MBE Advance Access published online on May 5, 2008
Molecular Biology and Evolution, doi:10.1093/molbev/msn106
Research Article |
Long-Term Balancing Selection at the West-Nile Virus Resistance Gene, Oas1b, Maintains Trans-Specific Polymorphisms in the House Mouse
* Department of Biology, Queens College, the City University of New York, 65-30 Kissena Boulevard, Flushing, NY 11367, USA
Graduate School and University center, the City University of New York, 365 Fifth Avenue, New York, NY 10016, USA
Biologie Intégrative, Institut des Sciences de l'Evolution, Université Montpellier 2 – CNRS, case courrier 63, Place Eugène Bataillon, 34095 Montpellier Cedex 5, France
Corresponding author: Stéphane Boissinot, Department of Biology, Queens College, CUNY, 65-30 Kissena Boulevard, Flushing, NY 11367-1597, Tel: 718 997 3437, Fax: 718 997 3445, Email: stephane.boissinot{at}qc.cuny.edu
Received for publication November 27, 2007. Revision received March 17, 2008. Accepted for publication April 30, 2008.
Oligo-Adenylate Synthetases (OAS) 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 non-coding 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 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. Furthermore, a phylogenetic analysis of intronic sequences demonstrated that Oas1b alleles are ancient and that their divergence pre-dates several speciation events, resulting in trans-specific 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 non-synonymous 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.
Key Words: Balancing selection • Mus musculus • Oas1b • West Nile virus • flavivirus