Department of Molecular, Cellular and Developmental Biology; BioFrontiers Institute, University of Colorado Boulder, Boulder, USA.
BMC Ecol Evol. 2021 Apr 26;21(1):65. doi: 10.1186/s12862-021-01783-z.
The Type I interferon response is an important first-line defense against viruses. In turn, viruses antagonize (i.e., degrade, mis-localize, etc.) many proteins in interferon pathways. Thus, hosts and viruses are locked in an evolutionary arms race for dominance of the Type I interferon pathway. As a result, many genes in interferon pathways have experienced positive natural selection in favor of new allelic forms that can better recognize viruses or escape viral antagonists. Here, we performed a holistic analysis of selective pressures acting on genes in the Type I interferon family. We initially hypothesized that the genes responsible for inducing the production of interferon would be antagonized more heavily by viruses than genes that are turned on as a result of interferon. Our logic was that viruses would have greater effect if they worked upstream of the production of interferon molecules because, once interferon is produced, hundreds of interferon-stimulated proteins would activate and the virus would need to counteract them one-by-one.
We curated multiple sequence alignments of primate orthologs for 131 genes active in interferon production and signaling (herein, "induction" genes), 100 interferon-stimulated genes, and 100 randomly chosen genes. We analyzed each multiple sequence alignment for the signatures of recurrent positive selection. Counter to our hypothesis, we found the interferon-stimulated genes, and not interferon induction genes, are evolving significantly more rapidly than a random set of genes. Interferon induction genes evolve in a way that is indistinguishable from a matched set of random genes (22% and 18% of genes bear signatures of positive selection, respectively). In contrast, interferon-stimulated genes evolve differently, with 33% of genes evolving under positive selection and containing a significantly higher fraction of codons that have experienced selection for recurrent replacement of the encoded amino acid.
Viruses may antagonize individual products of the interferon response more often than trying to neutralize the system altogether.
I 型干扰素反应是抵御病毒的重要第一道防线。反过来，病毒拮抗（即降解、错误定位等）干扰素途径中的许多蛋白质。因此，宿主和病毒被锁定在 I 型干扰素途径的进化军备竞赛中。结果，干扰素途径中的许多基因经历了有利于识别病毒或逃避病毒拮抗剂的新等位基因形式的正选择。在这里，我们对 I 型干扰素家族中基因所受选择压力进行了全面分析。我们最初假设，负责诱导干扰素产生的基因比干扰素激活的基因更容易受到病毒的拮抗。我们的逻辑是，如果病毒在干扰素分子产生的上游起作用，它们会产生更大的影响，因为一旦产生干扰素，数百种干扰素刺激蛋白就会被激活，病毒需要一个一个地对抗它们。
我们为干扰素产生和信号转导（以下简称“诱导”基因）中 131 个活性基因、100 个干扰素刺激基因和 100 个随机选择基因的灵长类同源物进行了多次序列比对。我们分析了每个多重序列比对以确定反复出现的正选择特征。与我们的假设相反，我们发现干扰素刺激基因而不是干扰素诱导基因的进化速度明显快于随机基因集。干扰素诱导基因的进化方式与匹配的随机基因集无法区分（分别有 22%和 18%的基因具有正选择的特征）。相比之下，干扰素刺激基因的进化方式不同，有 33%的基因在正选择下进化，并且包含经历选择以反复取代编码氨基酸的密码子的比例明显更高。
病毒可能更频繁地拮抗干扰素反应的单个产物，而不是试图完全中和该系统。
