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This work was supported by Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation (COVID-19 Research Call COV20/00181), and co-financed by European Development Regional Fund 'A way to achieve Europe'. The work was also supported by grants CSIC-COV19-014 from Consejo Superior de Investigaciones Cientificas (CSIC), project 525/C/2021 from Fundacio La Marato de TV3, PID2020-113888RB-I00 from Ministerio de Ciencia e Innovacion, BFU2017-91384-EXP from Ministerio de Ciencia, Innovacion y Universidades (MCIU), PI18/00210 and PI21/00139 from Instituto de Salud Carlos III, and S2018/BAA-4370 (PLATESA2 from Comunidad de Madrid/FEDER). C.P., M.C., and P.M. are supported by the Miguel Servet programme of the Instituto de Salud Carlos III (CPII19/00001, CPII17/00006, and CP16/00116, respectively) cofinanced by the European Regional Development Fund (ERDF). CIBERehd (Centro de Investigacion en Red de Enfermedades Hepaticas y Digestivas) is funded by Instituto de Salud Carlos III. Institutional grants from the Fundacion Ramon Areces and Banco Santander to the CBMSO are also acknowledged. The team at CBMSO belongs to the Global Virus Network (GVN). B.M.-G. is supported by predoctoral contract PFIS FI19/00119 from Instituto de Salud Carlos III (Ministerio de Sanidad y Consumo) cofinanced by Fondo Social Europeo (FSE). R.L.-V. is supported by predoctoral contract PEJD-2019-PRE/BMD-16414 from Comunidad de Madrid. C.G.-C. is supported by predoctoral contract PRE2018-083422 from MCIU. P.S. is supported by postdoctoral contract "Margarita Salas" CA1/RSUE/2021 from MCIU. B.S. was supported by a predoctoral research fellowship (Doctorados Industriales, DI-17-09134) from Spanish MINECO.

Analysis of institutional authors

Somovilla, PilarAuthorEsteban, JaimeAuthorFernandez-Roblas, RicardoAuthorGadea, IgnacioAuthorAyuso, CarmenAuthor

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Article

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

Publicated to:Pathogens. 11 (6): 662- - 2022-06-01 11(6), DOI: 10.3390/pathogens11060662

Authors: Martinez-Gonzalez, Brenda; Eugenia Soria, Maria; Vazquez-Sirvent, Lucia; Ferrer-Orta, Cristina; Lobo-Vega, Rebeca; Minguez, Pablo; de la Fuente, Lorena; Llorens, Carlos; Soriano, Beatriz; Ramos-Ruiz, Ricardo; Corton, Marta; Lopez-Rodriguez, Rosario; Garcia-Crespo, Carlos; Somovilla, Pilar; Duran-Pastor, Antoni; Gallego, Isabel; Isabel de Avila, Ana; Delgado, Soledad; Moran, Federico; Lopez-Galindez, Cecilio; Gomez, Jordi; Enjuanes, Luis; Salar-Vidal, Llanos; Esteban-Munoz, Mario; Esteban, Jaime; Fernandez-Roblas, Ricardo; Gadea, Ignacio; Ayuso, Carmen; Ruiz-Hornillos, Javier; Verdaguer, Nuria; Domingo, Esteban; Perales, Celia

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Abstract

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.

Keywords

Covid-19DeletionFitnesGenotype 2Hepatitis-c virusInfectionLethal mutagenesisMutationNsp12 (polymerase)Resistance-associated substitutionsRna virusSars-associated coronavirusSofosbuvirSpikSpikeUltra-deep sequencingVariantsViral quasispecies

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Pathogens due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2022, it was in position 62/135, thus managing to position itself as a Q2 (Segundo Cuartil), in the category Microbiology. Notably, the journal is positioned en el Cuartil Q2 para la agencia Scopus (SJR) en la categoría Immunology and Microbiology (Miscellaneous).

From a relative perspective, and based on the normalized impact indicator calculated from World Citations provided by WoS (ESI, Clarivate), it yields a value for the citation normalization relative to the expected citation rate of: 4.08. This indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: ESI Nov 14, 2024)

This information is reinforced by other indicators of the same type, which, although dynamic over time and dependent on the set of average global citations at the time of their calculation, consistently position the work at some point among the top 50% most cited in its field:

  • Weighted Average of Normalized Impact by the Scopus agency: 2.76 (source consulted: FECYT Feb 2024)
  • Field Citation Ratio (FCR) from Dimensions: 6.93 (source consulted: Dimensions Jun 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-06-01, the following number of citations:

  • WoS: 17
  • Scopus: 16
  • Europe PMC: 14
  • Google Scholar: 21
  • OpenCitations: 17

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-06-01:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 16.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 16 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 9.23.
  • The number of mentions on the social network X (formerly Twitter): 4 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.

Leadership analysis of institutional authors

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: First Author (Martinez-Gonzalez, Brenda) and Last Author (Perales, Celia).

the author responsible for correspondence tasks has been Perales, Celia.