Comparative RNA editomics prioritizes candidate adaptive RNA editing sites

Abstract

A-to-I mRNA editing is a widespread RNA modification that introduces A-to-G variations at mRNA level, enhancing transcriptomic and proteomic diversity without altering the genome. Recently, the term adaptation has gained significant attention but lacks a mechanistic classification. This article aims to discuss conceptual frameworks and research methods related to adaptive and non-adaptive RNA editing. We begin by discussing neutral evolution and the molecular error theory, highlighting that while identifying adaptive signals is desirable, most molecular complexity may be non-adaptive. Conceptually, adaptation could be understood as a continuum between two poles: (1) the permanent mutations leading to fixed adaptation, which is pleiotropic, and (2) the acquisition of plasticity to cope with changing environments, which is anti-pleiotropic. Adaptive RNA editing actually belongs to the latter class due to its regulatable nature. We introduce the term “comparative RNA editomics” to encompass the analyses related to RNA editing, including identification, selection analysis, linkage analysis, condition-specificity, and evolutionary dynamics based on multi-omics data. Such pipelines allow us to prioritize potential adaptive editing sites (e.g., Adar auto-recoding in insects) from non-adaptive editing (e.g., Drosophila lncRNA roX1 editing). The adaptive nature of several recoding and stop-codon read-through editing sites in Fusarium graminearum have been experimentally validated due to the high feasibility of genetic manipulation and phenotypical assays in fungi. Our deep insights complement traditional views on adaptation and facilitate future studies in functional genomics.