Abstract
BackgroundThe 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.ResultsWe 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.ConclusionViruses may antagonize individual products of the interferon response more often than trying to neutralize the system altogether.
Highlights
The interferon response plays an important role in defending human cells against viruses [1]
We separated genes involved in Type I interferon responses into two temporal categories with the dividing line being the expression of interferon-stimulated genes (Fig. 1)
We reviewed recent literature and curated lists of between 100 and 150 genes in each of these three categories: induction genes, interferon-stimulated genes, and random genes
Summary
The interferon response plays an important role in defending human cells against viruses [1]. Because viruses replicate within cells of the host, their nucleic acids and proteins are exposed, at least to some degree, to the cellular environment. Interferons produce transcriptional changes in the infected cell, inducing expression of hundreds of host genes (called “interferon-stimulated genes,” or ISGs) that collectively act to limit viral replication [5]. Viruses antagonize (i.e., degrade, mis-localize, etc.) many proteins in interferon pathways. 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. 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
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