Dissertation
Sheep Cis-Regulatory Element Polymorphisms Confer Resilience in Ovine Lentivirus Infection
Washington State University
Doctor of Philosophy (PhD), Washington State University
01/2021
DOI:
https://doi.org/10.7273/000005457
Handle:
https://hdl.handle.net/2376/119107
Abstract
Ovine progressive pneumonia is an incurable, slowly fatal infection that affects up to half of all flocks in the United States, caused by ovine lentivirus. Sheep suffer debilitating pneumonia, arthritis, encephalitis, and mastitis. Infection causes significant losses to all aspects of sheep production endangering supply of meat, milk, and wool products for human consumption. Identification of host factors that decrease susceptibility to infectious disease is a key step in combating ovine lentivirus and other retroviruses such as human immunodeficiency virus. We built upon previous work that detected a genomic region at four zinc finger genes ZNF389, ZNF192, ZSCAN16, and ZNF165 as strongly associated with 50% reduction in proviral load. Since proviral load is correlated with severity of disease and lifespan in production flocks, the aim was to find genetic variants to predict this resilient phenotype and that may be causal mutations. DNA regulatory elements in sheep macrophages were annotated because most mutations responsible for phenotypic consequences are found within these elements. Alveolar macrophages function in innate and adaptive immunity as well as wound healing in the lungs dependent on tissue-specific gene expression under epigenetic regulation. The functional diversity of tissue-resident macrophages highlights the need to study tissue-specific regulatory elements that control gene expression. This study reported the first genome-wide survey of regulatory elements in any sheep immune cell, specifically those enriched for H3K4me3 (active promoters), H3K27ac (active enhancers), H3K4me1 (enhancers), CTCF (domain anchors), and H3K27me3 (silencers) which allowed assignment of putative biological function to 12% of the sheep genome. This annotation of transcriptional regulatory elements in target tissues will aid researchers in identifying genetic mutations of immunological consequence for many infectious diseases. A haplotype cluster of at least ten small DNA polymorphisms within the active cis-regulatory elements for ZNF389 were significantly associated with the resilient phenotype to ovine lentivirus in multiple sheep populations. Other zinc finger transcription factors, like ZAP, have been implicated in restriction of retroviral replication from several host species. These data will empower research into functional mutations at sheep regulatory elements and development of marker-assisted selection schemes to develop disease-resilient production flocks.
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Details
- Title
- Sheep Cis-Regulatory Element Polymorphisms Confer Resilience in Ovine Lentivirus Infection
- Creators
- Alisha Therese Massa
- Contributors
- Stephen N. White (Advisor)Holly L. Neibergs (Advisor)Kelly A. Brayton (Committee Member)Donald P. Knowles (Committee Member)Michelle R. Mousel (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- College of Veterinary Medicine
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Publisher
- Washington State University
- Number of pages
- 141
- Identifiers
- 99900592359601842
- Language
- English
- Resource Type
- Dissertation