Long-Term Balancing Selection at the West Nile Virus Resistance Gene, Oas1b, Maintains Transspecific Polymorphisms in the House Mouse

Abstract

Oligoadenylate synthetases (OASs) are interferon-inducible enzymes that participate in the first line of defense against a wide range of viral infection. Recent studies have determined that Oas1b, a member of the OAS gene family in the house mouse (Mus musculus), provides specific protection against flavivirus infection (e.g., West Nile virus, dengue fever virus, and yellow fever virus). We characterized the nucleotide sequence variation in coding and noncoding regions of the Oas1b gene for a large number of wild-derived strains of M. musculus and related species. Our sequence analyses determined that this gene is one of the most polymorphic genes ever described in any mammal. The level of variation in noncoding 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 intraspecific variation expected under neutrality. Furthermore, a phylogenetic analysis of intronic sequences demonstrated that Oas1b alleles are ancient and that their divergence predates several speciation events, resulting in transspecific polymorphisms. The amino acid sequence of Oas1b is also extremely variable, with 1 out of 7 amino acid positions being polymorphic within M. musculus. Oas1b alleles are comparatively more divergent at synonymous positions than most autosomal genes and the ratio of nonsynonymous to synonymous substitution is remarkably high, suggesting that positive selection has been acting on Oas1b. The ancestry of Oas1b polymorphisms and the high level of amino acid polymorphisms strongly suggest that the allelic variation at Oas1b has been maintained in mouse populations by long-term balancing selection.