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Functional Variants Surrounding Endothelin 2 Are Associated With Mycobacterium avium Subspecies paratuberculosis
Jennifer N Kiser1, Zeping Wang1, Ricardo Zanella1
1Department of Animal Sciences, Washington State University, Pullman, WA, United States.
Abstract:
Bovine paratuberculosis, caused by Mycobacterium avium subspecies paratuberculosis (MAP), continues to impact the dairy industry through increased morbidity, mortality, and lost production. Although genome-wide association analyses (GWAAs) have identified loci associated with susceptibility to MAP, limited progress has been made in identifying mutations that cause disease susceptibility. A 235-kb region on Bos taurus chromosome 3 (BTA3), containing a 70-kb haplotype block surrounding endothelin 2 (EDN2), has previously been associated with the risk of MAP infection. EDN2 is highly expressed in the gut and is involved in intracellular calcium signaling and a wide array of biological processes. The objective of this study was to identify putative causal mutations for disease susceptibility in the region surrounding EDN2 in Holstein and Jersey cattle. Using sequence data from 10 Holstein and 10 Jersey cattle, common variants within the 70-kb region containing EDN2 were identified. A custom SNP genotyping array fine-mapped the region using 221 Holstein and 51 Jersey cattle and identified 17 putative causal variants (P < 0.01) located in the 5' region of EDN2 and a SNP in the 3' UTR (P = 0.00009) associated with MAP infection. MicroRNA interference assays, mRNA stability assays, and electrophoretic mobility shift assays were performed to determine if allelic changes at each SNP resulted in differences in EDN2 stability or expression. Two SNPs [rs109651404 (G/A) and rs110287192 (G/T)] located within the promoter region of EDN2 displayed differential binding affinity for transcription factors in binding sequences harboring the alternate SNP alleles. The luciferase reporter assay revealed that the transcriptional activity of the EDN2 promoter was increased (P < 0.05) with the A allele for rs109651404 and the G allele for rs110287192. These results suggest that the variants rs109651404 and rs110287192 are mutations that alter transcription and thus may alter susceptibility to MAP infection in Holstein and Jersey cattle.
Insights
Researchers identified two specific gene variants, rs109651404 and rs110287192, that increase susceptibility to Mycobacterium avium subspecies paratuberculosis (MAP) infection in cattle. These variants affect gene transcription, offering new insights into bovine paratuberculosis.
Area of Science:
- Genetics
- Animal Science
- Veterinary Medicine
Background:
- Bovine paratuberculosis (MAP) causes significant economic losses in the dairy industry.
- Genome-wide association studies have identified regions associated with MAP susceptibility but not specific causal mutations.
- A previously identified region on chromosome 3, including the endothelin 2 (EDN2) gene, is linked to MAP infection risk.
Purpose of the Study:
- To identify causal mutations within the EDN2 region associated with susceptibility to Mycobacterium avium subspecies paratuberculosis (MAP) infection in Holstein and Jersey cattle.
- To investigate the functional impact of identified variants on EDN2 gene expression and regulation.
Main Methods:
- Whole-genome sequencing and SNP genotyping were used to identify variants in the EDN2 region.
- Functional assays including microRNA interference, mRNA stability, electrophoretic mobility shift, and luciferase reporter assays were performed.
- Analysis focused on two specific SNPs, rs109651404 and rs110287192, in the EDN2 promoter and 3' UTR.
Main Results:
- Seventeen putative causal variants were identified, with two SNPs (rs109651404 and rs110287192) in the EDN2 promoter region showing significant association with MAP infection.
- These SNPs demonstrated differential binding affinity for transcription factors.
- Luciferase reporter assays indicated that specific alleles of these SNPs increased EDN2 promoter activity.
Conclusions:
- The identified variants rs109651404 and rs110287192 likely alter EDN2 transcription.
- These genetic variations may contribute to differential susceptibility to MAP infection in Holstein and Jersey cattle.
- The findings provide potential targets for genetic selection to improve resistance to bovine paratuberculosis.
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