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ARS Home » Pacific West Area » Pullman, Washington » Animal Disease Research » Research » Publications at this Location » Publication #384031

Research Project: Identification of Host Factors and Immunopathogenesis of Pneumonia in Domestic and Bighorn Sheep

Location: Animal Disease Research

Title: A DNA regulatory element haplotype at zinc finger genes is associated with host resilience to small ruminant lentivirus in two sheep populations

item MASSA, ALISHA - Washington State University
item Mousel, Michelle
item Durfee, Codie
item HERNDON, MARIA - Washington State University
item HEMMERLING, KANEESHA - Washington State University
item Taylor, Joshua - Bret
item NEIBERGS, H - Washington State University
item White, Stephen

Submitted to: Animals
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/22/2021
Publication Date: 6/26/2021
Citation: Massa, A.T., Mousel, M.R., Durfee, C.J., Herndon, M.K., Hemmerling, K.M., Taylor, J.B., Neibergs, H.L., White, S.N. 2021. A DNA regulatory element haplotype at zinc finger genes is associated with host resilience to small ruminant lentivirus in two sheep populations. Animals. 11(7). Article 1907.

Interpretive Summary: Sheep are affected by ovine lentivirus that causes an incurable and difficult to treat disease that can affect lung, joint, and brain which decreases production efficiency. This virus is closely related to immunodeficiency virus (HIV) that causes AIDS in humans. There are known differences in breed susceptibility to disease in sheep that indicate genetic, or hereditary, resilience mechanisms exist. We evaluated 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 due to the rudimentary status of the sheep genome at the time, 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 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 amount of virus present than previously studied mutations. An association was found in two different flocks of sheep that were reared in different states, which indicates an increased likelihood that a genetic mechanism is producing increased resilience to ovine lentivirus.

Technical Abstract: Ovine lentivirus, the cause of Maedi-Visna or Ovine Progressive Pneumonia, creates long-term, insidious livestock losses throughout the world. This retrovirus is closely related to human immunodeficiency virus and currently has no vaccines and no cure. Genetic marker assisted selection for host resiliency to disease presents an attractive management solution in sheep. Previously, we identified a region containing a cluster of zinc finger genes that had significant association with ovine lentivirus proviral concentration. This phenotypic measure is predictive of disease and lesion severity. Trait-association analysis validated a small insertion/deletion variant near ZNF389 (rs397514112) in multiple sheep breeds, but putative functional significance of this intergenic mutation was unknown. The nearby C2H2 zinc finger genes may repress proviral replication as evidenced by coevolution of this gene family with retroviruses. In the current study, 701 sheep from three distinct populations were genotyped at 36 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 in divergent breeds for selective breeding and are targets for future functional mutation assays.