Nuclear and mitochondrial RNA editing systems have opposite effects on protein diversity

RNA editing can yield protein products that differ from those directly encoded by genomic DNA. This process is pervasive in the mitochondria of many eukaryotes, where it predominantly results in the restoration of ancestral protein sequences. Nuclear mRNAs in metazoans also undergo editing (adenosine-to-inosine or 'A-to-I' substitutions), and most of these edits appear to be nonadaptive 'misfirings' of adenosine deaminases. However, recent analysis of cephalopod transcriptomes found that many editing sites are shared by anciently divergent lineages within this group, suggesting they play some adaptive role. Recent discoveries have also revealed that some fungi have an independently evolved A-to-I editing mechanism, resulting in extensive recoding of their nuclear mRNAs. Here, phylogenetic comparisons were used to determine whether RNA editing generally restores ancestral protein sequences or creates derived variants. Unlike in mitochondrial systems, RNA editing in metazoan and fungal nuclear transcripts overwhelmingly leads to novel sequences not found in inferred ancestral proteins. Even for the subset of RNA editing sites shared by deeply divergent cephalopod lineages, the primary effect of nuclear editing is an increase-not a decrease-in protein divergence. These findings suggest fundamental differences in the forces responsible for the evolution of RNA editing in nuclear versus mitochondrial systems.