Puzzles, challenges, and information reservoir of SARS-CoV-2 quasispecies

Abstract

Upon the emergence of SARS-CoV-2 in the human population, it was conjectured that for this coronavirus the dynamic intra-host heterogeneity typical of RNA viruses would be toned down. Nothing of this sort is observed. Here we review the main observations on the complexity and diverse composition of SARS-CoV-2 mutant spectra sampled from infected patients, within the framework of quasispecies dynamics. The analyses suggest that the information provided by myriads of genomic sequences within infected individuals may have a predictive value of the genomic sequences that acquire epidemiological relevance. Possibilities to reconcile the presence of broad mutant spectra in the large RNA coronavirus genome with its encoding a 3' to 5' exonuclease proofreading-repair activity are considered. Indeterminations in the behavior of individual viral genomes provide a benefit for the survival of the ensemble. We propose that this concept falls in the domain of "stochastic thinking," a notion that applies also to cellular processes, as a means for biological systems to face unexpected needs.

Keywords: cancer heterogeneity; coronavirus; deletion; error threshold; mutant spectrum; mutation; prion; ultra-deep sequencing; viral disease control; virus complexity.

Fig 1

The expanded capacity to detect minority mutations using high resolution ultra-deep sequencing. The scheme depicts the relative number of different mutations (number duplicated symmetrically for clarity in the bottom axis) with increasing mutant frequency cut-off (percentage given on the left and right sides of the scheme). The relative number of mutations in the nsp12-coding region is given by the left-most and right-most borders of the blue rectangles; the corresponding number in the spike-coding region is given by the left-most and right-most borders of the orange rectangles. The relative number of mutations is drawn with a scale according to the quantification of different mutations considering the entire patient cohort described in (34). The red arrows highlight the exponential increase in the number of mutations.