Canine genetics and epidemiology最新文献

Background: Progressive retinal atrophy (PRA) belongs to a group of inherited retinal disorders associated with gradual vision impairment due to degeneration of retinal photoreceptors in various dog breeds. PRA is highly heterogeneous, with autosomal dominant, recessive or X-linked modes of inheritance. In this study we used exome sequencing to investigate the molecular genetic basis of a new type of PRA, which occurred spontaneously in a litter of German short-hair Weimaraner dogs.

Results: Whole exome sequencing in two PRA-affected Weimaraner dogs identified a large deletion comprising the first four exons of the X-linked retinitis pigmentosa GTPase regulator (RPGR) gene known to be involved in human retinitis pigmentosa and canine PRA. Screening of 16 individuals in the corresponding pedigree of short-hair Weimaraners by qPCR, verified the deletion in hemizygous or heterozygous state in one male and six female dogs, respectively. The mutation was absent in 88 additional unrelated Weimaraners. The deletion was not detectable in the parents of one older female which transmitted the mutation to her offspring, indicating that the RPGR deletion represents a de novo mutation concerning only recent generations of the Weimaraner breed in Germany.

Conclusion: Our results demonstrate the value of an existing DNA biobank combined with exome sequencing to identify the underlying genetic cause of a spontaneously occurring inherited disease. Identification of the genetic cause has allowed the development of a diagnostic test, which should help to eradicate the PRA causing mutation from the respective canine line. Thus, planning of future pairings is facilitated and manifestation of this type of PRA can be prevented.

Background: The Pug is an ancient dog breed and was the fifth most commonly registered UK pedigree breed in 2014. However, the breed has been reported to be predisposed to several disorders including ocular, respiratory and dermatological problems. The VetCompass Programme collates de-identified clinical data from primary-care veterinary practices in the UK for epidemiological research. Using VetCompass clinical data, this study aimed to characterise the demography and common disorders of the general population of Pugs under veterinary care in England.

Results: Pugs comprised 2709 (1.03 %) of 264,260 study dogs under veterinary care from September 1(st), 2009 to 30(th) April, 2015. Annual proportional birth rates showed that Pugs rose from less than 1 % of annual birth cohorts before 2008 to comprise 2.8 % of the 2013 annual birth cohort. The most common colours of Pugs were fawn (63.1 %), black (27.7 %), apricot (7.6 %) and silver (2.1 %). Of the 1009 pugs under veterinary care in the study during 2013, 688 (68.19 %) had at least one disorder recorded. The most prevalent disorders recorded overall were overweight/obesity (number of events: 133, prevalence: 13.18 %, 95 % CI: 11.12-15.43), corneal disorder (88, 8.72 %, 95 % CI: 7.05-10.63) and otitis externa (76, 7.53 %, 95 % CI: 5.98-9.34). The most prevalent disorder groups were ophthalmological (n = 164, prevalence: 16.25 %, 95 % CI: 14.03-18.68), dermatological (157, 15.60 %, 95 % CI: 13.38-17.95) and aural (152, 15.06 %, 95 % CI: 12.91-17.42). The most prevalent body locations affected were the head-and-neck (n = 439, prevalence = 43.51 %, 95 % CI: 40.42-46.63) and abdomen (195, 19.33 %, 95 % CI: 16.93-21.90). The most prevalent organ systems affected were the integument (321, 31.81 %, 95 % CI: 28.15-35.72) and digestive (257, 25.47 %, 95 % CI: 22.54-28.65). The most prevalent pathophysiologic processes recorded were inflammation (386, 38.26 %, 95 % CI: 34.39-42.27) and congenital/developmental (153, 15.16 %, 95 % CI: 12.61-18.13).

Conclusions: Ownership of Pugs in England is rising steeply. Overweight/obesity, corneal disorder and otitis externa are the most common disorders in Pugs. Identification of health priorities based on VetComapss data can support evidence-based reforms to improve health and welfare within the breed.

Background: Canine patellar luxation is one of the most common orthopaedic disorders of dogs and is a potential welfare concern because it can lead to lameness, osteoarthritis and pain. However, there are limited epidemiological data on the disorder relating to the general population of dogs in England. This study aimed to investigate the VetCompass Programme database of dogs attending primary-care veterinary practices in England to report on the prevalence, risk factors and clinical management of diagnosed patellar luxation cases.

Results: The study included all dogs with at least one electronic patient record in the VetCompass database from September 1(st), 2009 to August 31(st), 2014. Candidate patellar luxation cases were identified using free-text word searching of the clinical notes and VeNom diagnosis term fields. Univariable and multivariable binary logistic regression modelling was used for risk factor analysis. The overall dataset comprised 210,824 dogs attending 119 clinics in England. The prevalence of patellar luxation diagnosis in dogs was 1.30 % (95 % confidence interval (CI) 1.21-1.39). Of the 751 incident cases, 293 (39.0 %) received medical management, 99 (13.2 %) received surgical intervention and 28 (3.7 %) were referred for further management. Multivariable modelling documented 11 breeds with increased odds of patellar luxation compared with crossbred dogs, including the Pomeranian (odds ratio [OR]: 6.5, 95 % CI 4.0-10.7, P < 0.001), Chihuahua (OR: 5.9, 95 % CI 4.4-7.9, P < 0.001), Yorkshire Terrier (OR: 5.5, 95 % CI 4.3-7.1, P < 0.001) and French Bulldog (OR: 5.4, 95 % CI 3.1-9.3, P < 0.001). Dogs with bodyweight below their mean for breed and sex had a 1.4 times odds of diagnosis (95 % CI 1.2-1.6, P < 0.001). Dogs aged ≥ 12.0 years showed 0.4 times the odds (95 % CI 0.3-0.5, P < 0.001) compared with dogs aged < 3.0 years. Females had 1.3 times the odds (95 % CI 1.1-1.5, P < 0.001), neutered dogs had 2.4 times the odds (95 % CI 1.8-3.2, P < 0.001) and insured dogs had 1.9 times the odds (95 % CI 1.6-2.3, P < 0.001).

Conclusions: Patellar luxation warrants inclusion as a welfare priority in dogs and control strategies that include this disorder should be considered as worthwhile breeding goals, especially in predisposed breeds.

Background: Valued for trainability in diverse tasks, dogs are the primary service animal used to assist individuals with disabilities. Despite their utility, many people in need of service dogs are sensitive to the primary dog allergen, Can f 1, encoded by the Lipocalin 1 gene (LCN1). Several organizations specifically breed service dogs to meet special needs and would like to reduce allergenic potential if possible. In this study, we evaluated the expression of Can f 1 protein and the inherent variability of LCN1 in two breeds used extensively as service dogs. Saliva samples from equal numbers of male and female Labrador retrievers (n = 12), golden retrievers (n = 12), and Labrador-golden crosses (n = 12) were collected 1 h after the morning meal. Can f 1 protein concentrations in the saliva were measured by ELISA, and the LCN1 5' and 3' UTRs and exons sequenced.

Results: There was no sex effect (p > 0.2) nor time-of-day effect; however, Can f 1 protein levels varied by breed with Labrador retrievers being lower than golden retrievers (3.18 ± 0.51 and 5.35 ± 0.52 μg/ml, respectively, p < 0.0075), and the Labrador-golden crosses having intermediate levels (3.77 ± 0.48 μg/ml). Although several novel SNPs were identified in LCN1, there were no significant breed-specific sequence differences in the gene and no association of LCN1 genotypes with Can f 1 expression.

Conclusions: As service dogs, Labrador retrievers likely have lower allergenic potential and, though there were no DNA sequence differences identified, classical genetic selection on the estimated breeding values associated with salivary Can f 1 expression may further reduce that potential.

Background: Next generation sequencing (NGS) has traditionally been performed by large genome centers, but in recent years, the costs for whole-genome sequencing (WGS) have decreased substantially. With the introduction of smaller and less expensive "desktop" systems, NGS is now moving into the general laboratory. To evaluate the Ion Proton system for WGS we sequenced four Chinese Crested dogs and analyzed the data quality in terms of genome and exome coverage, the number of detected single nucleotide variants (SNVs) and insertions and deletions (INDELs) and the genotype concordance with the Illumina HD canine SNP array. For each of the four dogs, a 200 bp fragment library was constructed from genomic DNA and sequenced on two Ion PI chips per dog to reach mean coverage of 6-8x of the canine genome (genome size ≈ 2.4 Gb).

Results: On average, each Ion PI chip yielded approximately 73.3 million reads with a mean read length of 130 bp (~9.5 Gb sequence data) of which 98.5 % could be aligned to the canine reference genome (CanFam3.1). By sequencing a single dog using one fragment library and two Ion PI chips, on average 80 % of the genome and 77 % exome was covered by at least four reads. After removing duplicate reads (20.7 %) the mean coverage across the whole genome was 6x. Using sequence data from all four individuals (four fragment libraries and eight Ion PI chips) the genome and exome coverage could be further increased to 97.2 and 94.3 %, respectively. We detected 4.83 million unique SNPs and 6.10 million unique INDEL positions across all individuals. A comparison between SNP genotypes detected with the WGS and the 170 K Illumina HD canine SNP array showed 90 % concordance.

Conclusions: We have evaluated whole-genome sequencing on the Ion Proton system for genetic variant detection in four Chinese crested dogs. Even though INDEL calling with Ion Proton data is challenging due to specific platform errors, in case of SNP calling it can serve as an alternative to other next-generation sequencing platforms and SNP genotyping arrays, in studies aiming to identify causative mutations for rare monogenic diseases. In addition, we have identified new genetic variants of the Chinese Crested dog that will contribute to further whole-genome sequencing studies aimed to identify mutations associated with monogenic diseases with autosomal recessive inheritance.

Background: Inbreeding is inevitable in closed populations with a finite number of ancestors and where there is selection. Therefore, management of the rate of inbreeding at sustainable levels is required to avoid the associated detrimental effects of inbreeding. Studies have shown some pedigree dog breeds to have high levels of inbreeding and a high burden of inherited disease unrelated to selection objectives, implying loss of genetic diversity may be a particular problem for pedigree dogs. Pedigree analysis of all 215 breeds currently recognised by the UK Kennel Club over the period 1980-2014 was undertaken to ascertain parameters describing the rate of loss of genetic diversity due to inbreeding, and the presence of any general trend across all breeds.

Results: The trend over all breeds was for the rate of inbreeding to be highest in the 1980s and 1990s, tending to decline after 2000. The trend was comparable in very common and rarer breeds, although was more pronounced in rarer breeds. Rates of inbreeding over the entire period 1980-2014 were not correlated with census population size. The existence of popular sires was apparent in all breeds.

Conclusion: The trends detected over 1980-2014 imply an initial excessive loss of genetic diversity which has latterly fallen to sustainable levels, even with modest restoration in some cases. The theory of genetic contributions, which demonstrates the fundamental relationship of inbreeding and selection, implies that popular sires are the major contributor to high rate of inbreeding.

Background: Urothelial carcinoma (UC), also known as transitional cell carcinoma (TCC), of the bladder is the most common neoplasm affecting the canine urogenital system. To facilitate study of the disease in vitro, cell line models have been established from primary tumor biopsies. Their resemblance to the primary disease, however, has not been well defined. In the present study, we evaluated five canine UC cell lines via oligonucleotide array comparative genomic hybridization (oaCGH), fluorescence in situ hybridization (FISH), and gene expression analysis.

Results: Comparison of genome wide DNA copy number profiles of the cell lines with primary biopsy specimens revealed redundancies in genomic aberrations, indicating that the cell lines retain the gross genomic architecture of primary tumors. As in the primary tumors, gain of canine chromosomes 13 and 36 and loss of chromosome 19 were among the most frequent aberrations evident in the cell lines. FISH analysis revealed chromosome structural aberrations, including tandem duplications, bi-armed chromosomes, and chromosome fusions, suggesting genome instability during neoplastic transformation. Gene expression profiling highlighted numerous differentially expressed genes, including many previously shown as dysregulated in primary canine UC and human bladder cancer. Pathway enrichment analysis emphasized pathways suspected to be at the crux of UC pathogenesis, including xenobiotic and lipid compound metabolism.

Conclusions: These data support valid use of the canine UC cell lines evaluated by confirming they provide an accurate and practical means to interrogate the UC at a molecular level. Moreover, the cell lines may provide a valuable model for furthering our understanding of aberrant metabolic pathways in UC development.