Frameshift Mutations in the Microevolution and Macroevolution of Viruses

Some nucleotide insertions or deletions (indels) in open reading frames of virus genes lead to frameshift mutations (FSMs) which can change amino acid sequences drastically. Most FSMs are deleterious and inhibited by natural selection, but a few FSMs could aid viruses to adapt to new hosts, escape immunity, or change viral pathogenicity or transmissibility. Surprisingly, various fundamental aspects of FSMs in virus evolution remain unknown. In this report, we identified 667 FSMs in the genomes of viruses from 13 families. Each FSM changed approximately 11.3 ± 6.6 amino acid residues. Of the 667 FSMs, 89.2% were 2-indel compensatory FSMs, and the remaining FSMs contained 1-, 3-, 4-, or 5-indels. FSMs occurred more frequently in the sequences with identities of 60.0–69.9% than in the sequences of the same viral gene with identities of 90.0–99.9%, 80.0–89.9%, and 70.0–79.9% by approximately 34.9, 13.1, and 3.1 times, respectively. These results suggested that most FSMs were fixed through the compensatory mechanism with 2 to 5 indels, and that FSMs are more important to the macroevolution (i.e., inter-species evolution including speciation) than to the microevolution (i.e., intra-species evolution) of viruses. They provided novel evidence for the hopeful monster hypothesis in evolutionary biology. Furthermore, we found that FSMs occurred at different frequencies among genes in the same virus genome, among species in the same virus family, and among virus families. Collectively, this study revealed multiple fundamental features of FSMs in virus evolution for the first time and provided novel insights into the mechanisms of speciation. IMPORTANCE Frameshift mutations (FSMs) can change amino acid sequences drastically, and this concept is well known to biomedical researchers. However, various fundamental aspects of FSMs, including their roles in virus evolution, remain unknown. In this report, we identified hundreds of FSMs in the genomes of viruses from a dozen of families. We found that most FSMs were fixed through the compensatory mechanism with 2 to 5 indels, and that FSMs are more important to the macroevolution (i.e., inter-species evolution) than to the microevolution (i.e., intra-species evolution) of viruses. This study revealed multiple fundamental features of FSMs in virus evolution for the first time and provided novel evidence for the hopeful monster hypothesis in evolutionary biology pertaining to the mechanisms of speciation.