The Emergence of SARS-CoV-2 Variants of Concern Is Driven by Acceleration of the Substitution Rate.

ABSTRACT

The ongoing SARS-CoV-2 pandemic has seen an unprecedented amount of rapidly generated genome data. These data have revealed the emergence of lineages with mutations associated to transmissibility and antigenicity, known as variants of concern (VOCs). A striking aspect of VOCs is that many of them involve an unusually large number of defining mutations. Current phylogenetic estimates of the substitution rate of SARS-CoV-2 suggest that its genome accrues around two mutations per month. However, VOCs can have 15 or more defining mutations and it is hypothesized that they emerged over the course of a few months, implying that they must have evolved faster for a period of time. We analyzed genome sequence data from the GISAID database to assess whether the emergence of VOCs can be attributed to changes in the substitution rate of the virus and whether this pattern can be detected at a phylogenetic level using genome data. We fit a range of molecular clock models and assessed their statistical performance. Our analyses indicate that the emergence of VOCs is driven by an episodic increase in the substitution rate of around 4-fold the background phylogenetic rate estimate that may have lasted several weeks or months. These results underscore the importance of monitoring the molecular evolution of the virus as a means of understanding the circumstances under which VOCs may emerge.