SARS-CoV-2 mutant spectra as variant of concern nurseries: endless variation?

Brenda Martínez-González, María Eugenia Soria, Pablo Mínguez, Ramón Lorenzo-Redondo, Llanos Salar-Vidal, Alberto López-García, Mario Esteban-Muñoz, Antoni Durán-Pastor, Pilar Somovilla, Carlos García-Crespo, Ana Isabel de Ávila, Jordi Gómez, Jaime Esteban, Ricardo Fernández-Roblas, Ignacio Gadea, Esteban Domingo*, Celia Perales*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Introduction: SARS-CoV-2 isolates of a given clade may contain low frequency genomes that encode amino acids or deletions which are typical of a different clade. Methods: Here we use high resolution ultra-deep sequencing to analyze SARS-CoV-2 mutant spectra. Results: In 6 out of 11 SARS-CoV-2 isolates from COVID-19 patients, the mutant spectrum of the spike (S)-coding region included two or more amino acids or deletions, that correspond to discordant viral clades. A similar observation is reported for laboratory populations of SARS-CoV-2 USA-WA1/2020, following a cell culture infection in the presence of remdesivir, ribavirin or their combinations. Moreover, some of the clade-discordant genome residues are found in the same haplotype within an amplicon. Discussion: We evaluate possible interpretations of these findings, and reviewed precedents for rapid selection of genomes with multiple mutations in RNA viruses. These considerations suggest that intra-host evolution may be sufficient to generate minority sequences which are closely related to sequences typical of other clades. The results provide a model for the origin of variants of concern during epidemic spread─in particular Omicron lineages─that does not require prolonged infection, involvement of immunocompromised individuals, or participation of intermediate, non-human hosts.

Original languageEnglish (US)
Article number1358258
JournalFrontiers in Microbiology
StatePublished - 2024


  • COVID-19
  • clade-discordant residues
  • ultra-deep sequencing
  • variant of concern
  • viral emergence
  • viral quasispecies

ASJC Scopus subject areas

  • Microbiology (medical)
  • Microbiology


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