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. 2015;12(2):149-61.
doi: 10.1080/15476286.2015.1017215.

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

Diego Forni  1 , Alessandra Mozzi, Chiara Pontremoli, Jacopo Vertemara, Uberto Pozzoli, Mara Biasin, Nereo Bresolin, Mario Clerici, Rachele Cagliani, Manuela Sironi
Affiliations

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

Diego Forni et al. RNA Biol. 2015.

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.

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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Figures

Figure 1.
Figure 1.
Adaptive evolution at ADAR genes in primates. Schematic representation of the domain structure of ADAR family members. Domains are color-coded: nuclear export signal (NES), yellow; Z-DNA binding domains, cyan; RNA binding motifs (RBD), green; deaminase domain, pink. The position of positively selected sites is shown together with sequence alignments for a few representative primates. Positively selected sites in primates and in the human lineage are shown in red and blue, respectively. Some missense mutations associated with AGS and DSH are shown in gray and black, respectively.
Figure 2.
Figure 2.
Analysis of selective pressure in the human and chimpanzee lineages. Violin plot of selection coefficients (median, white dot; interquartile range, black bar). Selection coefficients (γ) are classified as strongly beneficial (100, 50), moderately beneficial (10, 5), weakly beneficial (1), neutral (0), weakly deleterious (−1), moderately deleterious (−5, −10), strongly deleterious (−50, −100), and inviable (−500).
Figure 3.
Figure 3.
Location of the most likely selection targets in human populations. Candidate targets are shown for ADAR (A), ADARB1 (B), ADARB2 (C) within the UCSC Genome Browser view. Relevant annotation tracks are shown. For ADARB2 a sliding-window analysis of DH is also shown in green (YRI) and blue (CEU). The horizontal dashed line represents the 5th percentile of DH. Variants in blue, red and green represent selection targets in CEU, CHBJPT, and YRI, respectively. Additional color codes are as follows: yellow highlight indicates SNPs mapping to regulatory elements; cyan indicates eQTL.
Figure 4.
Figure 4.
Conservation at ADAR editing sites. (A) Box plot representation of GERP conservation scores for A-to-I editing events that cause nonsynonymous substitutions. Red and orange denote “non-shared” editing sites and their flanking sites, respectively; blue and cyan indicate “shared” editing sites and their flanking sites; dark gray indicates control nonsynonymous positions with their flanking codons in light gray (see text). Wilcoxon rank sum test (2-tailed) p values are also reported. (B) Box plot representation of GERP conservation scores for A-to-I editing events that cause synonymous substitutions. Dark and light green indicate editing sites and their flanking regions, respectively; dark gray indicates control synonymous positions, with light gray indicating their flanking sites. Wilcoxon rank sum test (2-tailed) p values are reported. (C) Distributions of GERP scores at editing-sites are reported for "non-shared" and "shared" nonsynonymous editing sites, as well as for synonymous editing sites. Color codes are as in the previous panels, with 100 random control distributions in gray. Flanking sites are represented with dashed lines.
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