The SARS-CoV-2 mutation landscape is shaped before replication starts

Mutation landscapes and signatures have been thoroughly studied in SARS-CoV-2. Here, we analyse those patterns and link their changes to the viral replication tissue in the respiratory tract. Surprisingly, a substantial difference in those patterns is observed in samples from vaccinated patients. Hence, we propose a model to explain where those mutations could originate during the replication cycle.

Keywords:
SBS spectra; viral replication niche; COVID19 vaccination status

Authorship

Diego Masone

conducted the experiments

analysed the data

read

approved the final version

Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional de Cuyo (UNCuyo), Instituto de Histología y Embriología de Mendoza (IHEM), Mendoza, Argentina. Consejo Nacional de Investigaciones Científicas y TécnicasArgentinaMendoza, ArgentinaConsejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional de Cuyo (UNCuyo), Instituto de Histología y Embriología de Mendoza (IHEM), Mendoza, Argentina.

Universidad Nacional de Cuyo (UNCuyo), Facultad de Ingeniería, Mendoza, Argentina. Universidad Nacional de CuyoArgentinaMendoza, ArgentinaUniversidad Nacional de Cuyo (UNCuyo), Facultad de Ingeniería, Mendoza, Argentina.

http://orcid.org/0000-0001-5770-8614

Maria Soledad Alvarez

conceived and the study

wrote the manuscript

analysed the data

read

approved the final version

Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional de Cuyo (UNCuyo), Instituto de Medicina y Biología Experimental de Cuyo (IMBECU), Mendoza, Argentina.Consejo Nacional de Investigaciones Científicas y TécnicasArgentinaMendoza, ArgentinaConsejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional de Cuyo (UNCuyo), Instituto de Medicina y Biología Experimental de Cuyo (IMBECU), Mendoza, Argentina.

http://orcid.org/0000-0001-7062-014X

Luis Mariano Polo

conceived and the study

wrote the manuscript

analysed the data

read

approved the final version

http://orcid.org/0000-0001-9257-6127

Send correspondence to Luis Mariano Polo. Universidad Nacional de Cuyo (UNCuyo), Instituto de Histología y Embriología de Mendoza (IHEM), Av. Libertador 80, M5502JMA, Mendoza, Argentina. E-mail: marianopolo@gmail.com.

Associate Editor:

Carlos F. M. Menck

Conflict of Interest

The authors have no competing interests to declare.

Authors Contributions

DM conducted the experiments. MSA and LMP conceived and the study and wrote the manuscript. All authors analysed the data, read, and approved the final version.

SCIMAGO INSTITUTIONS RANKINGS

Figures

Figures (2)

Thumbnail

Figure 1 -
The environment of infected cells alters the G>U substitution incidence in SARS-CoV-2. (A) Analysis on SBS proportions across alpha and delta variants from unvaccinated (samples collected worldwide before 15th of January 2021, when less than 0.5% of the world population was vaccinated) and vaccinated patients. (B) Diagrammatic representation of standard (Watson and Crick) pairing of guanine and cytosine (top panel) and Hoogsteen base pairing between 8-oxoguanine and adenine (bottom panel). (C) Comparison of SBS spectra of different variants from vaccinated patients. Error bars denote confidence intervals (CI). (D) Proportion of G>U and C>A within the variants, coloured as in (C). The dotted line denotes no asymmetry (ratio=1).

Thumbnail

Figure 2 -
The influence of compartmentalisation on SBS patterns generated by oxidation. Differential pattern caused by mutagen exposure of vRNA guanines inside (A) or outside (B) double-membrane vesicles (DMVs), where vRNA replicates. Nucleotides circled in orange denote mutations that will occur in that scenario, while those in black mark the final product of the process. DMVs are delimited by double green lines. G* indicates 8-oxoguanine. (C) Proportion of C>U/G>A and G>C/C>G within the variants, coloured as in Figure 1C.

Figure 1 - The environment of infected cells alters the G>U substitution incidence in SARS-CoV-2. (A) Analysis on SBS proportions across alpha and delta variants from unvaccinated (samples collected worldwide before 15th of January 2021, when less than 0.5% of the world population was vaccinated) and vaccinated patients. (B) Diagrammatic representation of standard (Watson and Crick) pairing of guanine and cytosine (top panel) and Hoogsteen base pairing between 8-oxoguanine and adenine (bottom panel). (C) Comparison of SBS spectra of different variants from vaccinated patients. Error bars denote confidence intervals (CI). (D) Proportion of G>U and C>A within the variants, coloured as in (C). The dotted line denotes no asymmetry (ratio=1).

Figure 2 - The influence of compartmentalisation on SBS patterns generated by oxidation. Differential pattern caused by mutagen exposure of vRNA guanines inside (A) or outside (B) double-membrane vesicles (DMVs), where vRNA replicates. Nucleotides circled in orange denote mutations that will occur in that scenario, while those in black mark the final product of the process. DMVs are delimited by double green lines. G* indicates 8-oxoguanine. (C) Proportion of C>U/G>A and G>C/C>G within the variants, coloured as in Figure 1C.

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The SARS-CoV-2 mutation landscape is shaped before replication starts

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[1] Send correspondence to Luis Mariano Polo. Universidad Nacional de Cuyo (UNCuyo), Instituto de Histología y Embriología de Mendoza (IHEM), Av. Libertador 80, M5502JMA, Mendoza, Argentina. E-mail: marianopolo@gmail.com.