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.