Forni Diego, Mozzi Alessandra, Pontremoli Chiara, Vertemara Jacopo, Pozzoli Uberto, Biasin Mara, Bresolin Nereo, Clerici Mario, Cagliani Rachele, Sironi Manuela
a Bioinformatics ; Scientific Institute IRCCS E. MEDEA ; Bosisio Parini , Italy.
RNA Biol. 2015;12(2):149-61. doi: 10.1080/15476286.2015.1017215.
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.
由ADAR酶介导的A-to-I RNA编辑在哺乳动物中极为常见。编码区域的多个编辑事件具有关键的生理作用，并影响蛋白质序列（重新编码事件）或功能。我们分析了3个ADAR家族基因及其编码靶点的进化历史。进化分析表明，ADAR在灵长类动物中经历了适应性进化，在干扰素诱导亚型独特的N端结构域中受到的选择最强。在人类谱系中，ADAR脱氨酶结构域以及ADARB1和ADARB2的RNA结合结构域中也检测到了正选择的残基。在人类群体的近代历史中，由于局部选择压力，这3个基因中的不同变体频率增加。大多数选择的变体位于调控区域内，有些与单核细胞中的eQTL处于连锁不平衡状态。最后，对编码编辑位点保守性得分的分析表明，编辑事件在对变化耐受性较差的区域内受到负选择。然而，少数重新编码事件发生在高度保守的位置，可能代表了功能部分。这些事件在与HIV-1感染以及表皮/毛发发育相关的途径中富集。因此，ADAR基因及其靶点在包括纯化选择和正选择在内的可变选择机制下进化。与免疫反应相关的压力可能是ADAR基因进化的主要驱动力。至于它们的编码靶点，我们认为大多数编辑事件可能略有有害，尽管少数可能是有益的，并有助于抗病毒反应和皮肤稳态。
