Cagliani Rachele, Forni Diego, Biasin Mara, Comabella Manuel, Guerini Franca R, Riva Stefania, Pozzoli Uberto, Agliardi Cristina, Caputo Domenico, Malhotra Sunny, Montalban Xavier, Bresolin Nereo, Clerici Mario, Sironi Manuela
Bioinformatics Laboratory, Scientific Institute IRCCS E. Medea, Bosisio Parini (LC), Italy.
Genome Biol Evol. 2014 Apr;6(4):830-45. doi: 10.1093/gbe/evu066.
AIM2-like receptors (ALRs) are a family of nucleic acid sensors essential for innate immune responses against viruses and bacteria. We performed an evolutionary analysis of ALR genes (MNDA, PYHIN1, IFI16, and AIM2) by analyzing inter- and intraspecies diversity. Maximum-likelihood analyses indicated that IFI16 and AIM2 evolved adaptively in primates, with branch-specific selection at the catarrhini lineage for IFI16. Application of a population genetics-phylogenetics approach also allowed identification of positive selection events in the human lineage. Positive selection in primates targeted sites located at the DNA-binding interface in both IFI16 and AIM2. In IFI16, several sites positively selected in primates and in the human lineage were located in the PYD domain, which is involved in protein-protein interaction and is bound by a human cytomegalovirus immune evasion protein. Finally, positive selection was found to target nuclear localization signals in IFI16 and the spacer region separating the two HIN domains. Population genetic analysis in humans revealed that an IFI16 genic region has been a target of long-standing balancing selection, possibly acting on two nonsynonymous polymorphisms located in the spacer region. Data herein indicate that ALRs have been repeatedly targeted by natural selection. The balancing selection region in IFI16 carries a variant with opposite risk effect for distinct autoimmune diseases, suggesting antagonistic pleiotropy. We propose that the underlying scenario is the result of an ancestral and still ongoing host-pathogen arms race and that the maintenance of susceptibility alleles for autoimmune diseases at IFI16 represents an evolutionary trade-off.
AIM2样受体（ALRs）是一类核酸传感器，对于针对病毒和细菌的先天性免疫反应至关重要。我们通过分析种间和种内多样性对ALR基因（MNDA、PYHIN1、IFI16和AIM2）进行了进化分析。最大似然分析表明，IFI16和AIM2在灵长类动物中适应性进化，在旧世界猴谱系中IFI16存在分支特异性选择。应用群体遗传学-系统发育学方法也能够识别人类谱系中的正选择事件。灵长类动物中的正选择靶向IFI16和AIM2中位于DNA结合界面的位点。在IFI16中，在灵长类动物和人类谱系中被正选择的几个位点位于PYD结构域，该结构域参与蛋白质-蛋白质相互作用并被人巨细胞病毒免疫逃避蛋白结合。最后，发现正选择靶向IFI16中的核定位信号以及分隔两个HIN结构域的间隔区。人类群体遗传分析表明，一个IFI16基因区域一直是长期平衡选择的目标，可能作用于位于间隔区的两个非同义多态性。本文数据表明，ALRs反复成为自然选择的目标。IFI16中的平衡选择区域携带一种对不同自身免疫性疾病具有相反风险效应的变体，提示拮抗性多效性。我们提出，潜在情况是祖先时期且仍在进行的宿主-病原体军备竞赛的结果，并且IFI16中自身免疫性疾病易感性等位基因的维持代表了一种进化权衡。
