One of the major questions in infectious disease research is: why do some individuals get sick, while others remain healthy or mildly affected by viral infection? The genetic background of individuals significantly influences the outcome of viral infection and he oligo-adenylate (OAS) pathway has been shown to play a major role in this process. Association studies in humans and infection experiments in mice strongly suggest that genetic variation at the OAS1 gene could be influencing host susceptibility to viral infection. OASs are interferon-inducible enzymes that are activated by viral dsRNA. They participate in the first line of defense against a wide range of viral infection, including West Nile virus, influenza and HIV1.
Evolution of the mouse Oas1b gene
Functional studies have demonstrated that a member of the OAS gene family in the house mouse, Oas1b, provide specific protection against flavivirus infection. We examined the evolution of this gene in wild house mice and in related species (Ferguson et al 2008 pdf). We determined that this gene is one of the most polymorphic genes ever described in any mammal. The level of variation in non-coding regions of Oas1b is an order of magnitude higher than the level reported for other regions of the mouse genome and is significantly different from the level of intra-specific variation expected under neutrality. A phylogenetic analysis further demonstrated that Oas1b alleles are ancient and that their divergence pre-dates several speciation events, resulting in trans-specific polymorphisms. The ancestry of Oas1b polymorphisms strongly suggests that the allelic variation at Oas1b has been maintained by long-term balancing selection.
Long-term balancing selection in chimpanzee
The next step of our work in mice was its extension to primates. Our most surprising result came from the analysis of OAS1 in chimpanzee (Ferguson et al 2012 pdf). We found that the OAS1 gene is extremely variable and that two very divergent groups of alleles have been maintained in Central African chimpanzees by long-term balancing selection, since the split between chimpanzee, human and gorilla. The two divergent classes of alleles differ by a large number of amino acids, including several amino acids putatively involved in RNA binding. This suggests that these alleles could have different dsRNA binding affinity and could confer resistance against different viral pathogens.