Mutation bias implicates RNA editing in a wide range of mammalian RNA viruses

The rapid evolution of RNA viruses has been long considered to result from a combination of high copying error frequencies during RNA replication, short generation times and the consequent extensive fixation of neutral or adaptive changes over short periods. While both the identities and sites of mutations are typically modelled as being random, recent investigations of sequence diversity of SARS coronavirus 2 (SARS-CoV-2) have identified a preponderance of C->U transitions, potentially driven by an APOBEC-like RNA editing process. The current study investigated whether this phenomenon could be observed in the more genetically diverse datasets of other RNA viruses. Using a 5% divergence filter to infer directionality, 18 from 32 datasets of aligned coding region sequences from a diverse range of mammalian RNA viruses (including Picornaviridae, Flaviviridae, Matonaviridae, Caliciviridae and Coronaviridae) showed a >2-fold base composition normalised excess of C->U transitions compared to U->C (range 2.1x-7.5x). C->U transitions showed a favoured 5' U upstream context consistent with previous analyses of APOBEC-mediated RNA targeting. Amongst several genomic compositional and structural parameters, the presence of genome scale RNA secondary structure (GORS) was associated with C->U/U->C transition asymmetries (p U changes were specifically over-represented at phylogenetically uninformative sites, consistent with extensive homoplasy documented in SARS-CoV-2. Excess C->U substitutions accounted for 15-20% of standing sequence variability of HCV and other RNA viruses; RNA editing may therefore represent a potent driver of RNA virus sequence diversification and longer term evolution.