TY - JOUR
T1 - Mutation rate of SARS-CoV-2 and emergence of mutators during experimental evolution
AU - Amicone, Massimo
AU - Borges, Vítor
AU - Alves, Maria João
AU - Isidro, Joana
AU - Zé-Zé, Líbia
AU - Duarte, Sílvia
AU - Vieira, Luís
AU - Guiomar, Raquel
AU - Gomes, João Paulo
AU - Gordo, Isabel
N1 - Funding: M.A. was supported by ‘Fundação para a Ciência e Tecnologia’ (FCT), fellowships PD/BD/138735/2018. Research was supported by FCT Project PTDC/BIA-EVL/31528/2017 to I.G. and by funds from Portuguese NIH.
PY - 2022/3/29
Y1 - 2022/3/29
N2 - Background and objectives: To understand how organisms evolve, it is fundamental to study how mutations emerge and establish. Here, we estimated the rate of mutation accumulation of SARS-CoV-2 in vitro and investigated the repeatability of its evolution when facing a new cell type but no immune or drug pressures. Methodology: We performed experimental evolution with two strains of SARS-CoV-2, one carrying the originally described spike protein (CoV-2-D) and another carrying the D614G mutation that has spread worldwide (CoV-2-G). After 15 passages in Vero cells and whole genome sequencing, we characterized the spectrum and rate of the emerging mutations and looked for evidences of selection across the genomes of both strains. Results: From the frequencies of the mutations accumulated, and excluding the genes with signals of selection, we estimate a spontaneous mutation rate of 1.3 × 10-6 ± 0.2 × 10-6 per-base per-infection cycle (mean across both lineages of SARS-CoV-2 ± 2SEM). We further show that mutation accumulation is larger in the CoV-2-D lineage and heterogeneous along the genome, consistent with the action of positive selection on the spike protein, which accumulated five times more mutations than the corresponding genomic average. We also observe the emergence of mutators in the CoV-2-G background, likely linked to mutations in the RNA-dependent RNA polymerase and/or in the error-correcting exonuclease protein. Conclusions and implications: These results provide valuable information on how spontaneous mutations emerge in SARS-CoV-2 and on how selection can shape its genome toward adaptation to new environments. Lay Summary: Each time a virus replicates inside a cell, errors (mutations) occur. Here, via laboratory propagation in cells originally isolated from the kidney epithelium of African green monkeys, we estimated the rate at which the SARS-CoV-2 virus mutates - an important parameter for understanding how it can evolve within and across humans. We also confirm the potential of its Spike protein to adapt to a new environment and report the emergence of mutators - viral populations where mutations occur at a significantly faster rate.
AB - Background and objectives: To understand how organisms evolve, it is fundamental to study how mutations emerge and establish. Here, we estimated the rate of mutation accumulation of SARS-CoV-2 in vitro and investigated the repeatability of its evolution when facing a new cell type but no immune or drug pressures. Methodology: We performed experimental evolution with two strains of SARS-CoV-2, one carrying the originally described spike protein (CoV-2-D) and another carrying the D614G mutation that has spread worldwide (CoV-2-G). After 15 passages in Vero cells and whole genome sequencing, we characterized the spectrum and rate of the emerging mutations and looked for evidences of selection across the genomes of both strains. Results: From the frequencies of the mutations accumulated, and excluding the genes with signals of selection, we estimate a spontaneous mutation rate of 1.3 × 10-6 ± 0.2 × 10-6 per-base per-infection cycle (mean across both lineages of SARS-CoV-2 ± 2SEM). We further show that mutation accumulation is larger in the CoV-2-D lineage and heterogeneous along the genome, consistent with the action of positive selection on the spike protein, which accumulated five times more mutations than the corresponding genomic average. We also observe the emergence of mutators in the CoV-2-G background, likely linked to mutations in the RNA-dependent RNA polymerase and/or in the error-correcting exonuclease protein. Conclusions and implications: These results provide valuable information on how spontaneous mutations emerge in SARS-CoV-2 and on how selection can shape its genome toward adaptation to new environments. Lay Summary: Each time a virus replicates inside a cell, errors (mutations) occur. Here, via laboratory propagation in cells originally isolated from the kidney epithelium of African green monkeys, we estimated the rate at which the SARS-CoV-2 virus mutates - an important parameter for understanding how it can evolve within and across humans. We also confirm the potential of its Spike protein to adapt to a new environment and report the emergence of mutators - viral populations where mutations occur at a significantly faster rate.
KW - experimental evolution
KW - mutation rate
KW - mutator
KW - SARS-CoV-2
KW - virus adaptation
UR - http://www.scopus.com/inward/record.url?scp=85128566574&partnerID=8YFLogxK
U2 - 10.1093/emph/eoac010
DO - 10.1093/emph/eoac010
M3 - Article
AN - SCOPUS:85128566574
SN - 2050-6201
VL - 10
SP - 142
EP - 155
JO - Evolution, Medicine and Public Health
JF - Evolution, Medicine and Public Health
IS - 1
ER -