Knowledge on the genetic epidemiology of disorders in the dog population has implications for both veterinary medicine and sustainable breeding. Limited data on frequencies of genetic disease variants across breeds exists, and the disease heritage of mixed breed dogs remains poorly explored to date. Advances in genetic screening technologies now enable comprehensive investigations of the canine disease heritage, and generate health-related big data that can be turned into action. We pursued population screening of genetic variants implicated in Mendelian disorders in the largest canine study sample examined to date by examining over 83,000 mixed breed and 18,000 purebred dogs representing 330 breeds for 152 known variants using a custom-designed beadchip microarray. We further announce the creation of MyBreedData (www.mybreeddata.com), an online updated inherited disorder prevalence resource with its foundation in the generated data. We identified the most prevalent, and rare, disease susceptibility variants across the general dog population while providing the first extensive snapshot of the mixed breed disease heritage. Approximately two in five dogs carried at least one copy of a tested disease variant. Most disease variants are shared by both mixed breeds and purebreds, while breed- or line-specificity of others is strongly suggested. Mixed breed dogs were more likely to carry a common recessive disease, whereas purebreds were more likely to be genetically affected with one, providing DNA-based evidence for hybrid vigor. We discovered genetic presence of 22 disease variants in at least one additional breed in which they were previously undescribed. Some mutations likely manifest similarly independently of breed background; however, we emphasize the need for follow up investigations in each case and provide a suggested validation protocol for broader consideration. In conclusion, our study provides unique insight into genetic epidemiology of canine disease risk variants, and their relevance for veterinary medicine, breeding programs and animal welfare.
BackgroundThe growing number of identified genetic disease risk variants across dog breeds challenges the current state-of-the-art of population screening, veterinary molecular diagnostics, and genetic counseling. Multiplex screening of such variants is now technologically feasible, but its practical potential as a supportive tool for canine breeding, disease diagnostics, pet care, and genetics research is still unexplored.ResultsTo demonstrate the utility of comprehensive genetic panel screening, we tested nearly 7000 dogs representing around 230 breeds for 93 disease-associated variants using a custom-designed genotyping microarray (the MyDogDNA® panel test). In addition to known breed disease-associated mutations, we discovered 15 risk variants in a total of 34 breeds in which their presence was previously undocumented. We followed up on seven of these genetic findings to demonstrate their clinical relevance. We report additional breeds harboring variants causing factor VII deficiency, hyperuricosuria, lens luxation, von Willebrand’s disease, multifocal retinopathy, multidrug resistance, and rod-cone dysplasia. Moreover, we provide plausible molecular explanations for chondrodysplasia in the Chinook, cerebellar ataxia in the Norrbottenspitz, and familiar nephropathy in the Welsh Springer Spaniel.ConclusionsThese practical examples illustrate how genetic panel screening represents a comprehensive, efficient and powerful diagnostic and research discovery tool with a range of applications in veterinary care, disease research, and breeding. We conclude that several known disease alleles are more widespread across different breeds than previously recognized. However, careful follow up studies of any unexpected discoveries are essential to establish genotype-phenotype correlations, as is readiness to provide genetic counseling on their implications for the dog and its breed.
BackgroundHuman anxiety disorders are complex diseases with largely unknown etiology. We have taken a cross-species approach to identify genes that regulate anxiety-like behavior with inbred mouse strains that differ in their innate anxiety levels as a model. We previously identified 17 genes with expression levels that correlate with anxiety behavior across the studied strains. In the present study, we tested their 13 known human homologues as candidate genes for human anxiety disorders with a genetic association study.MethodsWe describe an anxiety disorder study sample derived from a Finnish population-based cohort and consisting of 321 patients and 653 carefully matched control subjects, all interviewed to obtain DSM-IV diagnoses. We genotyped altogether 208 single nucleotide polymorphisms (SNPs) (all non-synonymous SNPs, SNPs that alter potential microRNA binding sites, and gap-filling SNPs selected on the basis of HapMap information) from the investigated anxiety candidate genes.ResultsSpecific alleles and haplotypes of six of the examined genes revealed some evidence for association (p ≤ .01). The most significant evidence for association with different anxiety disorder subtypes were: p = .0009 with ALAD (δ-aminolevulinate dehydratase) in social phobia, p = .009 with DYNLL2 (dynein light chain 2) in generalized anxiety disorder, and p = .004 with PSAP (prosaposin) in panic disorder.ConclusionsOur findings suggest that variants in these genes might predispose to specific human anxiety disorders. These results illustrate the potential utility of cross-species approaches in identification of candidate genes for psychiatric disorders.
Direct-to-consumer canine genetic testing is becoming increasingly popular among dog owners. The data collected therein provides intriguing insight into the current status of morphological variation present within purebred populations. Mars WISDOM PANELTM data from 11,790 anonymized dogs, representing 212 breeds and 4 wild canine species, were evaluated at genes associated with 7 coat color traits and 5 physical characteristics. Frequencies for all tested alleles at these 12 genes were determined by breed and by phylogenetic grouping. A sub-set of the data, consisting of 30 breeds, was divided into separate same-breed populations based on country of collection, body size, coat variation, or lineages selected for working or conformation traits. Significantly different (p ≤ 0.00167) allele frequencies were observed between populations for at least one of the tested genes in 26 of the 30 breeds. Next, standard breed descriptions from major American and international registries were used to determine colors and tail lengths (e.g. genetic bobtail) accepted within each breed. Alleles capable of producing traits incongruous with breed descriptions were observed in 143 breeds, such that random mating within breeds has probabilities of between 4.9e−7 and 0.25 of creating undesirable phenotypes. Finally, the presence of rare alleles within breeds, such as those for the recessive black coloration and natural bobtail, was combined with previously published identity-by-decent haplotype sharing levels to propose pathways by which the alleles may have spread throughout dog breeds. Taken together, this work demonstrates that: 1) the occurrence of low frequency alleles within breeds can reveal the influence of regional or functional selection practices; 2) it is possible to trace the mode by which characteristics have spread across breeds during historical breed formation; and 3) the necessity of addressing conflicting ideals in breed descriptions relative to actual genetic potential is crucial.Author SummaryFrom the sleek Doberman Pinscher to the coifed Poodle, the sunny Golden Retriever to the aristocratic Pekingese, the world of purebred dogs offers options that appeal to nearly all aesthetics. Pure dog breeds, of which there are over 400 worldwide, are created through selective breeding over multiple generations, toward an ideal goal of temperament, behavior, and physical appearance. Written descriptions of these breed-specific ideals are produced and maintained by dedicated breed enthusiasts, and provide guidelines that direct breeders in their selection choices. However, the genetic mechanisms that produce the spectrum of canine colors and patterns, sculpt the small triangular ears of a Siberian Husky or the long soft ears of a Basset Hound, are complicated and intertwined. This means that some breeds can carry rare, hidden traits for many generations, hampering selection efforts toward uniformity. We have determined the genotypes of >11,000 dogs, representing >200 breeds, at 12 genes that impact coat color and physical characteristics. In doing so, we can now present realistic trait frequencies within each breed, report occurrences of gene variants that can produce undesirable traits, and draw conclusions about the historic spread of characteristics across modern related breeds and those with distant shared ancestry.
Background Dog breeds are known for their distinctive body shape, size, coat color, head type and behaviors, features that are relatively similar across members of a breed. Unfortunately, dog breeds are also characterized by distinct predispositions to disease. We explored the relationships between inbreeding, morphology and health using genotype based inbreeding estimates, body weight and insurance data for morbidity. Results The average inbreeding based on genotype across 227 breeds was Fadj = 0.249 (95% CI 0.235–0.263). There were significant differences in morbidity between breeds with low and high inbreeding (H = 16.49, P = 0.0004). There was also a significant difference in morbidity between brachycephalic breeds and non-brachycephalic breeds (P = 0.0048) and between functionally distinct groups of breeds (H = 14.95 P < 0.0001). Morbidity was modeled using robust regression analysis and both body weight (P < 0.0001) and inbreeding (P = 0.013) were significant (r2 = 0.77). Smaller less inbred breeds were healthier than larger more inbred breeds. Conclusions In this study, body size and inbreeding along with deleterious morphologies contributed to increases in necessary health care in dogs.
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