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Title: Investigating host genetic susceptibility to bovine digital dermatitis
Author: Scholey, Rachel Anne
ISNI:       0000 0004 2736 2271
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2011
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Bovine digital dermatitis (BDD) is a bacterial infectious disease of bovine hoof skin and is the leading cause of dairy cattle lameness. The disease presents as painful "strawberry-like" lesions that develop on the hind hoof digital skin, in between the heel bulbs. Holstein cattle are very susceptible to BDD and anecdotal evidence suggests BDD is less frequently seen in other breeds of cattle, both dairy and beef. Also, within a herd with BDD, there is great variation in how individual cattle are affected; some are recurrently and severely affected, whereas others are apparently untouched. This between and within breed variation in individual responses strongly suggests an underlying genetic susceptibility or resistance to BDD. This thesis presents the first study of host genetic susceptibility to BDD. Chronically affected BDD cases (n=72) and controls that did not present with BDD lesions (n=97) were identified from Holstein Friesian herds in England and Wales endemic ally affected by BDD during longitudinal farm visits. BDD candidate single nucleotide polymorphisms (SNPs) were identified using two approaches. In the first approach, 16 candidate genes were chosen from the available literature and extensive SNP discovery was conducted for each gene. This was achieved by "in silica" database searching for publicly available SNPs and also by dHPLC (WAVE) screening and sequencing of gene regions. Secondly, a genome-wide association study (GWAS), using the Illumina bovine SNP50beadchip, was performed with a small number of BDD cases (n=23) and controls (n=24). From these two approaches, the most likely associated SNPs were selected for analysis on the full cohort. Sequenom iPLEXTm Gold genotyping was used to genotype 125 candidate gene- identified SNPs and 81 GWAS-identifIed SNPs on the full cohort of cases and controls. The allele frequencies were analysed using Fisher's exact test and Cochran- Mantel- Haenszel 2x2xk test, where herd origin was a stratifying factor. P values were corrected for multiple testing after point-wise 100,000 maxT permutations testing. Eight SNPs were significantly associated (p<0.05) with BDD risk or protection; seven informed from the GWAS and one from the candidate gene study. vii One significant SNP was located in an intron of Anaphase promoting complex subunit 4 (ANAPC4), two were located in introns of HTRA Serine Peptidase 1 (HTRAl) and one was located upstream of SI 00 calcium binding protein A8 (SI OOA8). Six of the eight significant SNPs were located across a gene-rich 3.5Mb region on chromosome 26. This was considered a BDD candidate region requiring further investigation. A haplotype analysis revealed one haplotype block, spanning the HTRAl gene, which was significantly associated with BDD protection. The frequencies of the risk alleles for the eight significant SNPs were compared in eleven BDD unaffected breeds (beef and dairy). Three of the SNPs had lower risk allele frequencies in all breeds tested, and a further three had no more than two breeds where risk allele frequency was higher than in Holstein cases. This might indicate that non Holstein Friesian breeds are at lower BDD risk, at least for some SNPs. However, a lot of questions regarding whether other breeds are exposed to the causative pathogens in the same way as Holstein Friesians remain unanswered. These preliminary BDD-genetic associations need to be validated in independent populations of Holstein Friesian cattle. Susceptibility to infectious disease is governed by a complex interaction of genes and environment, and the sample size in this study was probably too small to detect all underlying BDD genetic variation. However, the significant associations that have been yielded demonstrate that this approach is successful for genetic study of bacterial infectious diseases in cattle, and provides the foundations on which to base further study of BDD host genetic susceptibility.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available