Rampant C->U hypermutation in the genomes of SARS-CoV-2 and other coronaviruses - causes and consequences for their short and long evolutionary trajectories

Abstract

The pandemic of SARS coronavirus 2 (SARS-CoV-2) has motivated an intensive analysis of its molecular epidemiology following its worldwide spread. To understand the early evolutionary events following its emergence, a dataset of 985 complete SARS-CoV-2 sequences was assembled. Variants showed a mean 5.5-9.5 nucleotide differences from each other, commensurate with a mid-range coronavirus substitution rate of 3x10-4 substitutions/site/year. Almost half of sequence changes were C->U transitions with an 8-fold base frequency normalised directional asymmetry between C->U and U->C substitutions. Elevated ratios were observed in other recently emerged coronaviruses (SARS-CoV and MERS-CoV) and to a decreasing degree in other human coronaviruses (HCoV-NL63, -OC43, -229E and -HKU1) proportionate to their increasing divergence. C->U transitions underpinned almost half of the amino acid differences between SARS-CoV-2 variants, and occurred preferentially in both 5U/A and 3U/A flanking sequence contexts comparable to favoured motifs of human APOBEC3 proteins. Marked base asymmetries observed in non-pandemic human coronaviruses (U>>A>G>>C) and low G+C contents may represent long term effects of prolonged C->U hypermutation in their hosts. ImportanceThe evidence that much of sequence change in SARS-CoV-2 and other coronaviruses may be driven by a host APOBEC-like editing process has profound implications for understanding their short and long term evolution. Repeated cycles of mutation and reversion in favoured mutational hotspots and the widespread occurrence of amino acid changes with no adaptive value for the virus represents a quite different paradigm of virus sequence change from neutral and Darwinian evolutionary frameworks that are typically used in molecular epidemiology investigations.