Large-scale analysis of synonymous viral variants reveals global adaptation of the SARS-CoV-2 to the human codon usage

Ramazzotti, Daniele; Angaroni, Fabrizio; Maspero, Davide; Mauri, Mario; D’Aliberti, Deborah; Antoniotti, Marco; Graudenzi, Alex; Piazza, Rocco

Many large national and transnational studies were dedicated to the analysis of SARS-CoV-2 genome. Most studies are focused on missense and nonsense mutations, however approximately 30% of the SARS-CoV-2 variants are synonymous, therefore changing the target codon without affecting the corresponding protein sequence. Here, by performing a large-scale analysis of more than 40000 SARS-CoV-2 genome sequences, we show that, over time, the virus is adapting its codon usage to that of the human host through the accumulation of silent mutations, thus likely improving its effectiveness in using the human aminoacyl-tRNA set. The sole exception to this rule is represented by mutations bearing the signature of the defensive APOlipoprotein B Editing Complex (APOBEC) machinery, which show a negative profile. Taken globally, this study indicates that codon usage adaptation may play a relevant role in the evolution of SARS-CoV-2, which appears to be much more complex than previously anticipated. One-Sentence Summary Synonymous SARS-CoV-2 mutations positively impact viral evolution by increasing adaptation to the human codon usage.