Genetic analysis of equine 2', 5'-oligoadenylate synthetase (OASI) and ribonculclease L (RNASEL) polymorphims and association to severe West Nile Virus disease

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Title: Genetic analysis of equine 2', 5'-oligoadenylate synthetase (OASI) and ribonculclease L (RNASEL) polymorphims and association to severe West Nile Virus disease
Author: Rios, Jonathan Joseph
Abstract: West Nile virus (WNV ) , a member of the Flaviviridae family of RNA viruses , was first introduced to the United States in 1999 with rapid transmission across a variety of hosts throughout the continental states . Genetic research to identify genes involved in resistance and susceptibility to WNV began in mice , where it was observed that natural populations were resistant or fatally susceptible . Further investigation led to the identification of the Flavivirus resistance gene as the oligoadenylate synthetase 1b gene in mice . A nonsense mutation was found within the coding region of this gene that associated absolutely with susceptibility to WNV . A two -stage association study was conducted to identify similar genetic associations to West Nile encephalitis in naturally susceptible and resistant populations of horses in the United States . Genomic sequence of a majority of the equine 2 ? ,5 ? -oligoadenylate synthetase 1 (OAS1 ) gene was assembled by shotgun -sequencing CHORI BAC 100 :I10 (3 .95X ) . A contig map spanning the entire gene was constructed , including 8 kilobases of promoter sequence upstream of the first exon . Coding regions of equine OAS1 and ribonuclease L (RNASEL ) genes , as well as the OAS1 promoter , were screened for mutations from a random sample of horses of multiple breeds . Numerous polymorphisms were identified for case -control analyses . Analysis using Fisher ?s Exact test identified allelic and genotypic associations . Odds ratios were also determined to measure strength of the associations . Case -control analysis of haplotype frequencies identified significant differences in haplotype frequencies between populations and association to West Nile encephalitis . A conserved interferon -stimulated response element was mapped to within 518 basepairs upstream of the transcription start site of OAS1 . Promoter polymorphisms were not found to affect induction by interferon -tau ; however , additional analyses are necessary to further characterize the equine OAS1 promoter and the host factors involved in regulating expression . Statistical analyses of the genotype data from the case and control populations identified significant associations between polymorphisms of the OAS1 and RNASEL genes with severe West Nile encephalitis . The similarity between human and horse OAS immunity genes suggests that the horse may provide a genetic model to further investigate mammalian SNP -associated viral susceptibility .
URI: http : / /hdl .handle .net /1969 .1 /ETD -TAMU -2749
Date: 2009-05-15

Citation

Genetic analysis of equine 2', 5'-oligoadenylate synthetase (OASI) and ribonculclease L (RNASEL) polymorphims and association to severe West Nile Virus disease. Available electronically from http : / /hdl .handle .net /1969 .1 /ETD -TAMU -2749 .

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