Roan, ticked and clear coat patterns in the canine are associated with three haplotypes near usherin on CFA38.

White coat patterning is a feature of many dog breeds and is known to be coded primarily by the gene micropthalmia-associated transcription factor (MITF). This patterning in the coat can be modified by other factors to produce the attractive phenotypes termed 'ticked' and 'roan' that describe the presence of flecks of color that vary in distribution and intensity within otherwise 'clear' white markings. The appearance of the pigment in the white patterning caused by ticking and roaning intensifies in the weeks after birth. We applied genome-wide association to compare English Cocker Spaniels of roan phenotype (N = 34) with parti-color (non-roan) English Cocker Spaniels (N = 9) and identified an associated locus on CFA 38, CFA38:11 057 040 (Praw  = 8.9 × 10-10 , Pgenome  = 2.7 × 10-5 ). A local case-control association in English Springer Spaniels comparing 11 ticked and six clear dogs identified indicative association with a different haplotype, CFA38:11 122 467G>T (Praw  = 1.7 × 10-5 ) and CFA38:11 124 294A>C (Praw  = 1.7 × 10-5 ). We characterize three haplotypes in Spaniels according to their putative functional variant profiles at CFA38:11 111 286C>T (missense), CFA38:11 131 841-11 143 239DUP.insTTAA (using strongly linked marker CFA38:11 143 243C>T) and CFA38:11 156 425T>C (splice site). In Spaniels, the haplotypes work as an allelic series including alleles (t, recessive clear; T, dominant ticked/parti-color; and TR , incomplete dominant roan) to control the appearance of pigmented spots or flecks in otherwise white areas of the canine coat. In Spaniels the associated haplotypes are t (CCT), T (TCC) and TR (TTT) for SNP markers on CFA38 at 11 111 286C>T, 11 143 243C>T and 11 156 425T>C respectively. It is likely that other alleles exist in this series and together the haplotypes result in a complex range of patterning that is only visible when dogs have white patterning resulting from the epistatic gene Micropthalmia-associated transcription factor (the S-locus).

Neuronal ceroid lipofuscinosis in Salukis is caused by a single base pair insertion in CLN8.

Neuronal ceroid lipofuscinoses (NCLs) are heterogenic inherited lysosomal storage diseases that have been described in a number of species including humans, sheep, cattle, cats and a number of different dog breeds, including Salukis. Here we present a novel genetic variant associated with the disease in this particular breed of dog. In a clinical case, a Saluki developed progressive neurological signs, including disorientation, anxiety, difficulties in eating, seizures and loss of vision, and for welfare reasons, was euthanized at 22 months of age. Microscopy showed aggregation of autofluorescent storage material in the neurons of several brain regions and also in the retina. The aggregates showed positive staining with Sudan black B and periodic acid Schiff, all features consistent with NCL. Whole genome sequencing of the case and both its parents, followed by variant calling in candidate genes, identified a new variant in the CLN8 gene: a single bp insertion (c.349dupT) in exon 2, introducing an immediate stop codon (p.Glu117*). The case was homozygous for the insertion, and both parents were heterozygous. A retrospective study of a Saluki from Australia diagnosed with NCL identified this case as being homozygous for the same mutation. This is the fourth variant identified in CLN8 that causes NCL in dogs.

A genome-wide association study identifies a region strongly associated with symmetrical onychomadesis on chromosome 12 in dogs.

Symmetrical onychomadesis causes periodic loss of claws in otherwise healthy dogs. Genome-wide association analysis in 225 Gordon Setters identified a single region associated with symmetrical onychomadesis on chromosome 12 (spanning about 3.3 mb). A meta-analysis including also English Setters indicated that this genomic region predisposes for symmetrical onychomadesis in English Setters as well. The associated region spans most of the major histocompatibility complex and nearly 1 Mb downstream. Like many other autoimmune diseases, associations of symmetrical onychomadesis with DLA class II alleles have been reported. In this study, no associated markers were revealed within any of the DLA-DRB1, -DQA1 or -DQB1 genes, and the odds for symmetrical onychomadesis in the Gordon Setters were much higher, carrying significant single nucleotide polymorphisms compared to the odds of any of the recorded DLA-DRB1/DQA1/DQB1 haplotypes. We noticed that some of the associated DLA haplotypes were different between the English Setters and the Gordon Setters. Interestingly, associated SNP chip markers showed a more consistent pattern of allelic variants related to cases or controls regardless of breed. In conclusion, the associated genetic markers identified in this study hold the potential to aid in selection of breeding animals to reduce the frequency of symmetrical onychomadesis in the dog.

Progressive retinal atrophy in Shetland sheepdog is associated with a mutation in the CNGA1 gene.

Progressive retinal atrophy (PRA) is the collective name of a class of hereditary retinal dystrophies in the dog and is often described as the equivalent of retinitis pigmentosa in humans. PRA is characterized by visual impairment due to degeneration of the photoreceptors in the retina, usually leading to blindness. PRA has been reported in dogs from more than 100 breeds and can be genetically heterogeneous both between and within breeds. The disease can be subdivided by age at onset and rate of progression. Using genome-wide association with 15 Shetland Sheepdog (Sheltie) cases and 14 controls, we identified a novel PRA locus on CFA13 (Praw  = 8.55 × 10(-7) , Pgenome  = 1.7 × 10(-4) ). CNGA1, which is known to be involved in human cases of retinitis pigmentosa, was located within the associated region and was considered a likely candidate gene. Sequencing of this gene identified a 4-bp deletion in exon 9 (c.1752_1755delAACT), leading to a frameshift and a premature stop codon. The study indicated genetic heterogeneity as the mutation was present in all PRA-affected individuals in one large family of Shelties, whereas some other cases in the studied Sheltie population were not associated with this CNGA1 mutation. To our knowledge, this is the first report of a mutation in CNGA1 causing PRA in dogs.

Glomerular Collagen V Codeposition and Hepatic Perisinusoidal Collagen III Accumulation in Canine Collagen Type III Glomerulopathy.

Collagen type III glomerulopathy, also known as collagenofibrotic glomerulopathy, is a rare renal disease of unknown pathogenesis. The disease occurs in humans and animals and is characterized by massive glomerular accumulations of collagen type III. In the present study, we describe a Drever dog litter affected by an early onset variant of this glomerular disease, where 4 of 9 puppies developed renal failure within 50 days of age. Necropsy specimens of kidney from the 4 affected cases were studied by light microscopy, electron microscopy, and immunohistochemistry, and characteristic lesions compatible with a diagnosis of collagen type III glomerulopathy were found. In addition, 2 cases showed atypical epithelium in the collecting ducts of the medulla, so-called adenomatoid change. Immunohistochemistry of renal specimens from collagen type III glomerulopathy-affected dogs (n = 10) originating from two different dog strains, the Drever dogs and a mixed-breed strain, demonstrated that the deposited glomerular collagen is composed of a mixture of collagen III and collagen V. The distribution of the collagen V corresponded to the localization of collagen III; however, differences in staining intensity showed that collagen type III is the dominating component. Immunohistochemistry for collagen III (n = 9) and a transmission electron microscopic study (n = 1) showed hepatic perisinusoidal collagen type III deposition in affected cases from both dog strains. This is the first report documenting glomerular accumulations of collagen type V and perisinusoidal liver collagen III deposition in canine collagen type III glomerulopathy.

Lumbosacral transitional vertebra in 14 dog breeds in Norway: Occurrence, risk factors and association with hip dysplasia.

A lumbosacral transitional vertebra (LTV) is a congenital anomaly of the spine and has been suggested to predispose to canine hip dysplasia (CHD). This retrospective, cross-sectional study investigated the prevalence of LTV and CHD among 14 dog breeds in Norway, the possible associations with risk factors, and whether LTV was a risk factor for the development of hip dysplasia. The results were based on evaluation of ventrodorsal radiographs from the CHD screening program from the Norwegian Kennel Club from February 2014 to January 2022. A total of 13,950 dogs were included in the study. For statistical analysis, CHD grades were reclassified from the official Federation Cynologique Internationale (FCI) grades into three grades: CHD free (CHD=A, B), CHD mild (CHD=C), and CHD severe (CHD=D, E). In the study sample, the overall occurrence of LTV was 18.5%, of which 32.9% were type 1, 45.7% type 2% and 21.4% type 3. The occurrence of LTV varied significantly among the included breeds, ranging from 9.5% to 46.2%. There was no association between sex and LTV. The frequencies of CHD grades were A: 43.1%; B: 31.4%; C: 18.4%; D: 6.0%; E: 1.1%. There was a statistically significant association with mild and severe CHD in dogs with LTV type 2 and LTV type 3 (P< 0.001). In the population studied, the prevalence of LTV was different among breeds. This supports initial data on the heredity of LTV and the diverse occurrence of LTV among breeds. Our results indicate that LTV type 2 and type 3 are associated with mild and severe CHD development. Therefore, this study has potentially identified an additional risk factor for the development of hip dysplasia.

Breed distributions for diabetes mellitus and hypothyroidism in Norwegian dogs.

BACKGROUND: Diabetes mellitus (DM) and hypothyroidism are common canine endocrinopathies. Both canine DM and primary hypothyroidism are assumed to originate from autoimmune destruction of the respective endocrine glands and have been associated with the major histocompatibility complex (MHC) gene region. This study aims to investigate breed distributions for DM and hypothyroidism in the Norwegian canine population by calculating odds ratios (OR) from two different comparator groups. METHODS: Results from canine serum samples submitted from 2001 to 2018 to the Veterinary Clinical Pathology Laboratory (VCPL) at the Faculty of Veterinary Medicine, Norwegian University of Life Sciences for analysis of fructosamine and thyroid hormones in serum were used as cases in a retrospective bivariate analysis of canine breeds. The ORs were calculated as a measure of risk for the included breeds, where all the submitted blood samples to the VCPL and dogs registered in the Norwegian Kennel Club (NKK), the national organization for dog owners, were used as two comparator groups. RESULTS: Significant differences in disease prevalence between breeds were discovered using both comparator groups. Australian terrier, Swedish lapphund, Samoyed, and Schipperke were at highest risk for DM. German Shepherd, Golden retriever, German pointing dog, and Collie presented as the breeds with lowest risk for DM. For hypothyroidism, Schnauzer, Eurasier, Dunker, and English setter were at highest risk for developing the disease. The breeds at lowest risk of developing hypothyroidism were Rottweiler, Dachshund, German shepherd, and Border collie. The results from the different comparator groups gave different ORs and ranks, but the breeds with highest and lowest odds showed the same susceptibility using both comparators. CONCLUSIONS: These findings support that there are breeds more and less prone to develop DM and hypothyroidism. A strong genetic predisposition involved in the aetiology of these two diseases is therefore likely. Interestingly, there also appeared to be an inverse relationship of odds for the two diseases for some of the breeds since some breeds that had a high OR for DM or hypothyroidism had a lower OR for the other disease. This indicates that there may be different risk alleles/haplotypes for the two diseases. The possible aetiological relationship between canine DM and hypothyroidism should be further investigated.

A population study of a mutation allele associated with cone-rod dystrophy in the standard wire-haired dachshund.

Cone-rod dystrophy in the standard wire-haired dachshund (SWHD) is inherited as a simple autosomal recessive trait and the recently discovered mutation is widespread within the SWHD population in Norway and other Scandinavian countries. The gene frequency was estimated to be 4.8%. On the basis of the assumption that the size of the ancestral haplotype around a mutation is inversely correlated with the number of generations since the mutation arose, we have found that the mutation is of a relatively recent origin. The conserved haplotype was found to be 8 Mb in size and therefore we estimate that the mutation arose roughly eight generations (approximately 37 years) ago. This indicates that the mutation arose after breed separation.

A study of inherited short tail and taillessness in Pembroke Welsh corgi.

OBJECTIVES: To study whether natural short tail in adult Pembroke Welsh corgi is associated with congenital spinal defects. To report anatomical defects in two newborn tailless puppies from short-tailed parents, and to check whether they were homozygous for the dominant mutation in the T-gene (C295G). METHODS: The vertebral column of 19 adult dogs with natural short tail, from short-tail x long-tail crossings, was radiographically examined. Two tailless puppies were radiographed and submitted for necropsy. Samples from the puppies, their parents and five siblings were analysed for the mutation of the T-gene. RESULTS: No congenital spinal defects were diagnosed in any of the short-tailed dogs. The tailless puppies had anorectal atresia, had multiple spinal defects and were homozygous for the mutation in the T-gene. CLINICAL SIGNIFICANCE: As tail docking is forbidden in many countries, breeding Pembroke Welsh corgis with natural short tail is becoming increasingly common. Previous studies indicated that the mutation in homozygotes is lethal in early fetal life. It is of clinical significance that natural short tail is probably not associated with congenital spinal defects, as is known from studies of other species, and that homozygotes for this mutation with serious anatomical defects may be born.

A statistical assessment of the biological relationship between simultaneous canine mammary tumours.

Simultaneous canine mammary tumours (CMTs) are frequently reported in the literature, but few studies have addressed their biological relationship in detail or performed statistical assessments. In this study, 269 canine mammary gland tumours from 216 dogs were categorized using an extended histopathological classification, where semiquantitative and binomial scales enumerated morphological parameters of the tumours. The classification facilitated a statistical study of the biological relationship between simultaneous within-dog tumours. Seventy-seven percent of the dogs had single tumours and 23% had simultaneous tumours. Sixty-one percent of the neoplasias were benign, with complex adenoma as the most frequent diagnosis and 39% were malignant, with complex carcinoma as the most common malignancy. Simultaneous tumours within dogs more often had equal diagnoses and neoplastic level (benign or malignant) than would be expected by chance alone, as compared with random pairs of single tumours from different dogs. This statistically supported finding indicated the presence of a biological relationship between simultaneous tumours.

Renal microcystic tubular lesions in two 1Year-old dogs - an early sign of hereditary renal cystadenocarcinoma?

As a part of a study of early renal changes in renal cystadenocarcinoma (RC), a 5-year-old German shepherd dog and two 1-year-old German shepherd mixed-breed dogs were examined. All three animals had bilateral, microscopic renal cysts, and the 5-year-old dog also had RC. Microscopical examination showed papillary hyperplastic tubular epithelial cells lining the inner wall of the renal cysts in all dogs. These cells showed strong reactivity with a monoclonal antibody against a broad-spectrum type of cytokeratin. The dam of the young dogs had suffered from autosomal dominant inherited RC and nodular dermatofibrosis (ND) syndrome. It is likely that the microscopic renal cystic lesions seen in the young dogs represented an early renal change in the RC/ND syndrome. This suggests that the diagnosis of RC can be made on suspected carriers by microscopical examination of renal biopsies as early as 1 year of age, i.e., before the dogs are used for breeding.

Turbidimetric measurement of immunoglobulin G in serum using an automatic centrifugal analyser.

Turbidimetry and radial immunodiffusion techniques are compared for measuring the average amounts of IgG in serum from healthy sheep, swine and chickens using different rabbit antisera. The correlation coefficients (r) between the IgG values measured by the two techniques, were high; r greater than 0.97. Turbidimetric measurement was found to be a reliable, rapid and simple method for IgG determination in serum.

Epidemiological and genetical studies in Norwegian pig herds. IV. Breed effects, recurrence of disease, and relationship between disease and some performance traits.

Individual health records collected from 1984 to 1986 in 70 swine-herds in the south-eastern part of Norway were analysed by epidemiological methods. The incidence rate for most of the reported diseases was less than 1% per farrowing, and a majority of disease recordings concerned 6 frequently-occurring conditions. The incidence of several diseases was lower in crossbred sows compared to purebred Norwegian landrace sows. The risk of most diseases increased in sows that had been ill previously, and also in litters from sows that had previously had diseased litters. Disease risk in piglets also increased if the sow became ill during the first few days after farrowing. The reduced performance associated with most of the common diseases impacts adversely on economic returns.

Epidemiological and genetical studies in Norwegian pig herds. III. Herd effects.

Herd differences in disease incidence in 70 Norwegian pig herds were assessed by health card registrations. Such differences proved to be considerable. The incidence of the MMA-syndrome, mastitis, metritis and neonatal diarrhoea was higher in herds producing only weaners ("weaner herds") than in herds with combined production. The mean disease incidence in herds providing breeding stock for the Norwegian Pig Breeders' Association ("breeding herds") was at the same level as in ordinary combined production herds. There was no consistent relationship between changes in disease incidence and herd size, though the incidence of the MMA-syndrome was lower in the largest herds.

Epidemiological and genetical studies in Norwegian pig herds. V. Estimates of heritability and phenotypic correlations of the most common diseases in Norwegian pigs.

A genetic analysis was performed on disease registrations from 70 Norwegian pig herds. This analysis was complicated by the small degree of cross classification of dams and sires across herds, and the relatively sparse use of artificial insemination. Herd effects seemed to be responsible for much of the variation in disease frequencies. The estimated heritabilities were relatively low. The results of this investigation also revealed positive phenotypic correlations between the investigated diseases.

Epidemiological and genetical studies in Norwegian pig herds. II. Overall disease incidence and seasonal variation.

The present epidemiological study is based on individual health records from 1984 to 1986 in 70 pig herds in the south-eastern part of Norway. For most of the recorded diseases, the incidence rate was less than 1% per farrowing. The majority of disease recordings concerned 6 frequently-occurring conditions; the MMA-syndrome, mastitis, metritis, neonatal diarhoea, arthritis and scrotal hernia. A seasonal effect on the incidence rate was shown for several diseases. The incidence rate for the MMA-syndrome of about 17.5% seems to be of the highest recorded for this disease in a population study.

Epidemiological and genetical studies in Norwegian pig herds. I. Design of a disease recording system.

The study was based on 70 pig herds in the south-eastern part of Norway during the period from 1984 to 1986. The purpose was to design a health card system based on individual disease records covering diseases in sows, piglets and slaughter pigs. It is concluded that individual health records on a herd basis may well be suited for use in epidemiological and genetical studies of disease frequencies and disease resistance. Feedback of results to farmers and veterinarians seems to be important for satisfactory follow-up in the herds.

Spondylosis deformans in the boxer: estimates of heritability.

This study presents the estimates of heritability for spondylosis deformans in the boxer based on 353 offspring from 24 randomly selected sires, each with at least three radiographically investigated offspring. The estimated heritability (h2) for maximum degree of osteophyte development was high, both when estimated by paternal half-sib correlation (0.42) and by the regression of offspring based on the parents (0.62). The heritability for the number of affected discs estimated by paternal half-sib correlation was also high (0.47). The estimate of heritability for the number of affected discs based on regression of offspring on the parents was lower at 0.13. All heritabilities had large standard errors. A positive phenotypic correlation between spondylosis deformans and hip dysplasia was observed. Assuming a significant portion of the correlation is genetic, this fact may permit selection against spondylosis deformans without negatively influencing the incidence of hip dysplasia. Since the incidence of spondylosis deformans is high even in young dogs, it should be possible to detect a large proportion of genetically predisposed animals by radiographic examination of the spine at one year of age; at the same time that dogs are presented for a routine test for hip dysplasia.

Identification of genetic variation in 11 candidate genes of canine mammary tumour.

The incidence of canine mammary tumours (CMTs) differs significantly between breeds, strongly supporting an influence of genetic risk factors. We aimed at identifying germline genetic variations in mammary tumour-associated genes in dogs and survey whether these might alter the encoded proteins. We sequenced 11 genes (BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EGFR, ESR1, HER2, PTEN, STK11 and TP53) and screened for genetic variations. Sixty-four single nucleotide polymorphisms (SNPs) were identified. Nine of the coding SNPs were non-synonymous, of which four were located in gene regions conserved across four species. Three of the non-synonymous SNPs might be damaging according to PolyPhen predictions. One of the indels identified has previously been associated with CMTs. Because of the founder effects, genetic drift and inbreeding in many dog breeds the allele frequencies of the genes studied are likely to vary significantly between breeds and contribute to the considerable difference in genetic risk associated with cancer.

Association of dopamine- and serotonin-related genes with canine aggression.

Human-directed canine aggression was studied using 50 aggressive and 81 non-aggressive dogs. We examined 62 single nucleotide polymorphisms (SNPs) occurring in or in the close vicinity of 16 neurotransmitter-related genes. Allelic associations with aggression were identified for DRD1, HTR1D, HTR2C and SLC6A1. Risk or protective haplotypes for aggressive behaviour based on 2-5 SNPs were identified. The frequency of aggressive dogs varied significantly between the haplotypes within loci and the odds ratios of aggression in dogs with risk haplotypes compared with protective haplotypes varied from 4.4 (HTR2C) to 9.0 (SLC6A1). A risk haplotype across the neurotransmitter receptor gene HTR1D harboured a non-synonymous SNP with a potential effect on protein function. We identified no haplotypes in complete association with the recorded phenotypes, supporting a complex inheritance of aggression.