Investigation of a Possible Novel Genetic Mutation in Brangus Calves with Proportionate Dwarfism




Perkins, Thomas

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The University of Nebraska - Lincoln was contacted in May, 2018, with reports of calves born with proportionate dwarfism and in at least one case, mild scoliosis. The calves share the same sire and pedigree relationships observed between the sire and dams of the affected calves suggested a genetic basis of the condition. The purpose of this study was to use genomic tools to attempt to identify genomic variant(s) causative of small size and skeletal deformities in these Brangus calves. After many analyses, no clear candidate variants were identified by any method employed. Variants that fit one of the hypothesized modes of inheritance across all cases in the regions of interest were rare, and when present, had no clear functional impact. If the phenotype observed were due to a simple Mendelian cause, it would be expected that GWAS and homozygosity mapping analyses would each point to a similar region of the genome, and GWAS associations would include multiple, linked markers; this unfortunately was not the case.


Data Collection Methodology: Genome-wide association studies (GWAS) were conducted in GenABEL (Aulchenko et al. 2007) with sex as a covariate and accounting for population stratification in the sample using a relationship matrix and/or principle components; the means most appropriate and thus the model assumed for various iterations of the data (e.g., with and without additional samples) was determined by the estimate of lambda, a measure of genomic inflation. For an additional means to conduct association analyses and to allow for investigation of regions of significance from the GWAS studies, DNA from four affected calves and their dams as well as from the semen of the sire was isolated and whole-genome sequenced. The resulting sequence was aligned to the UCD-ARS1.2 reference genome with BWA-MEM (Li 2013) and variants identified with freebayes (Garrison & Marth 2012). The functional impact of each variant was predicted using SNPEff (Cingolani et al. 2012). Expected Findings: Mapping and variant calling of WGS from the nine Brangus individuals resulted in 6.9 million variants for evaluation. Assuming a genetic cause of this condition is rare across breeds, WGS data from Heaton et al. (2016) representing over 100 individuals of over 20 breeds (including 6 Angus, 5 Brangus, and 5 Brahman) and that of the 12 other calves sequenced by our lab were utilized to remove common variants (found at >5% frequency). This reduced the data set to be more manageable with 51,460 candidate variants fitting a recessive mode of inheritance. 43,000 of the total variants remaining after filtering were predicted to have either a “high” or “moderate” impact on gene function. The WGS data were utilized to investigate the regions identified by GWAS of possible interest as well as to investigate possible variants in genes previously implicated in dwarfism in cattle and other species (Table 3). In regions of interest, variants were first examined to find any that may fit a recessive mode of inheritance (heterozygous in each parent but homozygous in the affected calves). As no clear candidate were resolved, variants having a predicted impact were also considered allowing for some error in phenotype assignment (e.g. only 3⁄4 calves affected). The possibility of a dominant trait resulting from mosaicism of the sire, in which case he may show no symptoms but pass this defect to a proportion of his offspring, was also considered by examining loci where the sire and calves are all heterozygous while the dams do not have the variant. In all evaluations, the position of each variant in the genome (e.g., intergenic, intronic, exonic) and predicted function was noted to prioritize variants with possible functional relevance.



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