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Figure 1. 

Classification of A-to-I recoding sites and their evolutionary dynamics. (a) Recoding sites can be classified as A-preferring, G-preferring, and A/I-preferring based on the fitness effects of the edited and unedited variants. Editing at A-preferring sites is neutral or slightly deleterious, becoming fixed in the genome primarily through genetic drift. A/I-preferring sites are positively selected for their ability to enhance protein diversity and flexibility. In contrast, G-preferring sites may be fixed through positive selection due to their compensatory or transitional roles, or through genetic drift if they are harm-permitted by editing. These sites can also be categorized into restorative or diversifying editing based on the amino acid changes relative to ancestral states. Restorative editing includes compensatory editing, which corrects pre-existing harmful genomic G-to-A mutations, and harm-permitting editing, which corrects genomic G-to-A mutations that it itself promotes. Both G-preferring and A/I-preferring compensatory editing are adaptive, while only A/I-preferring harm-permitting editing can be adaptive. (b) The expected A-to-G substitution rate at the three types of recoding sites is shown relative to synonymous editing sites (neutral rate) and nonsynonymous uneditable sites.

Figure 2. 

The potential evolutionary processes of two types of restorative editing: compensatory editing and harm-permitting editing. (a) When G-to-A mutations that were once advantageous at Time 1 become harmful at Time 2, compensatory A-to-I editing can be established through positive selection due to its role in compensating for these mutations or enhancing protein diversity and flexibility. (b) Pre-existing editing activity can relax functional constraints at the genomic level, allowing G-to-A mutations to create new edited A sites, resulting in harm-permitting editing. This process underscores the intricate relationship between A-to-I editing and G-to-A mutations, as the formation of edited A sites relies on A-to-I editing. Consequently, no intermediate individuals can possess the corresponding editable A sites without the associated editing events. If harm-permitting editing only serves a restorative function, it should be nonadaptive and fixed by genetic drift, as it does not confer a fitness advantage over the original genomic G. However, it can be adaptive and fixed by positive selection when the protein diversity and flexibility provided by harm-permitting editing confer a competitive advantage.

Figure 3. 

The advantages of A-to-I RNA editing in navigating trade-offs arising from antagonistic pleiotropy and the anticipated phenotypes or fitness of uneditable and edited mutants. (a) The A variant is detrimental in tissue/stage A but beneficial in tissue/stage B, and/or the G variant is beneficial in tissue/stage A but detrimental in tissue/stage B. Tissue/stage A-specific RNA editing can alleviate the trade-offs resulting from the antagonistic pleiotropy of these two variants across both tissues/stages. (b) The anticipated developmental or physiological phenotypes and fitness of uneditable mutants (expressing only the A variant) and edited mutants (expressing only the G variant) for each type of recoding sites, as determined through genetic studies.