The discovery of novel recessive genetic disorders in dairy cattle : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Animal Science at AL Rae Centre of Genetics and Breeding, Massey University, Palmerston North, New Zealand

The selection of desirable characteristics in livestock has resulted in the transmission of advantageous genetic variants for generations. The advent of artificial insemination has accelerated the propagation of these advantageous genetic variants and led to tremendous advances in animal productivity. However, this intensive selection has led to the rapid uptake of deleterious alleles as well. Recently, a recessive mutation in the GALNT2 gene was identified to dramatically impair growth and production traits in dairy cattle causing small calf syndrome. The research presented here seeks to further investigate the presence and impact of recessive mutations in dairy cattle. A primary aim of genetics is to identify causal variants and understand how they act to manipulate a phenotype. As datasets have expanded, larger analyses are now possible and statistical methods to discover causal mutations have become commonplace. One such method, the genome-wide association study (GWAS), presents considerable exploratory utility in identifying quantitative trait loci (QTL) and causal mutations. GWAS' have predominantly focused on identifying additive genetic effects assuming that each allele at a locus acts independently of the other, whereas non-additive effects including dominant, recessive, and epistatic effects have been neglected. Here, we developed a single-locus non-additive GWAS model intended for the detection of dominant and recessive genetic mechanisms. We applied our non-additive GWAS model to growth, developmental, and lactation phenotypes in dairy cattle. We identified several candidate causal mutations that are associated with moderate to large deleterious recessive disorders of animal welfare and production. These mutations included premature-stop (MUS81, ITGAL, LRCH4, RBM34), splice disrupting (FGD4, GALNT2), and missense (PLCD4, MTRF1, DPF2, DOCK8, SLC25A4, KIAA0556, IL4R) variants, and these occur at surprisingly high frequencies in cattle. We further investigated these candidates for anatomical, molecular, and metabolic phenotypes to understand how these disorders might manifest. In some cases, these mutations were analogous to disorder-causing mutations in other species, these included: Coffin-Siris syndrome (DPF2); Charcot Marie Tooth disease (FGD4); a congenital disorder of glycosylation (GALNT2); hyper Immunoglobulin-E syndrome (DOCK8); Joubert syndrome (KIAA0556); and mitochondrial disease (SLC25A4). These discoveries demonstrate that deleterious recessive mutations exist in dairy cattle at remarkably high frequencies and we are able to detect these disorders through modern genotyping and phenotyping capabilities. These are important findings that can be used to improve the health and productivity of dairy cattle in New Zealand and internationally