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Abstract
Adenosine-to-inosine RNA editing diversifies the transcriptome and promotes functional diversity, particularly in the brain. A plethora of editing sites has been recently identified; however, how they are selected and regulated and which are functionally important are largely unknown. Here we show the cis-regulation and stepwise selection of RNA editing during Drosophila evolution and pinpoint a large number of functional editing sites. We found that the establishment of editing and variation in editing levels across Drosophila species are largely explained and predicted by cis-regulatory elements. Furthermore, editing events that arose early in the species tree tend to be more highly edited in clusters and enriched in slowly-evolved neuronal genes, thus suggesting that the main role of RNA editing is for fine-tuning neurological functions. While nonsynonymous editing events have been long recognized as playing a functional role, in addition to nonsynonymous editing sites, a large fraction of 3’UTR editing sites is evolutionarily constrained, highly edited, and thus likely functional. We find that these 3’UTR editing events can alter mRNA stability and affect miRNA binding and thus highlight the functional roles of noncoding RNA editing. Our work, through evolutionary analyses of RNA editing in Drosophila, uncovers novel insights of RNA editing regulation as well as its functions in both coding and non-coding regions.
Highlights
Adenosine-to-inosine (A-to-I) RNA editing converts adenosine to inosine in RNA, which is read by the cellular machinery as guanosine (G) [1,2,3]
RNA editing occurs at thousands of sites across the genomes of various animals, the functions of most editing events– those in non-coding regions–have not been studied, and what determines whether particular adenosines across the genome are edited has not been fully explored
Using the Drosophila genus as model organisms, we analyze the evolution of A-to-I RNA editing to identify a large fraction of both coding and non-coding editing events that are under evolutionary constraint and likely functionally
Summary
Adenosine-to-inosine (A-to-I) RNA editing converts adenosine to inosine in RNA, which is read by the cellular machinery as guanosine (G) [1,2,3]. Recent studies have found that, human RNA editing events are generally non-adaptive [19] possibly because the vast majority are in primate-specific Alu repeats, high-level nonsynonymous editing events, which cause amino acid changes, are most likely beneficial in humans [20,21]. In species such as squid and Drosophila, a significant fraction of editing events are located in coding regions, and many are likely to be beneficial [22,23,24]
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