The extraordinary phenotypic diversity of dog breeds has been sculpted by a unique population history accompanied by selection for novel and desirable traits. Here we perform a comprehensive analysis using multiple test statistics to identify regions under selection in 509 dogs from 46 diverse breeds using a newly developed high-density genotyping array consisting of >170,000 evenly spaced SNPs. We first identify 44 genomic regions exhibiting extreme differentiation across multiple breeds. Genetic variation in these regions correlates with variation in several phenotypic traits that vary between breeds, and we identify novel associations with both morphological and behavioral traits. We next scan the genome for signatures of selective sweeps in single breeds, characterized by long regions of reduced heterozygosity and fixation of extended haplotypes. These scans identify hundreds of regions, including 22 blocks of homozygosity longer than one megabase in certain breeds. Candidate selection loci are strongly enriched for developmental genes. We chose one highly differentiated region, associated with body size and ear morphology, and characterized it using high-throughput sequencing to provide a list of variants that may directly affect these traits. This study provides a catalogue of genomic regions showing extreme reduction in genetic variation or population differentiation in dogs, including many linked to phenotypic variation. The many blocks of reduced haplotype diversity observed across the genome in dog breeds are the result of both selection and genetic drift, but extended blocks of homozygosity on a megabase scale appear to be best explained by selection. Further elucidation of the variants under selection will help to uncover the genetic basis of complex traits and disease.

In order to evaluate the genetic structure of purebred dogs, six Y chromosome microsatellite markers were used to analyze DNA samples from 824 unrelated dogs from 50 recognized breeds. A relatively small number of haplotypes (67) were identified in this large sample set due to extensive sharing of haplotypes between breeds and low haplotype diversity within breeds. Fifteen breeds were characterized by a single Y chromosome haplotype. Breed-specific haplotypes were identified for 26 of the 50 breeds, and haplotype sharing between some breeds indicated a common history. A molecular variance analysis (AMOVA) demonstrated significant genetic variation across breeds (63.7%) and with geographic origin of the breeds (11.5%). A network analysis of the haplotypes revealed further relationships between the breeds as well as deep rooting of many of the breed-specific haplotypes, particularly among breeds of African origin.

BackgroundGonadectomy, or neutering, is a very common surgery for dogs having many positive effects on behavior, health, and longevity. There are also certain risks associated with neutering including the development of orthopedic conditions, cognitive decline, and a predisposition to some neoplasias. This study was designed specifically to identify if a correlation exists between neuter status and inherited conditions in a large aggregate cohort of dogs representing many different breeds.ResultsNeutered dogs were at less risk for early and congenital conditions (aortic stenosis, early onset cataracts, mitral valve disease, patent ductus arteriosus, portosystemic shunt, and ventricular septal defect) than intact dogs. Neutering was also associated with reduced risk of dilated cardiomyopathy and gastric dilatation volvulus in males. Neutering was significantly associated with an increased risk for males and females for cancers (hemangiosarcoma, hyperadrenocorticism, lymphoma, mast cell tumor, and osteosarcoma), ruptured anterior cruciate ligament and epilepsy. Intervertebral disk disease was associated with increased risk in females only. For elbow dysplasia, hip dysplasia, lens luxation, and patellar luxation neutering had no significant effect on the risk for those conditions. Neutering was associated with a reduced risk of vehicular injury, a condition chosen as a control.ConclusionsIn this retrospective study, several conditions showed an increased risk associated with neutering whereas other conditions were less likely to be expressed in neutered dogs. The complexity of the interactions between neutering and inherited conditions underscores the need for reflective consultation between the client and the clinician when considering neutering. The convenience and advantages of neutering dogs that will not be included in a breeding program must be weighed against possible risk associated with neutering.Electronic supplementary materialThe online version of this article (doi:10.1186/s40575-017-0044-6) contains supplementary material, which is available to authorized users.

Metaphyseal osteopathy (MO) (hypertrophic osteodystrophy) is a developmental disorder of unexplained etiology affecting dogs during rapid growth. Affected dogs experience relapsing episodes of lytic/sclerotic metaphyseal lesions and systemic inflammation. MO is rare in the general dog population; however, some breeds (Weimaraner, Great Dane and Irish Setter) have a much higher incidence, supporting a hereditary etiology. Autoinflammatory childhood disorders of parallel presentation such as chronic recurrent multi-focal osteomyelitis (CRMO), and deficiency of interleukin-1 receptor antagonist (DIRA), involve impaired innate immunity pathways and aberrant cytokine production. Given the similarities between these diseases, we hypothesize that MO is an autoinflammatory disease mediated by cytokines involved in innate immunity. To characterize immune dysregulation in MO dogs we measured serum levels of inflammatory markers in 26 MO and 102 control dogs. MO dogs had significantly higher levels (pg/ml) of serum Interleukin-1beta (IL-1β), IL-18, IL-6, Granulocyte-macrophage colony stimulating factor (GM-CSF), C-X-C motif chemokine 10 (CXCL10), tumor necrosis factor (TNF), and IL-10. Notably, recovered MO dogs were not different from dogs during active MO disease, providing a suggestive mechanism for disease predisposition. This is the first documentation of elevated immune markers in MO dogs, uncovering an immune profile similar to comparable autoinflammatory disorders in children.

Advances in DNA sequencing and other technologies have greatly facilitated the identification of genetic risk factors for inherited diseases in dogs. We review recent technological developments based on selected examples from canine disease genetics. The identification of disease-causing variants in dogs with monogenic diseases may become a widely employed diagnostic approach in clinical veterinary medicine in the not-too-distant future. Diseases with complex modes of inheritance continue to pose challenges to researchers but have also become much more tangible than in the past. In addition to strategies for identifying genetic risk factors, we provide some thoughts on the interpretation of sequence variants that are largely inspired by developments in human clinical genetics. Expected final online publication date for the Annual Review of Animal Biosciences, Volume 11 is February 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.