Human coding RNA editing is generally nonadaptive

Abstract

Impairment of RNA editing at a handful of coding sites causes severe disorders, prompting the view that coding RNA editing is highly advantageous. Recent genomic studies have expanded the list of human coding RNA editing sites by more than 100 times, raising the question of how common advantageous RNA editing is. Analyzing 1,783 human coding A-to-G editing sites, we show that both the frequency and level of RNA editing decrease as the importance of a site or gene increases; that during evolution, edited As are more likely than unedited As to be replaced with Gs but not with Ts or Cs; and that among nonsynonymously edited As, those that are evolutionarily least conserved exhibit the highest editing levels. These and other observations reveal the overall nonadaptive nature of coding RNA editing, despite the presence of a few sites in which editing is clearly beneficial. We propose that most observed coding RNA editing results from tolerable promiscuous targeting by RNA editing enzymes, the original physiological functions of which remain elusive.deleterious | neutral | synonymous

ADAR1 is required for differentiation and neural induction by regulating microRNA processing in a catalytically independent manner

“…It has been shown that at least 40% of miRNAs have altered levels in ADAR mutant C. elegans strains, although editing in small RNAs is rare [20]. Interestingly, a recent report found that despite the presence of a few sites in which editing is clearly beneficial, human RNA editing sites in coding regions are generally nonadaptive and evolutionarily poorly conserved, arguing against the physiological significance of these editing events in human [56]. Strikingly, the observations that ADAR1-deficient mice exhibited embryonic lethality [23][24][25] and that ADAR1 KD hESCs exhibited significant differentiation defects (Figure 1) clearly demonstrate that ADAR1 is highly likely to be crucial for mammals.…”

The emerging role of RNA editing in plasticity

“…A recent compilation of human RNA editing sites, generated from multiple studies, estimated that there were ∼1200 in total (Xu and Zhang, 2014). Most of the sites, however, only occurred in a single sample and at very low frequency.…”

“…Guixia Xu and Jianzhi Zhang create a compelling argument that RNA editing is generally not used for adaptation in mammals (Xu and Zhang, 2014). In their study, the authors tabulated all the human recoding events in coding regions and found that, after normalizing for the abundance of adenosine targets, non-synonymous edits were less frequent than expected and synonymous changes more frequent.…”

Evidence for multiple, distinct ADAR-containing complexes in Xenopus laevis

“…This observation suggests that the presence of an editing event within an RNA is more important than the precise location of that event, supporting the hypothesis that editing has a function beyond recoding RNAs. Furthermore, it is unlikely that ADAR evolved primarily to diversify the coding potential of mRNAs as most editing in human coding sequences does not confer an adaptive advantage (Xu and Zhang 2014). Rather, it is postulated that ADAR had an unknown ancestral function and later evolved to target the codons of particular transcripts (Bass 2002;Gray 2012;Xu and Zhang 2014).…”

“…Furthermore, it is unlikely that ADAR evolved primarily to diversify the coding potential of mRNAs as most editing in human coding sequences does not confer an adaptive advantage (Xu and Zhang 2014). Rather, it is postulated that ADAR had an unknown ancestral function and later evolved to target the codons of particular transcripts (Bass 2002;Gray 2012;Xu and Zhang 2014). Although a few studies have reported specific roles for A-to-I editing beyond recoding, including influencing RNA stability (Scadden and Smith 1997;Scadden 2005) and driving nuclear localization (Zhang and Carmichael 2001), these roles have not proven widely generalizable (Hundley and Bass 2010;Nishikura 2010).…”