International Mammalian Genome Society

The 16th International Mouse Genome Conference (2002)


Oral Presentation

Monday 18 November

11:45 - 12:00 HRS

POSITIONAL CLONING OF THE FLAVIVIRUS RESISTANCE GENE (FLV)

A Perelygin
Department of Biology, Georgia State University

Co-Authors: Scherbik S, Stockman B, Li Y , Brinton M
Institutions: Georgia State University

Susceptibility to flavivirus infection in mice is controlled by the Flv locus located on mouse chromosome 5 close to the D5Mit159.  We used a positional cloning strategy to identify the Flv gene.  Using a probe designed from the D5Mit159 marker sequence, 14 genomic clones were selected from a BAC library.  Nine genes were identified within these BAC clones by direct cDNA selection and exon trapping.  Twelve additional genes were identified in the Flv region by searching the Celera mouse database.  Full-length cDNA sequences were obtained from congenic flavivirus resistant and susceptible mouse strains for each of these genes and compared.  For the majority of the genes, only silent substitutions were found between the congenic strains.  A random distribution of missence substitutions between a number of resistant and susceptible mouse strains was observed for a Na+/Ca2+ exchanger gene, indicating that none of these polymorphisms correlated with susceptibility to flaviviruses.  A C820T transversion in the Oas1b gene of 5 susceptible strains resulted in a premature stop-codon and a C-terminally truncated gene product that was missing 30% of its sequence.  In contrast, this gene encoded the full-length product in 4 resistant strains, indicating a complete correlation between this Oas1b mutation and the susceptibility phenotype.  Stable expression of the resistant Oas1b gene product in susceptible embryofibroblasts partially inhibited replication of a flavivirus, West Nile virus, but had no effect on two other RNA viruses.  The Oas1b protein differs from other members of the Oas family by the unique structure of its RNA-binding P-loop motif.


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