Genome-wide association studies for multiple diseases of the German Shepherd Dog.

The German Shepherd Dog (GSD) is a popular working and companion breed for which over 50 hereditary diseases have been documented. Herein, SNP profiles for 197 GSDs were generated using the Affymetrix v2 canine SNP array for a genome-wide association study to identify loci associated with four diseases: pituitary dwarfism, degenerative myelopathy (DM), congenital megaesophagus (ME), and pancreatic acinar atrophy (PAA). A locus on Chr 9 is strongly associated with pituitary dwarfism and is proximal to a plausible candidate gene, LHX3.

The function of dog models in developing gene therapy strategies for human health.

The domestic dog is of great benefit to humankind, not only through companionship and working activities cultivated through domestication and selective breeding, but also as a model for biomedical research. Many single-gene traits have been well-characterized at the genomic level, and recent advances in whole-genome association studies will allow for better understanding of complex, multigenic hereditary diseases. Additionally, the dog serves as an invaluable large animal model for assessment of novel therapeutic agents.

A missense mutation in the 20S proteasome β2 subunit of Great Danes having harlequin coat patterning.

Harlequin is a pigmentary trait of the domestic dog that is controlled by two autosomal loci: the melanosomal gene, SILV, and a modifier gene, harlequin (H), previously localized to chromosome 9. Heterozygosity for a retrotransposon insertion in SILV and a mutation in H causes a pattern of black patches on a white background. Homozygosity for H is embryonic lethal.

Naturally occurring mutations in the canine CFTR gene.

Naturally occurring cystic fibrosis (CF)-causing mutations in the CFTR gene have not been identified in any nonhuman animal species. Since domestic dogs are known to develop medical conditions associated with atypical CF in humans (e.g.

Analysis of gene expression in brain tissue from Greyhounds with meningoencephalitis.

Objective: To elucidate the pathogenesis of Greyhound meningoencephalitis by evaluating gene expression in diseased brain tissue.

Animals: Cadavers of 3 diseased (8- to 15-month-old) and 3 (10-month-old) control Greyhounds.

Procedures: Samples of RNA were extracted from brain tissue of all dogs and evaluated by use of a canine-specific microarray.

Evaluation of quantitative trait loci for hip dysplasia in Labrador Retrievers.

Objective: To identify the quantitative trait loci (QTL) that contribute to hip dysplasia in dogs.

Animals: 192 Labrador Retrievers.

Procedures: Hip dysplasia was measured by use of the Norberg angle (NA), dorsolateral subluxation (DLS) score, and distraction index (DI).

Heritability and transmission analysis of necrotizing meningoencephalitis in the Pug.

Necrotizing meningoencephalitis (NME) in the Pug is an invariably fatal disease with an early age of onset whose cause remains unknown. Breed predilection strongly suggests genetic component(s), and viral etiology proves negative in studied cases. The current study was undertaken as the first analysis of the heritable component(s) involved in NME in the Pug.

Identification of quantitative trait loci for osteoarthritis of hip joints in dogs.

Objective: To identify quantitative trait loci (QTL) associated with osteoarthritis (OA) of hip joints of dogs by use of a whole-genome microsatellite scan.

Animals: 116 founder, backcross, F1, and F2 dogs from a crossbred pedigree.

Procedures: Necropsy scores and an optimized set of 342 microsatellite markers were used for interval mapping by means of a combined backcross and F2 design module from an online statistical program.

MicroRNA expression in canine mammary cancer.

MicroRNAs (miRNAs) are 18-22-nt noncoding RNAs that are involved in post-transcriptional regulation of genes. Oncomirs, a subclass of miRNAs, include genes whose expression, or lack thereof, are associated with cancers. Until the last decade, the domestic dog was an underused model for the study of various human diseases that have genetic components.

Genome-wide linkage scan localizes the harlequin locus in the Great Dane to chromosome 9.

Harlequin is a coat pattern of the Great Dane characterized by ragged patches of full color on a white background. Harlequin patterning is a bigenic trait, resulting from the interaction of the merle allele of SILV, and a dominant modifier locus, H. Breeding data suggest that H is embryonic recessive lethal and that all harlequins are Hh.

Analysis of gene transcript profiling and immunobiology in Shetland sheepdogs with dermatomyositis.

Dermatomyositis (DM) is a canine and human inflammatory disease of the skin and muscle that is thought to be autoimmune in nature. In dogs, DM occurs most often in the rough collie and Shetland sheepdog. Characteristic skin lesions typically develop on the face, ears, tail, and distal extremities.

Isolation, culture, and characterization of canine Sertoli cells.

Primary Sertoli cell cultures have been established from several animals including the sheep and rhesus monkey; however, not for the domestic dog, Canis familiaris. Sertoli cells are the only readily accessible cell type in the body which expresses all six type IV collagens. These collagens play key roles in tissue structure, basement membrane formation, and filtration.

Identification, amplification and characterization of miR-17-92 from canine tissue.

Recently, a novel group of genes encoding small RNA molecules, termed microRNAs (miRNAs), has been discovered to play a vital role in eukaryotic gene expression. Known to act in a post-transcriptional fashion, miRNAs can inhibit translation by binding to messenger RNA (mRNA) or by targeting mRNA for degradation. A search of genetic databases revealed significant conservation of miRNA genes between the domestic dog and the human.

Understanding hereditary diseases using the dog and human as companion model systems.

Animal models are requisite for genetic dissection of, and improved treatment regimens for, human hereditary diseases. While several animals have been used in academic and industrial research, the primary model for dissection of hereditary diseases has been the many strains of the laboratory mouse. However, given its greater (than the mouse) genetic similarity to the human, high number of naturally occurring hereditary diseases, unique population structure, and the availability of the complete genome sequence, the purebred dog has emerged as a powerful model for study of diseases.

Hereditary evaluation of multiple developmental abnormalities in the Havanese dog breed.

The Havanese is a toy breed that presents with a wide range of developmental abnormalities. Skeletal defects, particularly osteochondrodysplasia (OCD), are the most frequently observed anomalies. Cataracts, liver shunts, heart murmurs, and missing incisors are also common in this breed.

Genetic cause of autosomal recessive hereditary nephropathy in the English Cocker Spaniel.

Background: Autosomal recessive hereditary nephropathy (ARHN) in the English Cocker Spaniel is caused by a type IV collagen defect, but the underlying mutation is unknown.

Animals: One hundred thirty-four English Cocker Spaniels (12 with ARHN, 8 obligate carriers, and 114 others), 3 mixed breed dogs with X-linked hereditary nephropathy (XLHN), and 7 other dogs without hereditary nephropathy were included.

Methods: Diagnosis of ARHN was based on transmission electron microscopy and immunostaining of kidney.

Linkage and segregation analysis of black and brindle coat color in domestic dogs.

Mutations of pigment type switching have provided basic insight into melanocortin physiology and evolutionary adaptation. In all vertebrates that have been studied to date, two key genes, Agouti and Melanocortin 1 receptor (Mc1r), encode a ligand-receptor system that controls the switch between synthesis of red-yellow pheomelanin vs. black-brown eumelanin.

Gene expression analysis in a canine model of X-linked Alport syndrome.

Chronic kidney disease (CKD) often culminates in renal failure as a consequence of progressive interstitial fibrosis and is an important cause of illness and death in dogs. Identification of disease biomarkers and gene expression changes will yield valuable information regarding the specific biological pathways involved in disease progression. Toward these goals, gene expression changes in the renal cortex of dogs with X-linked Alport syndrome (XLAS) were examined using microarray technology.

Statistical analysis regarding the effects of height and weight on life span of the domestic dog.

This study was undertaken to determine the association between life spans and breed size in the dog, based upon data derived from the pet population. Seventy-seven American Kennel Club breeds were analyzed with data collected for more than 700 dogs. Multiple linear regression analysis was carried out with longevity as the dependent variable and height or weight as the independent variable.

Aging-associated loci in Canis familiaris.

Although recent endeavors to discover the mechanisms of the aging process have been numerous and successful, there is still much to be learned. Genes implicated in the aging process were mapped to the canine genome and will serve as additional framework markers for the assignment of contiguous segments from the canine genome sequence to chromosomes. The 54 genes were selected because of their demonstrated contribution to longevity in other organisms or based upon their proximity to a marker, D4S1564, on human chromosome 4 (Puca et al.

Clinical and genetic assessments of hip joint laxity in the Boykin spaniel.

Canine hip dysplasia (CHD) is characterized by a malformation of the hip joint that leads to joint laxity and consequential degenerative joint disease. The most widely used method for diagnosis of CHD is the ventrodorsal hip-extended radiologic view, commonly referred to as the Orthopedic Foundation for Animals (OFA) method. The method of the University of Pennsylvania Hip Improvement Program (PennHIP), an alternative technique that is based on hip joint laxity, provides a quantitative assessment, the distraction index (DI), of the likelihood of the development of CHD because of increased laxity in the hip joint.

Retrotransposon insertion in SILV is responsible for merle patterning of the domestic dog.

Merle is a pattern of coloring observed in the coat of the domestic dog and is characterized by patches of diluted pigment. This trait is inherited in an autosomal, incompletely dominant fashion. Dogs heterozygous or homozygous for the merle locus exhibit a wide range of auditory and ophthalmologic abnormalities, which are similar to those observed for the human auditory-pigmentation disorder Waardenburg syndrome.

Linkage of dermatomyositis in the Shetland Sheepdog to chromosome 35.

Dermatomyositis is an inflammatory disease of the skin and muscle and is most commonly found in the Shetland sheepdog. Both the clinical presentation and the age of onset of dermatomyositis vary widely, and the inability to diagnose dermatomyositis before clinical symptoms ensue has made control of the disease difficult. Identification of a genetic marker that cosegregates with dermatomyositis would facilitate the development of a DNA-based test for the early detection of affected dogs.

Linkage analysis and gene expression profile of pancreatic acinar atrophy in the German Shepherd Dog.

Pancreatic acinar atrophy (PAA) is a degenerative disease of the exocrine pancreas and is the most common cause of exocrine pancreatic insufficiency in the German Shepherd Dog. Analyses of inheritance have shown that a single gene segregating in an autosomal recessive fashion is causative for PAA. To date the gene and causative mutation have not been determined.

Identification of microsatellite markers linked to progressive retinal atrophy in American Eskimo Dogs.

Objective: To identify microsatellite markers linked to progressive retinal atrophy (PRA) in American Eskimo Dogs.

Sample Population: Blood samples or buccal epithelial cells from 66 American Eskimo Dogs, including 53 PRA-unaffected and 13 PRA-affected dogs.

Procedure: The genotypes of unaffected and affected dogs were determined by use of microsatellite markers spanning canine chromosome 9 (CFA09).