Secondary structure of the SARS-CoV-2 genome is predictive of nucleotide substitution frequency

Abstract

AbstractAccurate estimation of the effects of mutations on SARS-CoV-2 viral fitness can inform public-health responses such as vaccine development and predicting the impact of a new variant; it can also illuminate biological mechanisms including those underlying the emergence of variants of concern1. Recently, Lan et al reported a high-quality model of SARS-CoV-2 secondary structure and its underlying dimethyl sulfate (DMS) reactivity data2. I investigated whether secondary structure can explain some variability in the frequency of observing different nucleotide substitutions across millions of patient sequences in the SARS-CoV-2 phylogenetic tree3. Nucleotide basepairing was compared to the estimated “mutational fitness” of substitutions, a measurement of the difference between a substitution’s observed and expected frequency that is correlated with other estimates of viral fitness4. This comparison revealed that secondary structure is often predictive of substitution frequency, with significant decreases in substitution frequencies at basepaired positions. Focusing on the mutational fitness of C→T, the most common type of substitution, I describe C→T substitutions at basepaired positions that characterize major SARS-CoV-2 variants; such mutations may have a greater impact on fitness than appreciated when considering substitution frequency alone.