verdaguer, Esteban Domingo, Celia Perales
bioRxiv 2022.01.10.475768; doi: https://doi.org/10.1101/2022.01.10.475768
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SARS-CoV-2 Point Mutation and Deletion Spectra, and Their Association with Different Disease Outcome
Brenda Martínez-González, María Eugenia Soria, Lucía Vázquez-Sirvent, Cristina Ferrer-Orta, Rebeca Lobo-Vega, Pablo Mínguez, Lorena de la Fuente, Carlos Llorens, Beatriz Soriano, Ricardo Ramos, Marta Cortón, Rosario López-Rodríguez, Carlos García-Crespo, Isabel Gallego, Ana Isabel de Ávila, Jordi Gómez, Luis Enjuanes, Llanos Salar-Vidal, Jaime Esteban, Ricardo Fernandez-Roblas, Ignacio Gadea, Carmen Ayuso, Javier Ruíz-Hornillos, Nuria Verdaguer, Esteban Domingo, Celia Perales
bioRxiv 2022.01.10.475768; doi: https://doi.org/10.1101/2022.01.10.475768

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