Fine Mapping a Sheep Genomic Locus Involved in Viral Restriction of Ovine Lentivirus

Ovine lentivirus (OvLV) affects half of all sheep flocks in the U.S. causing high economic and animal welfare costs.  Since there are no effective vaccines and no feasible treatments for ovine progressive pneumonia, breeding for improved control through marker assisted selection is a desirable way to combat OvLV. Proviral concentration correlates with disease severity, so we used genome-wide association (GWAS) followed by marker validation in diverse populations to identify a small insertion mutation that is associated with consistently lower proviral concentration; on average, insertion homozygotes have less than half the proviral concentration of other genotypes.  This insertion is located within 65 kilobases of four zinc-finger transcription factor genes, none of which are currently described as viral restriction factors in any mammalian system. We re-sequenced eight sheep from phenotypic extremes in multiple breeds and genotyped all predicted amino acid substitution and splice site variants within these four genes in a mapping population. Based on initial analysis of 15 out of 28 variants across all four genes, there is no improved or equivalent association with proviral concentration phenotype among our current marker set. Furthermore, joint modeling does not suggest synthetic association where the insertion marker might be a representation of multiple functional mutations already in our data set.  We hypothesize that one or more causal mutations lie within a gene regulatory region and not a protein coding gene. We will test our hypothesis with gene expression studies currently underway to help identify one or more novel viral restriction factors in this region.