Abstract
BackgroundThe bulk of variability in mRNA sequence arises due to mutation—change in DNA sequence which is heritable if it occurs in the germline. However, variation in mRNA can also be achieved by post-transcriptional modification including mRNA editing, changes in mRNA nucleotide sequence that mimic the effect of mutations. Such modifications are not inherited directly; however, as the processes affecting them are encoded in the genome, they have a heritable component, and therefore can be shaped by selection. In soft-bodied cephalopods, adenine-to-inosine RNA editing is very frequent, and much of it occurs at nonsynonymous sites, affecting the sequence of the encoded protein.MethodsWe study selection regimes at coleoid A-to-I editing sites, estimate the prevalence of positive selection, and analyze interdependencies between the editing level and contextual characteristics of editing site.ResultsHere, we show that mRNA editing of individual nonsynonymous sites in cephalopods originates in evolution through substitutions at regions adjacent to these sites. As such substitutions mimic the effect of the substitution at the edited site itself, we hypothesize that they are favored by selection if the inosine is selectively advantageous to adenine at the edited position. Consistent with this hypothesis, we show that edited adenines are more frequently substituted with guanine, an informational analog of inosine, in the course of evolution than their unedited counterparts, and for heavily edited adenines, these transitions are favored by positive selection. Our study shows that coleoid editing sites may enhance adaptation, which, together with recent observations on Drosophila and human editing sites, points at a general role of RNA editing in the molecular evolution of metazoans.
Highlights
The process of natural selection requires heritable variation to be present in a population and the absence of genetic variants selection could act upon is generally considered to be a factor hampering adaptation (Lush 1937; Smith 1976; Barton and Partridge 2000; Lanfear et al 2014; Rousselle et al 2020)
As A-to-I editing is to be affected by the local sequence context (Alon et al 2012; Liscovitch-Brauer et al 2017) and the RNA secondary RNA structure (Morse et al 2002; Reenan 2005; Gommans et al 2009; Savva et al 2012; Klironomos et al 2013; Rieder et al 2013), one would expect, firstly, contextual differences around weakly vs. heavily edited sites and, secondly, contextual mutations associated with changes in editing status
We have observed a previously unnoted dependence of the editing level (EL) (Fig. 1b), defined as the percent of transcripts containing I at the considered site at the moment of sequencing
Summary
The process of natural selection requires heritable variation to be present in a population and the absence of genetic variants selection could act upon is generally considered to be a factor hampering adaptation (Lush 1937; Smith 1976; Barton and Partridge 2000; Lanfear et al 2014; Rousselle et al 2020). Heritable variation is generated mainly by the mutational process (Lewontin 1964; Avery and Hill 1977; Lynch and Walsh 1998). The mutation rate may be a factor affecting the evolution rate, which we, following J. Maynard Smith, define here as the rate of accumulation of beneficial mutations (Smith 1976; Nam et al 2017; Rousselle et al 2020). In populations with low genetic variability the mutation rate is correlated with the evolution rate (Rousselle et al 2020). In order to adapt, a low-polymorphic population may need additional expressed genetic variability. We test the hypothesis that a potential source of such variability could be introduced by heritable epigenetic modifications, mRNA editing (Bass and Weintraub 1988; Gommans et al 2009; Klironomos et al 2013; Kronholm and Collins 2015)
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