The adenosine-to-inosine (A-to-I) RNA editomes have been systematically 
characterized in various metazoan species, and many editing sites were found in 
clusters. However, it remains unclear whether the clustered editing sites tend 
to be linked in the same RNA molecules or not. By adopting a method originally 
designed to detect linkage disequilibrium of DNA mutations, we examined the 
editomes of ten metazoan species and detected extensive linkage of editing in 
Drosophila and cephalopods. The prevalent linkages of editing in these two 
clades, many of which are conserved between closely related species and might be 
associated with the adaptive proteomic recoding, are maintained by natural 
selection at the cost of genome evolution. Nevertheless, in worms and humans, we 
only detected modest proportions of linked editing events, the majority of which 
were not conserved. Furthermore, the linkage of editing in coding regions of 
worms and humans might be overall deleterious, which drives the evolution of DNA 
sites to escape promiscuous editing. Altogether, our results suggest that the 
linkage landscape of A-to-I editing has evolved during metazoan evolution. This 
present study also suggests that linkage of editing should be considered in 
elucidating the functional consequences of RNA editing.