Predicting individual differences in viral susceptibility caused by natural genetic variation within species

Natural genetic variation within species can underlie different individual susceptibilities upon viral infection. The molecular mechanisms by which genetic variation affects the viral susceptibility are currently poorly understood. Here we use Caenorhabditis elegans as a model organism to identify which polymorphisms alter the viral susceptibility. Moreover, we predict how the molecular mechanisms behind altered susceptibilities may work. The viral susceptibility towards Orsay virus of the commonly used lab strain, N2, is higher than that of the Hawaiian isolate CB4856. The phenotype of N2xCB4856 recombinant inbred strains was obtained by measuring the viral load upon infection and these viral loads were correlated to the genotypes by quantitative trait locus (QTL) mapping. A region on chromosome IV was found to correlate with changes in the viral susceptibility. This QTL region, containing hundreds of candidate polymorphisms, was fine mapped using two introgression line panels. The first introgression line panel contained an introgression of N2 into the genome of CB4856, whereas the second panel contained an introgression of CB4856 into the genome of N2. Using these two panels the QTL region was fine mapped to a region containing about 30 polymorphisms. Using known protein structures we predicted possible effects of candidate polymorphisms. An example is a single nucleotide polymorphism in a conserved region of the known antiviral defence gene cul-6. This polymorphism may be responsible for an altered stability of the SCF complex that targets viral particles for degradation. A causal relationship could be experimentally verified by exchanging the polymorphism of the resistant and susceptible strain, an approach we are currently taking.