Multiple loci associated with canine hip dysplasia (CHD) in German shepherd dogs

Canine hip dysplasia (CHD) is the most common hereditary skeletal disorder in dogs. To identify common alleles associated with CHD, we developed 37 informative single nucleotide polymorphisms (SNPs) within 13 quantitative trait loci (QTL) previously identified for German shepherd dogs. These SNPs were genotyped in 95 German shepherd dogs affected by CHD and 95 breed, sex, and birth year-matched controls. A total of ten SNPs significant at a nominal P value of 0.05 were validated in 843 German shepherd dogs including 277 unaffected dogs and 566 CHD-affected dogs. Cases and controls were sampled from the whole German shepherd dog population in Germany in such a way that mean coancestry coefficients were below 0.1 % within cases and controls as well as among cases and controls. We identified nine SNPs significantly associated with CHD within five QTL on dog chromosomes (CFA) 3, 9, 26, 33, and 34. Genotype effects of these nine SNPs explained between 22 and 34 % of the phenotypic variance of hip dysplasia in German shepherd dogs. The strongest associated SNPs were located on CFA33 and 34 within the candidate genes PNCP, TRIO, and SLC6A3. Thus, the present study validated positional candidate genes within five QTL for CHD.     

Mapping quantitative trait loci for canine hip dysplasia in German Shepherd dogs

Canine hip dysplasia (CHD) is a common hereditary developmental disease of the coxofemoral joints. CHD is characterized by subluxation of the femoral head and deformation of the acetabulum leading to a painful osteoarthrosis. Analyses of mode of inheritance have shown the involvement of a major gene in expression of CHD in German Shepherd dogs. Thus, a whole genome scan for quantitative trait loci (QTL) was performed in German Shepherd dogs. For this purpose 11 paternal half-sib families, including a total of 459 purebred German Shepherd dogs with sires, dams, and offspring, were genotyped for 261 microsatellites. These markers were equidistantly distributed over all 38 autosomes and the X chromosome with an average marker distance of 11.7 cM. The mean observed heterozygosity of the marker set was 50%. The CHD status for the dogs was scored according to the official rules of the Fédération Cynologique Internationale. At the genome-wide level of significance at p < 0.05, QTL for CHD were located on nine different canine chromosomes: 1, 3, 4, 8, 9, 16, 19, 26, and 33. The minimal QTL regions containing the CHD genes spanned on average 5 Mb with a range between 1 and 8.2 Mb. Chromosome-wide level of significance at p < 0.05 was found for QTL on 19 chromosomes. Further analyses can now be performed to refine these map positions of QTL already identified in German Shepherd dogs. Electronic supplementary material The online version of this article (doi: ) contains supplementary material, which is available to authorized users.     

Association of polymorphisms in the dopamine D4 receptor gene and the activity-impulsivity endophenotype in dogs

A variable number of tandem repeats (VNTR) polymorphism in exon 3 of the human dopamine D4 receptor gene ( DRD4 ) has been associated with attention deficit hyperactivity disorder (ADHD). Rodents possess no analogous repeat sequence, whereas a similar tandem repeat polymorphism of the DRD4 gene was identified in dogs, horses and chimpanzees. Here, we present a genetic association study of the DRD4 VNTR and the activity-impulsivity dimension of the recently validated dog-ADHD Rating Scale. To avoid false positives arising from population stratification, a single breed of dogs (German shepherd) was studied. Two DRD4 alleles (referred to as 2 and 3a ) were detected in this breed, and genotype frequencies were in Hardy–Weinberg equilibrium. For modelling distinct environmental conditions, 'pet' and 'police' German shepherds were characterized. Police German shepherds possessing at least one 3a allele showed significantly higher scores in the activity-impulsivity dimension of the dog-ADHD Rating Scale than dogs without this allele ( P  = 0.0180). This difference was not significant in pet German shepherds. To the best of our knowledge, this is the first report of an association between a candidate gene and a behaviour trait in dogs, and it reinforces the functional role of DRD4 exon 3 polymorphism.     

Identification and Validation of Quantitative Trait Loci (QTL) for Canine Hip Dysplasia (CHD) in German Shepherd Dogs

Canine hip dysplasia (CHD) is the most common hereditary skeletal disorder in dogs. To identify common alleles associated with CHD, we genotyped 96 German Shepherd Dogs affected by mild, moderate and severe CHD and 96 breed, sex, age and birth year matched controls using the Affymetrix canine high density SNP chip. A mixed linear model analysis identified five SNPs associated with CHD scores on dog chromosomes (CFA) 19, 24, 26 and 34. These five SNPs were validated in a by sex, age, birth year and coancestry stratified sample of 843 German Shepherd Dogs including 277 unaffected dogs and 566 CHD-affected dogs. Mean coancestry coefficients among and within cases and controls were <0.1%. Genotype effects of these SNPs explained 20–32% of the phenotypic variance of CHD in German Shepherd Dogs employed for validation. Genome-wide significance in the validation data set could be shown for each one CHD-associated SNP on CFA24, 26 and 34. These SNPs are located within or in close proximity of genes involved in bone formation and related through a joint network. The present study validated positional candidate genes within two previously known quantitative trait loci (QTL) and a novel QTL for CHD in German Shepherd Dogs.     

A regressive model analysis of congenital sensorineural deafness in German Dalmatian dogs

The objective of the present study was to analyze the mode of inheritance for congenital sensorineural deafness (CSD) in German Dalmatian dogs by consideration of association between phenotypic breed characteristics and CSD. Segregation analysis with regressive logistic models was employed to test for different mechanisms of genetic transmission. Data were obtained from all three Dalmatian kennel clubs associated with the German Association for Dog Breeding and Husbandry (VDH). CSD was tested by veterinary practitioners using standardized protocols for Brainstem Auditory-Evoked Response (BAER). The sample included 1899 Dalmatian dogs from 354 litters in 169 different kennels. BAER testing results were from the years 1986 to 1999. Pedigree information was available for up to seven generations. The segregation analysis showed that a mixed monogenic-polygenic model including eye color as covariate among all other tested models best explained the segregation of affected animals in the pedigrees. The recessive major gene segregated in dogs with blue and brown eye color as well as in dogs with and without pigmented coat patches. Models which took into account the occurrence of patches, percentage of puppies tested per litter, or inbreeding coefficient gave no better adjustment to the most general (saturated) model. A procedure for the simultaneous prediction of breeding values and the estimation of genotype probabilities for CSD is expected to improve breeding programs significantly.     

Complex segregation analysis of dilated cardiomyopathy (DCM) in Irish wolfhounds

The objective of the present study was to analyse the mode of inheritance for dilated cardiomyopathy (DCM) in Irish wolfhounds using regressive logistic models by testing for mechanisms of genetic transmission. Insights from this spontaneous animal model should aid importantly in understanding basic pathogenic mechanisms with regard to genetics and molecular biology of DCM in humans. Moreover, a procedure for the simultaneous prediction of breeding values and the estimation of genotype probabilities for DCM is expected to markedly improve breeding programmes. Results of cardiovascular examinations of 1018 dogs carried out between 1987 and 2003 by one veterinarian were analysed. Data of 878 dogs from 531 litters in 147 different kennels were used for complex segregation analyses. Pedigree information was available for more than 15 generations. Male dogs were affected significantly more often by DCM than female dogs. The segregation analysis showed that among all other tested models a mixed monogenic-polygenic model including a sex-dependent allele effect best explained the segregation of affected animals in the pedigrees. A pure monogenic inheritance of DCM could be significantly rejected in favour of the major gene and most general model. The gene action of the major gene was significantly different between female and male dogs.     

Cloning, characterization, and physical mapping of the canine Prop-1 gene (PROP1): exclusion as a candidate for combined pituitary hormone deficiency in German shepherd dogs

Abnormalities in the genes encoding Pit-1 and Prop-1 have been reported to cause combined pituitary hormone deficiency (CPHD) in mice and humans. In dogs, a similar phenotype has been described in the German shepherd breed. We have previously reported that the Pit-1 gene (POU1F1) is not mutated in affected German shepherd dogs. In this study, we report the isolation and mapping of the canine Prop-1 gene (PROP1), and we assessed the involvement of PROP1 in German shepherd dog dwarfism. The canine PROP1 gene was found to contain three exons, encoding a 226 amino acid protein. The deduced amino acid sequence was 79% and 84% homologous with the mouse and human Prop-1 protein, respectively. Using fluorescence in situ hybridization, PROP1 was mapped to canine chromosome 11. Further mapping with a canine radiation hybrid panel showed co-localization with the polymorphic DNA marker AHT137. Sequence analysis of genomic DNA from dwarf German shepherd dogs revealed no alterations in the PROP1 gene. Moreover, linkage analysis of AHT137 revealed no co-segregation between the PROP1 locus and the CPHD phenotype, excluding this gene as candidate for canine CPHD and providing a new spontaneous model of hypopituitarism.     

Erythrocyte surface sialic acid levels of clinically healthy mongrel and exotic (alsatian and terrier) breeds of dogs

The erythrocyte surface sialic acid concentration of clinically healthy mongrel and exotic (Alsatian i.e. German shepherd and Terrier) breeds of dogs was analyzed in order to determine their role in the genetic resistance of these breeds of dogs to diseases that cause anaemia. The mean erythrocyte surface sialic acid (ESA) concentration was 57.08 ± 1.67, 34.50 ± 2.30 and 20.20 ± 3.54 mg/dl for Mongrel, Alsatian (German shepherd) and Terrier breeds of dogs, respectively, on acid hydrolysis. The mean values of ESA obtained following enzymic hydrolysis of haemoglobin-free erythrocyte membranes using Clostridium chauvoei (Jakari strain) sialidase were 49.08 ± 0.41, 30.97 ± 1.82 and 18.64 ± 0.75 mg/dl for Mongrel, Alsatian (German shepherd) and Terrier dogs respectively. When Trypanosoma vivax sialidase was used the ESA values obtained were 50.81 ± 0.37, 41.70 ±  0.94 and 19.65 + 0.65 mg/dl for Mongrel, Alsatian (German shepherd) and Terrier breeds of dogs respectively. This represents a statistically significant difference (P < 0.001) between the mean ESA concentration of all the breeds of dogs investigated in this study. The higher mean ESA concentration in Mongrel dogs, compared to the exotic breeds may be responsible for their resistance to disease conditions, whose aetiologic agents produce neuraminidase and also cause anaemia.     

Linkage analysis and the inheritance of arches in a Habbanite isolate.

A pedigree and linkage analysis was performed on a corrected version of the Habbanite pedigree 2 of Slatis et al. [1]. The trait "arch on any digit" was examined for major gene inheritance and possible linkage to several blood and serum group markers. The results confirm the proposed dominant major gene inheritance of this trait with almost complete penetrance. In addition, the analysis suggests linkage with the haptoglobin locus with evidence against linkage with Pl and Rhesus. These results are of particular interest in view of recently reported dermatoglyphic associations with haptoglobin.     

The genetic contribution to canine personality

The domestic dog may be exceptionally well suited for behavioral genetic studies owing to its population history and the striking behavior differences among breeds. To explore to what extent and how behavioral traits are transmitted between generations, heritabilities and genetic correlations for behavioral traits were estimated in a cohort containing over 10,000 behaviorally tested German shepherd and Rottweiler dogs. In both breeds, the pattern of co-inheritance was found to be similar for the 16 examined behavioral traits. Furthermore, over 50% of the additive genetic variation of the behavioral traits could be explained by one underlying principal component, indicating a shared genetic component behind most of the examined behavioral traits. Only aggression appears to be inherited independently of the other traits. The results support a genetic basis for a broad personality trait previously named shyness-boldness dimension, and heritability was estimated to be 0.25 in the two breeds. Therefore, breeds of dogs appear to constitute a valuable resource for behavioral genetic research on the normal behavioral differences in broad personality traits.     

Heritability and phenotypic variation of canine hip dysplasia radiographic traits in a cohort of Australian German shepherd dogs

Canine Hip Dysplasia (CHD) is a common, painful and debilitating orthopaedic disorder of dogs with a partly genetic, multifactorial aetiology. Worldwide, potential breeding dogs are evaluated for CHD using radiographically based screening schemes such as the nine ordinally-scored British Veterinary Association Hip Traits (BVAHTs). The effectiveness of selective breeding based on screening results requires that a significant proportion of the phenotypic variation is caused by the presence of favourable alleles segregating in the population. This proportion, heritability, was measured in a cohort of 13,124 Australian German Shepherd Dogs born between 1976 and 2005, displaying phenotypic variation for BVAHTs, using ordinal, linear and binary mixed models fitted by a Restricted Maximum Likelihood method. Heritability estimates for the nine BVAHTs ranged from 0.14-0.24 (ordinal models), 0.14-0.25 (linear models) and 0.12-0.40 (binary models). Heritability for the summed BVAHT phenotype was 0.30 ± 0.02. The presence of heritable variation demonstrates that selection based on BVAHTs has the potential to improve BVAHT scores in the population. Assuming a genetic correlation between BVAHT scores and CHD-related pain and dysfunction, the welfare of Australian German Shepherds can be improved by continuing to consider BVAHT scores in the selection of breeding dogs, but that as heritability values are only moderate in magnitude the accuracy, and effectiveness, of selection could be improved by the use of Estimated Breeding Values in preference to solely phenotype based selection of breeding animals.     

Epizootiology of tropical canine pancytopenia

Tropical canine pancytopenia (TCP) is a newly recognized infectious disease of dogs in diverse tropical and subtropical areas. The disease is characterized by hemorrhage, pancytopenia, severe emaciation and persistent infection. Dogs with TCP are often presented with epistaxis, which is the most dramatic sign of the disease; however, a large number of affected dogs develop severe pancytopenia and die without manifesting clinical signs of hemorrhage. The disease has been reported most frequently in the German Shepherd. Pathological findings consist of petechial and ecchymotic hemorrhages on serosal and mucosal surfaces of numerous organs. The most prominent histological finding is a perivascular plasma cell infiltrate in most organs. Disease, indistinguishable from the natural disease, has been produced in laboratory dogs inoculated with whole blood from affected dogs. Ehrlichia canis has been consistently recovered from all experimentally infected dogs. Attempts to transmit the disease to other laboratory animals and to propagate the agent in cell cultures and embryonating eggs have been unsuccessful. The tick is the probable vector of the disease.     

Segregation analysis of restless legs syndrome: possible evidence for a major gene in a family study using blinded diagnoses

OBJECTIVE: The objective of this study was to ascertain the most likely inheritance pattern of restless legs syndrome (RLS) using segregation analysis. METHODS: Probands were RLS patients presenting to the Neurology and Sleep clinics of the Johns-Hopkins Bayview medical center with willing first and second degree relatives. Blinded diagnosis was made in those who exhibited the four diagnostic features of RLS. Analysis was performed on RLS as a dichotomous trait and considering age of onset models on 590 phenotyped subjects from 77 pedigrees. RESULTS: All non-genetic models were rejected considering RLS as a dichotomous trait. A single locus Mendelian dominant model with gender as a covariate had best fit with allele frequency of 0.077 and complete penetrance. RLS frequency in non-carrier subjects was estimated to be 0.14. Two underlying distributions of age of onset, with a possible dichotomy at 26.3 years, were identified. Contrary to the results for RLS as a dichotomous trait, age of onset models did not indicate single major gene inheritance. CONCLUSION: This segregation analysis suggests that the pattern of segregation is consistent with that of a single major locus, when RLS is treated as a dichotomous trait without considering age of onset. The high rate of phenocopies matches known population frequencies and taken with significant residual familial effects and the lack of evidence for a major gene controlling age of onset, indicates that non-genetic causes of RLS may exist and RLS is a complex disorder.     

辣椒株高遗传分析

以辣椒矮秆自交系B9431（P1）和高秆自交系‘吉林长椒’（P2）为双亲,构建P1、F1、P1、B1、B2和F2 6个家系世代群体,应用植物数量性状主基因＋多基因混合遗传模型对该6个世代群体株高进行多世代联合分析,结果显示：株高遗传符合1对主基因＋多基因遗传模型,高秆对矮秆表现为不完全显性,F1代株高的势能比值为0．39,显性程度为0．91。B1、B2和F2群体主基因遗传率分别为20．35％、17．20％和35．29％,多基因遗传率分别为5．08％、19．75％和0;主基因效应表现为负向加性效应,其值为-6．43,显性效应为0;多基因加性效应值和显性效应值分别为-8．89和9．77。研究还表明,主基因与多基因间的基因效应存在一定差异,主基因加性效应值相当于多基因加性效应值的72．33％,主基因无显性效应,显性效应是由多基因控制遗传。     

An indication of major genes affecting hip and elbow dysplasia in four Finnish dog populations

The aim of the study was to assess the possible existence of major genes influencing hip and elbow dysplasia in four dog populations. A Bayesian segregation analysis was performed separately on each population. In total, 34 140 dogs were included in the data set. Data were analysed with both a polygenic and a mixed inheritance model. Polygenic models included fixed and random environmental effects and additive genetic effects. To apply mixed inheritance models, the effect of a major gene was added to the polygenic models. The major gene was modelled as an autosomal biallelic locus with Mendelian transmission probabilities. Gibbs sampling and a Monte Carlo Markov Chain algorithm were used. The goodness-of-fit of the different models were compared using the residual sum-of-squares. The existence of a major gene was considered likely for hip dysplasia in all the breeds and for elbow dysplasia in one breed. Several procedures were followed to exclude the possible false detection of major genes based on non-normality of data: permuted datasets were analysed, data-transformations were applied, and residuals were judged for normality. Allelic effects at the major gene locus showed nearly to complete dominance, with a recessive, unfavourable allele in both traits. Relatively high estimates of the frequencies of unfavourable alleles in each breed suggest that considerable genetic progress would be possible by selection against major genes. However, the major genes that are possibly affecting hip and elbow dysplasia in these populations will require further study.     

Progressive myelopathy in older German shepherd dogs. II. Presence of circulating suppressor cells

Progressive myelopathy in the German shepherd dog is a degenerative neurologic disease of unknown etiology. Results presented in a previous study indicated a depression in the response to thymus-dependent mitogens by peripheral blood leukocytes obtained from dogs with progressive myelopathy. Data presented here indicate that this depressed response to mitogens was associated with the presence of peripheral blood suppressor cells. Suppressor cell activity was detected in dogs that were severely affected with PM, but was not apparent in dogs that were mildly affected. Peripheral blood leukocytes obtained from dogs with progressive myelopathy suppressed the mitogenic response to autologous lymph node cells as well as allogeneic normal canine peripheral blood cells. The suppressor cells had the capacity to suppress mixed leukocyte reactions. Suppressor cell activity was radioresistant. Both nylon wool-adherent and -nonadherent peripheral blood leukocyte populations contained suppressor activity. Suppressive activity diminished after incubation of the suppressor cells with indomethacin, suggesting that suppression may be mediated by the release of prostaglandins. Although a role for peripheral blood suppressor cells in the disease process has not yet been established, it is possible that this abnormal regulatory activity reflects an attempt by the host to control an autoimmune event.     

Genetic evaluation with data presenting evidence of mixed major gene and polygenic inheritance

Summary A procedure for genetic evaluation with field data is proposed for situations in which there is mixed major gene and polygenic inheritance and the major genotype membership of some or of all individuals is unknown. Location parameters (fixed environmental, major genotype and polygenic effects), major genotype frequencies and variance components are estimated by the modal values of joint and marginal posterior distributions. The method is described for continuous and discontinuous data as well as for univariate and multivariate evaluations. Results from a simulation study are presented.Journal Paper No. J-12728 of the Iowa Agriculture and Home Economics Experiment Station, Ames, Iowa. Project No. 1901     

Detection of major gene for Gilles de la Tourette syndrome

The families of 250 consecutive, unselected patients with Tourette syndrome (TS) were analyzed. If the parents had either motor or vocal tics, but not both, there was an increased risk of both TS and tics in the offspring. The mode of inheritance of the combined tic-Tourette trait was evaluated in both nuclear families and extended pedigrees. Complex segregation analysis was carried out allowing for possible contributions from both a major autosomal locus and multifactorial inheritance of variation in the background of each genotype. The most likely mode of inheritance was a major semidominant gene, Ts, with low heritability of the multifactorial background variation. This was true regardless of assumptions about the prevalence of the disorder. The hypothesis of strict multifactorial inheritance could not be rejected with nuclear family data alone. However, the hypothesis of no major gene effect was rejected using data on 3 generations for any estimate of lifetime risk less than 12 per 1,000 in the general population. A pure recessive major gene effect was also rejected. With a gene frequency of approximately .5%, the penetrance was estimated to be about 94% in abnormal Ts/Ts homozygotes, 50% in Ts/ts heterozygotes, and less than 0.3% in normal ts/ts homozygotes. More than two of every three cases are heterozygotes, and nearly all other cases are phenocopies or new mutations. This is the first demonstration by segregation analysis of a major gene in a human neuropsychiatric disorder with a frequency approaching 1% of the population.     

Seroprevalence of antibodies to Neospora caninum in dogs from Spain

The prevalence of Neospora caninum antibodies was determined in sera of 139 dogs from Catalonia (northeastern Spain) using the indirect immunofluorescence antibody test (IFAT). Antibodies in the IFAT were found in 17 of 139 dogs (12.2%) with titers ranging from 1:50 to 1: 1,600. Seroprevalence was higher in dogs over 1 yr old compared with dogs younger than 1 yr (P < 0.05). No statistical difference was observed when sex, breed, purpose, or modus vivendi was compared with seropositivity. Most dogs had low antibody titers, which indicated subclinical infection in the area studied. No neosporosis-related disease was reported from any dog, although a German shepherd with an antibody titer of 1:800 showed pododermatitis. All sera were also screened using a commercial direct agglutination test (DAT). The DAT showed a similar specificity but a lower sensitivity when compared with IFAT as a reference technique.