title: Diverse selective regimes shape genetic diversity at ADAR genes and at their coding targets.
abstract: A-to-I RNA editing operated by ADAR enzymes is extremely common in mammals. Several editing events in coding regions have pivotal physiological roles and affect protein sequence (recoding events) or function. We analyzed the evolutionary history of the 3 ADAR family genes and of their coding targets. Evolutionary analysis indicated that ADAR evolved adaptively in primates, with the strongest selection in the unique N-terminal domain of the interferon-inducible isoform. Positively selected residues in the human lineage were also detected in the ADAR deaminase domain and in the RNA binding domains of ADARB1 and ADARB2. During the recent history of human populations distinct variants in the 3 genes increased in frequency as a result of local selective pressures. Most selected variants are located within regulatory regions and some are in linkage disequilibrium with eQTLs in monocytes. Finally, analysis of conservation scores of coding editing sites indicated that editing events are counter-selected within regions that are poorly tolerant to change. Nevertheless, a minority of recoding events occurs at highly conserved positions and possibly represents the functional fraction. These events are enriched in pathways related to HIV-1 infection and to epidermis/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 of evolution 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.
authors.affiliation: a Bioinformatics ; Scientific Institute IRCCS E. MEDEA ; Bosisio Parini , Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Forni
authors.forename: Alessandra
authors.initials: A
authors.lastname: Mozzi
authors.forename: Chiara
authors.initials: C
authors.lastname: Pontremoli
authors.forename: Jacopo
authors.initials: J
authors.lastname: Vertemara
authors.forename: Uberto
authors.initials: U
authors.lastname: Pozzoli
authors.forename: Mara
authors.initials: M
authors.lastname: Biasin
authors.forename: Nereo
authors.initials: N
authors.lastname: Bresolin
authors.forename: Mario
authors.initials: M
authors.lastname: Clerici
authors.forename: Rachele
authors.initials: R
authors.lastname: Cagliani
authors.forename: Manuela
authors.initials: M
authors.lastname: Sironi
mesh_terms: D000243:Adenosine Deaminase / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D005075:Biological Evolution; D003062:Codon; D014644:Genetic Variation; D006197:Hair / Q000166:cytology / Q000201:enzymology; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D015810:Linkage Disequilibrium; D008969:Molecular Sequence Data; D009000:Monocytes / Q000166:cytology / Q000201:enzymology; D016366:Open Reading Frames; D011323:Primates / Q000145:classification / Q000235:genetics*; D040641:Quantitative Trait Loci; D017393:RNA Editing; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D012641:Selection, Genetic; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D012867:Skin / Q000166:cytology / Q000201:enzymology
chemical_list: D003062:Codon; D007527:Isoenzymes; D016601:RNA-Binding Proteins; C000595356:ADAR protein, human; C567955:ADARB1 protein, human; D000243:Adenosine Deaminase
keywords: 1000G,1000 Genomes Pilot Project; A to I, adenosine to inosine; A-to-I editing; ADAR; ADAR editing sites; AGS, Aicardi-Goutières Syndrome; BEB, Bayes Empirical Bayes; BS-REL, branch site-random effects likelihood; CEU, Europeans; CHBJPT, Chinese plus Japanese; DAF, derived allele frequency; DIND, Derived Intra-allelic Nucleotide Diversity; DSH, dyschromatosis symmetrica hereditaria; FDR, false discovery rate; GARD, Genetic Algorithm Recombination Detection; GERP Genomic Evolutionary Rate Profiling; IFN, Interferon; LD, linkage disequilibrium; LRT, likelihood ratio test; MAF, minor allele frequency; MEME, Mixed Effects Model of Evolution; RBD, dsRNA binding domain; SLAC, single-likelihood ancestor counting; YRI, Yoruba; eQTL, Expression quantitative trait loci; evolutionary analysis; iHS, Integrated Haplotype Score; positive selection
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