A DNA Regulatory Element Haplotype at Zinc Finger Genes Is Associated with Host Resilience to Small Ruminant Lentivirus in Two Sheep Populations

Abstract

Simple Summary Sheep are affected by a viral infection that causes an incurable and difficult to treat lung, joint and brain disease that decreases production efficiency. This small ruminant lentivirus is closely related to human immunodeficiency virus (HIV) that causes AIDS in humans. Differences in breed susceptibility to disease are known in sheep that indicate genetic, or hereditary, resilience factors exist. Our objective was to study the source of this hereditary advantage so that it can eventually be translated into a tool for sheep breeders to improve herd health. Previously, one such hereditary region was detected, but little was known about possible mechanisms or nearby mutations. Here, we report several mutations that may underlie this hereditary mechanism and are in regions of DNA that are known to affect genes by increasing or decreasing gene expression, akin to gene “on/off switches.” These mutations were strongly associated with a predictor of disease severity in live animals and had a greater predicted effect on the degree of disease than previously studied mutations. Statistical association (p < 0.05) of disease was demonstrated in two different groups of sheep that were reared in different environments, which indicates increased likelihood that a genetic factor is producing this effect. Abstract Small ruminant lentivirus (SRLV) causes Maedi-Visna or Ovine Progressive Pneumonia in sheep and creates insidious livestock production losses. This retrovirus is closely related to human immunodeficiency virus and currently has no vaccines or cure. Genetic marker assisted selection for sheep disease resiliency presents an attractive management solution. Previously, we identified a region containing a cluster of zinc finger genes that had association with ovine SRLV proviral concentration. Trait-association analysis validated a small insertion/deletion variant near ZNF389 (rs397514112) in multiple sheep breeds. In the current study, 543 sheep from two distinct populations were genotyped at 34 additional variants for fine mapping of the regulatory elements within this locus. Variants were selected based on ChIP-seq annotation data from sheep alveolar macrophages that defined active cis-regulatory elements predicted to influence zinc finger gene expression. We present a haplotype block of variants within regulatory elements that have improved associations and larger effect sizes (up to 4.7-fold genotypic difference in proviral concentration) than the previously validated ZNF389 deletion marker. Hypotheses for the underlying causal mutation or mutations are presented based on changes to in silico transcription factor binding sites. These variants offer alternative markers for selective breeding and are targets for future functional mutation assays.