Susceptibility loci revealed for bovine respiratory disease complex in pre-weaned holstein calves.

BACKGROUND: Bovine respiratory disease complex (BRDC) is an infectious disease of cattle that is caused by a combination of viral and/or bacterial pathogens. Selection for cattle with reduced susceptibility to respiratory disease would provide a permanent tool for reducing the prevalence of BRDC. The objective of this study was to identify BRDC susceptibility loci in pre-weaned Holstein calves as a prerequisite to using genetic improvement as a tool for decreasing the prevalence of BRDC. High density SNP genotyping with the Illumina BovineHD BeadChip was conducted on 1257 male and 757 female Holstein calves from California (CA), and 767 calves identified as female from New Mexico (NM). Of these, 1382 were classified as BRDC cases, and 1396 were classified as controls, with all phenotypes assigned using the McGuirk health scoring system. During the acquisition of blood for DNA isolation, two deep pharyngeal and one mid-nasal diagnostic swab were obtained from each calf for the identification of bacterial and viral pathogens. Genome-wide association analyses were conducted using four analytical approaches (EIGENSTRAT, EMMAX-GRM, GBLUP and FvR). The most strongly associated SNPs from each individual analysis were ranked and evaluated for concordance. The heritability of susceptibility to BRDC in pre-weaned Holstein calves was estimated. RESULTS: The four statistical approaches produced highly concordant results for 373 top ranked SNPs that defined 126 chromosomal regions for the CA population. Similarly, in NM, 370 SNPs defined 138 genomic regions that were identified by all four approaches. When the two populations were combined (i.e., CA + NM) and analyzed, 324 SNPs defined 116 genomic regions that were associated with BRDC across all analytical methods. Heritability estimates for BRDC were 21% for both CA and NM as individual populations, but declined to 13% when the populations were combined. CONCLUSIONS: Four analytical approaches utilizing both single and multi-marker association methods revealed common genomic regions associated with BRDC susceptibility that can be further characterized and used for genomic selection. Moderate heritability estimates were observed for BRDC susceptibility in pre-weaned Holstein calves, thereby supporting the application of genomic selection to reduce the prevalence of BRDC in U.S. Holsteins.

Functional Variants Surrounding Endothelin 2 Are Associated With Mycobacterium avium Subspecies paratuberculosis Infection.

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.

A Population Genomics Analysis of the Native Irish Galway Sheep Breed.

The Galway sheep population is the only native Irish sheep breed and this livestock genetic resource is currently categorised as 'at-risk'. In the present study, comparative population genomics analyses of Galway sheep and other sheep populations of European origin were used to investigate the microevolution and recent genetic history of the breed. These analyses support the hypothesis that British Leicester sheep were used in the formation of the Galway. When compared to conventional and endangered breeds, the Galway breed was intermediate in effective population size, genomic inbreeding and runs of homozygosity. This indicates that, although the Galway breed is declining, it is still relatively genetically diverse and that conservation and management plans informed by genomic information may aid its recovery. The Galway breed also exhibited distinct genomic signatures of artificial or natural selection when compared to other breeds, which highlighted candidate genes that may be involved in production and health traits.

Results of the BRD CAP project: progress toward identifying genetic markers associated with BRD susceptibility.

The Bovine Respiratory Disease Coordinated Agricultural Project (BRD CAP) is a 5-year project funded by the United States Department of Agriculture (USDA), with an overriding objective to use the tools of modern genomics to identify cattle that are less susceptible to BRD. To do this, two large genome wide association studies (GWAS) were conducted using a case:control design on preweaned Holstein dairy heifers and beef feedlot cattle. A health scoring system was used to identify BRD cases and controls. Heritability estimates for BRD susceptibility ranged from 19 to 21% in dairy calves to 29.2% in beef cattle when using numerical scores as a semi-quantitative definition of BRD. A GWAS analysis conducted on the dairy calf data showed that single nucleotide polymorphism (SNP) effects explained 20% of the variation in BRD incidence and 17-20% of the variation in clinical signs. These results represent a preliminary analysis of ongoing work to identify loci associated with BRD. Future work includes validation of the chromosomal regions and SNPs that have been identified as important for BRD susceptibility, fine mapping of chromosomes to identify causal SNPs, and integration of predictive markers for BRD susceptibility into genetic tests and national cattle genetic evaluations.

Linkage mapping of the locus for inherited ovine arthrogryposis (IOA) to sheep chromosome 5.

Arthrogryposis is a congenital malformation affecting the limbs of newborn animals and infants. Previous work has demonstrated that inherited ovine arthrogryposis (IOA) has an autosomal recessive mode of inheritance. Two affected homozygous recessive (art/art) Suffolk rams were used as founders for a backcross pedigree of half-sib families segregating the IOA trait. A genome scan was performed using 187 microsatellite genetic markers and all backcross animals were phenotyped at birth for the presence and severity of arthrogryposis. Pairwise LOD scores of 1.86, 1.35, and 1.32 were detected for three microsatellites, BM741, JAZ, and RM006, that are located on sheep Chr 5 (OAR5). Additional markers in the region were identified from the genetic linkage map of BTA7 and by in silico analyses of the draft bovine genome sequence, three of which were informative. Interval mapping of all autosomes produced an F value of 21.97 (p < 0.01) for a causative locus in the region of OAR5 previously flagged by pairwise linkage analysis. Inspection of the orthologous region of HSA5 highlighted a previously fine-mapped locus for human arthrogryposis multiplex congenita neurogenic type (AMCN). A survey of the HSA5 genome sequence identified plausible candidate genes for both IOA and human AMCN.