ABOVE: Illustration of interferon-alpha


The paper
E.N. Judd et al., “Positive natural selection in primate genes of the type I interferon response,” BMC Ecol Evol, 21:65, 2021.

In humans, one of the host cell’s first lines of defense against viral infection is the interferon system, a set of molecular cascades that can ultimately lead to the activation of hundreds of genes that thwart different aspects of a viral assault. Viruses, in turn, have evolved their own arsenal of proteins that inhibit or otherwise disrupt the interferon system, leading to an evolutionary arms race between the virus and the host. Knowing which antiviral weapons are evolving fastest can provide clues to researchers about how to help hosts win, but given the sheer volume of genes involved in interferon pathways, pinpointing the most promising gene candidates can be difficult.

One approach is to look for strong positive selection, says Alison Gilchrist, an immunologist at New York University’s Langone School of Medicine, as that may indicate the gene product’s importance in immunity. While this had been done to some extent, a wealth of recent sequencing data, especially in nonhuman primates, created an opportunity for Gilchrist and her colleagues to perform a broader analysis that zeroed in on what kind of genes evolve rapidly. 

Initially, the researchers hypothesized that interferon-stimulated genes (ISGs) would evolve less quickly than those involved in inducing the interferon pathway, as induction genes act earlier in the immune cascade and thus might be a more common target for viruses to effectively inhibit the overall host response. But when Gilcrist, then a graduate student in Sara Sawyer’s lab at University of Colorado Boulder, and undergraduate Elena Judd looked for signatures of positive selection in the substitution patterns in sets of genes from 20 primate species, they found the opposite—ISGs had evolved more quickly than induction genes. In retrospect, Gilchrist says that makes sense, since the cascade is essentially pyramid-shaped, with relatively few induction genes activating a much larger set of ISGs, many of which overlap in their effects. A lack of redundancy in the induction genes likely constrains their ability to evolve, she says, since it means there are fewer proteins that can step in to cover for a protein’s old function as it adopts a new one. 

Ram Savan, a molecular immunologist at the University of Washington who was not involved in the study, has another hypothesis: that viruses actually benefit from mainly attacking ISGs rather than stopping the interferon cascade early on. That’s because viruses tend to spread best when their hosts survive infection, he says, and if a virus blocks interferons altogether, the viral load could skyrocket and trigger massive, potentially lethal inflammation. 

Either way, Savan says it’s “a good paper” that evaluates interferons from an evolutionary perspective. He was particularly excited by the ISGs that were newly identified as being under positive selection, as they may help researchers discover novel infection-fighting drugs. “I’m sure people will go and pick some of those ISGs and study further,” he says. 

Gilchrist says she’s also hopeful the analysis could lead to antiviral breakthroughs. She has set up Google alerts for all of the newly identified rapid-evolving genes, she tells The Scientist; “I have my eye on them now.”