Diverse selective regimes shape genetic diversity at ADAR genes and at their coding targets

A-to-I RNA editing operated by ADAR enzymes is extremely common in mammals. Several editing events in codingregions have pivotal physiological roles and affect protein sequence (recoding events) or function. We analyzed theevolutionary history of the 3 ADAR family genes and of their coding targets. Evolutionary analysis indicated that ADARevolved adaptively in primates, with the strongest selection in the unique N-terminal domain of the interferoninducibleisoform. Positively selected residues in the human lineage were also detected in the ADAR deaminase domainand in the RNA binding domains of ADARB1 and ADARB2. During the recent history of human populations distinctvariants in the 3 genes increased in frequency as a result of local selective pressures. Most selected variants are locatedwithin regulatory regions and some are in linkage disequilibrium with eQTLs in monocytes. Finally, analysis ofconservation scores of coding editing sites indicated that editing events are counter-selected within regions that arepoorly tolerant to change. Nevertheless, a minority of recoding events occurs at highly conserved positions andpossibly represents the functional fraction. These events are enriched in pathways related to HIV-1 infection and toepidermis/hair development. Thus, both ADAR genes and their targets evolved under variable selective regimes,including purifying and positive selection. Pressures related to immune response likely represented major drivers ofevolution for ADAR genes. As for their coding targets, we suggest that most editing events are slightly deleterious,although a minority may be beneficial and contribute to antiviral response and skin homeostasis.