Variant Near ZNF389 Is Associated with Control of Small Ruminant Lentivirus in Multiple Sheep Flocks

Small ruminant lentiviruses (SRLV) are macrophage-tropic RNA viruses found in many countries that cause pneumonia, mastitis, arthritis, and poor body condition in sheep. There is no preventive vaccine and no cure for SRLV, but breed differences suggest selective breeding might improve both odds of infection and post-infection control of SRLV. While variants in TMEM154 have consistent association with odds of infection, no gene variant has been associated with post-infection control of SRLV in multiple validation animal sets. Proviral concentration is a live-animal diagnostic measure for post-infection control of SRLV correlated to severity of SRLV-induced lesions. A region associated with proviral concentration was identified by a recent genome-wide association study that contained four zinc finger genes. To fine map this region, we tested additional variants and identified a small deletion variant near ZNF389 that was associated with proviral concentration in 3 flocks (P<0.05). These flocks contained Rambouillet, Polypay, and crossbred sheep from multiple locations and management conditions. Strikingly, one flock with significant association had a history of needle-sharing and both high prevalence (>87%) and exceptionally high mean proviral concentration (>950 copies/ug). An overall estimate of proviral concentration, based on all 1,310 SRLV-positive animals examined, showed insertion homozygotes had less than half the proviral concentration of other genotypes (P<0.0001). Future directions include testing additional management conditions, breeds, and viral subtypes, and identifying functional implications of the haplotype that this deletion variant tracks. To our knowledge, this is the first genetic marker associated with post-infection host control of SRLV in multiple sheep flocks.