Stability evolution as a major mechanism of human protein adaptation in response to viruses

Pathogens were a major driver of genetic adaptation during human evolution. Viruses in particular were a dominant driver of adaptation in the thousands of proteins that physically interact with viruses (VIPs for Virus-Interacting Proteins). This however poses a conundrum. The best understood cases of virus-driven adaptation in specialized immune antiviral factors or in host viral receptors are numerically vastly insufficient to explain abundant adaptations in VIPs. What adaptive mechanisms can then at least partly close this gap? VIPs tend to be broadly conserved proteins with conserved host native molecular functions. Because many amino acid changes in a protein can alter its stability -the balance between the folded and unfolded forms of a protein- without destroying conserved native activities, here we ask if stability evolution was an important mechanism of virus-driven human protein adaptation. Using predictions of protein stability changes based on Alphafold 2 structures and validated by multiple lines of evidence, we find that amino acid changes that altered stability experienced highly elevated adaptative evolution in VIPs, compared to changes with a weaker impact on stability. We further find that RNA viruses, rather DNA viruses, predominantly drove strong adaptation through stability changes in VIPs. We also observe that stability in immune antiviral VIPs preferentially evolved under directional selection. Conversely, stability in proviral VIPs needed by viruses evolved under compensatory evolution following viral epidemics. Together, these results suggest that stability evolution, and thus functional host protein abundance evolution, was a prominent mechanism of host protein adaptation during viral epidemics.