In Search of Beneficial Coding RNA Editing

Abstract

RNA editing is a posttranscriptional modification that can lead to a change in the encoded protein sequence of a gene. Although a few cases of mammalian coding RNA editing are known to be functionally important, the vast majority of over 2,000 A-to-I editing sites that have been identified from the coding regions of the human genome are likely nonadaptive, representing tolerable promiscuous targeting of editing enzymes. Finding the potentially tiny fraction of beneficial editing sites from the sea of mostly nearly neutral editing is a difficult but important task. Here, we propose and provide evidence that evolutionarily conserved or "hardwired" residues that experience high-level nonsynonymous RNA editing in a species are enriched with beneficial editing. This simple approach allows the prediction of sites where RNA editing is functionally important. We suggest that priority be given to these candidates in future characterizations of the functional and fitness consequences of RNA editing.

Adaptation of A-to-I RNA editing in Drosophila

“…In contrast to previous observations that nonsynonymous editing events were generally non-adaptive in mammals [67, 68] and in Drosophila [50], our analysis revealed the nonsynonymous editing events in Drosophila brains were predominantly adaptive. The ratio of nonsynonymous ( N ) to synonymous ( S ) editing sites ( N/S ) in different brain samples of D .…”

“…pseudoobscura (S12 Table). Altogether, our results suggest that the N editing sites in the PSEB genes are favored and maintained by natural selection while the S editing sites, which are putatively neutral, might degenerate during long-term evolution, which generates even higher N/S ratios in the sites with editing events conserved between species [50, 68]. …”

“…The functional consequences of the majority of A-to-I editing events, however, remain to be explored. In fact, comparative genomics has demonstrated that only a small fraction of the human A-to-I editing events were evolutionarily conserved [65–68]. Furthermore, it was nicely demonstrated that the editing events in primate coding regions were generally non-adaptive [60, 67, 68].…”

“…In fact, comparative genomics has demonstrated that only a small fraction of the human A-to-I editing events were evolutionarily conserved [65–68]. Furthermore, it was nicely demonstrated that the editing events in primate coding regions were generally non-adaptive [60, 67, 68]. Nevertheless, the targets of RNA editing might have evolved rapidly across species because A-to-I editing in mammals predominantly occurs in repetitive sequences [53–55, 61, 65, 66], while the editing events in Drosophila are mainly located in coding regions of genes encoding neurotransmitters or ion channels [47–50, 69, 70].…”

“…Nevertheless, the targets of RNA editing might have evolved rapidly across species because A-to-I editing in mammals predominantly occurs in repetitive sequences [53–55, 61, 65, 66], while the editing events in Drosophila are mainly located in coding regions of genes encoding neurotransmitters or ion channels [47–50, 69, 70]. Therefore, the evolutionary forces acting on A-to-I RNA editing might be different between Drosophila [50] and primates [60, 67, 68]. …”