TY - JOUR T1 - Mutation rate of SARS-CoV-2 and emergence of mutators during experimental evolution JF - bioRxiv DO - 10.1101/2021.05.19.444774 SP - 2021.05.19.444774 AU - Vítor Borges AU - Maria João Alves AU - Massimo Amicone AU - Joana Isidro AU - Líbia Zé-Zé AU - Sílvia Duarte AU - Luís Vieira AU - Raquel Guiomar AU - João Paulo Gomes AU - Isabel Gordo Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/05/19/2021.05.19.444774.abstract N2 - “How predictable is evolution?” is a key question in evolutionary biology. Experimental evolution has shown that the evolutionary path of microbes can be extraordinarily reproducible. Here, using experimental evolution in two circulating SARS-CoV-2, we estimate its mutation rate and demonstrate the repeatability of its evolution when facing a new cell type but no immune or drug pressures. We estimate a genomic mutation rate of 3.7×10-6 nt-1 cycle-1 for a lineage of SARS-CoV-2 with the originally described spike protein (CoV-2-D) and of 2.9×10-6 nt-1 cycle-1 for a lineage carrying the D614G mutation that has spread worldwide (CoV-2-G). We further show that mutation accumulation is heterogeneous along the genome, with the spike gene accumulating mutations at a mean rate 16×10-6 nt-1 per infection cycle across backgrounds, five-fold higher than the genomic average. We 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. Despite strong bottlenecks, several de novo mutations spread to high frequencies by selection and considerable convergent evolution in spike occurs. These results demonstrate the high adaptive potential of SARS-CoV-2 during the first stages of cell infection in the absence of immune surveillance.Competing Interest StatementThe authors have declared no competing interest. ER -