A-to-I editing sites are a genomically encoded G: Implications for the evolutionary significance and identification of novel editing sites

Ribonucleic acid (RNA) editing can extend transcriptomic and proteomic diversity by changing the identity of a particular codon. Genetic recoding as a result of adenosine-to-inosine (A-to-I) RNA editing can alter highly conserved or invariant coding positions in proteins. Interestingly, examples exist in which A-to-I editing sites in one species are fixed genomically as a G in a closely related species. Phylogenetic analysis indicates that G-to-A mutations at the DNA level may be corrected by post-transcriptional A-to-I RNA editing, while in turn, the edited I (G) may be hardwired into the genome, resulting in an A-to-G mutation. We propose a model in which nuclear A-to-I RNA editing acts as an evolutionary intermediate of genetic variation. We not only provide information on the mechanism behind the evolutionary acquisition of an A-to-I RNA editing site but also demonstrate how to predict nuclear A-to-I editing sites by identifying positions where an RNA editing event would maintain the conservation of a protein relative to its homologs in other species. We identified a novel edited site in the fourth exon of the cacophony transcript coding calcium channel α1 and verified it experimentally.