Rapid protein sequence evolution via compensatory frameshift is widespread in RNA virus genomes

• Main Authors: Hahn, Y. (Author), Park, D. (Author)
• Format: Article
• Language: English
• Published: BioMed Central Ltd 2021
• Subjects: amino acid sequence; Amino Acid Sequence; Amino acids; Amino-acids; Coding sequences; Compensatory frameshift; Frameshift; frameshift mutation; Frameshift Mutation; Genes; genetics; Genome, Viral; Nucleotides; Open reading frame; phylogeny; Phylogeny; Premature termination; Protein evolution; Protein sequences; Proteins; RNA; RNA virus; RNA Viruses; RNA, Viral; Viral genome; virus genome; virus RNA; Viruses
• Online Access: View Fulltext in Publisher

 Background: RNA viruses possess remarkable evolutionary versatility driven by the high mutability of their genomes. Frameshifting nucleotide insertions or deletions (indels), which cause the premature termination of proteins, are frequently observed in the coding sequences of various viral genomes. When a secondary indel occurs near the primary indel site, the open reading frame can be restored to produce functional proteins, a phenomenon known as the compensatory frameshift. Results: In this study, we systematically analyzed publicly available viral genome sequences and identified compensatory frameshift events in hundreds of viral protein-coding sequences. Compensatory frameshift events resulted in large-scale amino acid differences between the compensatory frameshift form and the wild type even though their nucleotide sequences were almost identical. Phylogenetic analyses revealed that the evolutionary distance between proteins with and without a compensatory frameshift were significantly overestimated because amino acid mismatches caused by compensatory frameshifts were counted as substitutions. Further, this could cause compensatory frameshift forms to branch in different locations in the protein and nucleotide trees, which may obscure the correct interpretation of phylogenetic relationships between variant viruses. Conclusions: Our results imply that the compensatory frameshift is one of the mechanisms driving the rapid protein evolution of RNA viruses and potentially assisting their host-range expansion and adaptation. © 2021, The Author(s).