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Description:
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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 . |