The release of DNA into the cytoplasm upon damage to the nucleus or during viral infection triggers an interferon-mediated defense response, inflammation and cell death. In human cells cytoplasmic DNA is sensed by cyclic GMP-AMP Synthase (cGAS) and Absent In Melanoma 2 (AIM2). Here, we report the identification of a “natural knockout” model of cGAS. Comparative genomics of phylogenetically diverse mammalian species showed that cGAS and its interaction partner Stimulator of Interferon Genes (STING) have been inactivated by mutations in the Malayan pangolin whereas other mammals retained intact copies of these genes. The coding sequences of CGAS and STING1 are also disrupted by premature stop codons and frame-shift mutations in Chinese and tree pangolins, suggesting that expression of these genes was lost in a common ancestor of all pangolins that lived more than 20 million years ago. AIM2 is retained in a functional form in pangolins whereas it is inactivated by mutations in carnivorans, the phylogenetic sister group of pangolins. The deficiency of cGAS and STING points to the existence of alternative mechanisms of controlling cytoplasmic DNA-associated cell damage and viral infections in pangolins.

在细胞核受损或病毒感染期间，DNA释放到细胞质中会触发干扰素介导的防御反应，炎症和细胞死亡。在人类细胞中，细胞质DNA通过环状GMP-AMP合酶（cGAS）和黑色素瘤2（AIM2）缺失检测。在这里，我们报告了cGAS的“自然敲除”模型的鉴定。系统发育多样的哺乳动物物种的比较基因组学表明，马来亚穿山甲中的突变使cGAS及其相互作用伙伴干扰素基因刺激剂（STING）失活，而其他哺乳动物则保留了这些基因的完整拷贝。的编码序列CGAS和STING1穿山甲和树穿山甲的过早终止密码子和移码突变也破坏了它们的表达，这表明这些基因的表达在生活在两千万年前的所有穿山甲的共同祖先中丢失了。AIM2以功能性形式保留在穿山甲中，而通过食肉动物（穿山甲的系统发育姊妹组）中的突变使其失活。cGAS和STING的缺乏表明穿山甲中存在控制细胞质DNA相关的细胞损伤和病毒感染的其他机制。