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C-to-U RNA editing enzymatically converts the base C to U in RNA molecules and could lead to nonsynonymous changes when occurring in coding regions. Hundreds to thousands of coding sites were recently found to be C-to-U edited or editable in humans, but the biological significance of this phenomenon is elusive. Here, we test the prevailing hypothesis that nonsynonymous editing is beneficial because it provides a means for tissue- or time-specific regulation of protein function that may be hard to accomplish by mutations due to pleiotropy. The adaptive hypothesis predicts that the fraction of sites edited and the median proportion of RNA molecules edited (i.e., editing level) are both higher for nonsynonymous than synonymous editing. However, our empirical observations are opposite to these predictions. Furthermore, the frequency of nonsynonymous editing, relative to that of synonymous editing, declines as genes become functionally more important or evolutionarily more constrained, and the nonsynonymous editing level at a site is negatively correlated with the evolutionary conservation of the site. Together, these findings refute the adaptive hypothesis; they instead indicate that the reported C-to-U coding RNA editing is mostly slightly deleterious or neutral, probably resulting from off-target activities of editing enzymes. Along with similar conclusions on the more prevalent A-to-I editing and m6A modification of coding RNAs, our study suggests that, at least in humans, most events of each type of posttranscriptional coding RNA modification likely manifest cellular errors rather than adaptations, demanding a paradigm shift in the research of posttranscriptional modification.

Human C-to-U Coding RNA Editing Is Largely Nonadaptive