Mozzi Alessandra, Pontremoli Chiara, Forni Diego, Clerici Mario, Pozzoli Uberto, Bresolin Nereo, Cagliani Rachele, Sironi Manuela
Bioinformatics, Scientific Institute IRCCS E.MEDEA, Bosisio Parini, Italy.
Department of Physiopathology and Transplantation, University of Milan, Italy Don C. Gnocchi Foundation ONLUS, IRCCS, Milan, Italy.
Genome Biol Evol. 2015 Mar 9;7(4):1016-32. doi: 10.1093/gbe/evv046.
OAS (2'-5'-oligoadenylate synthases) proteins and cyclic GMP-AMP synthase (cGAS, gene symbol: MB21D1) patrol the cytoplasm for the presence of foreign nucleic acids. Upon binding to double-stranded RNA or double-stranded DNA, OAS proteins and cGAS produce nucleotide second messengers to activate RNase L and STING (stimulator of interferon genes, gene symbol: TMEM173), respectively; this leads to the initiation of antiviral responses. We analyzed the evolutionary history of the MB21D1-TMEM173 and OAS-RNASEL axes in primates and bats and found evidence of widespread positive selection in both orders. In TMEM173, residue 230, a major determinant of response to natural ligands and to mimetic drugs (e.g., DMXAA), was positively selected in Primates and Chiroptera. In both orders, selection also targeted an α-helix/loop element in RNase L that modulates the enzyme preference for single-stranded RNA versus stem loops. Analysis of positively selected sites in OAS1, OAS2, and MB21D1 revealed parallel evolution, with the corresponding residues being selected in different genes. As this cannot result from gene conversion, these data suggest that selective pressure acting on OAS and MB21D1 genes is related to nucleic acid recognition and to the specific mechanism of enzyme activation, which requires a conformational change. Finally, a population genetics-phylogenetics analysis in humans, chimpanzees, and gorillas detected several positively selected sites in most genes. Data herein shed light into species-specific differences in infection susceptibility and in response to synthetic compounds, with relevance for the design of synthetic compounds as vaccine adjuvants.
2'-5'-寡腺苷酸合成酶（OAS）蛋白和环状GMP-AMP合成酶（cGAS，基因符号：MB21D1）在细胞质中巡查外来核酸的存在情况。一旦与双链RNA或双链DNA结合，OAS蛋白和cGAS会产生核苷酸第二信使，分别激活RNase L和干扰素基因刺激因子（STING，基因符号：TMEM173）；这会引发抗病毒反应。我们分析了灵长类动物和蝙蝠中MB21D1-TMEM173和OAS-RNASEL轴的进化历史，发现这两个目都存在广泛的正选择证据。在TMEM173中，第230位残基是对天然配体和模拟药物（如DMXAA）反应的主要决定因素，在灵长类动物和翼手目中受到正选择。在这两个目中，选择还针对RNase L中的一个α-螺旋/环元件，该元件调节酶对单链RNA与茎环的偏好。对OAS1、OAS2和MB21D1中正选择位点的分析揭示了平行进化，不同基因中选择了相应的残基。由于这不是由基因转换导致的，这些数据表明作用于OAS和MB21D1基因的选择压力与核酸识别以及酶激活的特定机制有关，而酶激活需要构象变化。最后，对人类、黑猩猩和大猩猩的群体遗传学-系统发育分析在大多数基因中检测到了几个正选择位点。本文的数据揭示了感染易感性和对合成化合物反应的物种特异性差异，这与作为疫苗佐剂的合成化合物设计相关。
