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Sökning: WFRF:(Lindblad Kerstin)

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1.
  • Ahlgren, Kerstin. M, et al. (författare)
  • Diabetes mellitus in dog - : No evidence for a type-1-like phenotype
  • Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
    • Aims/hypothesis Diabetes mellitus (DM) is one of the most common endocrine disorders in dogs, and is commonly proposed to be of autoimmune origin. Although the clinical symptoms of human type 1 diabetes (T1D) and canine DM are similar, the aetiologies may differ. The aim of this study was to investigate if autoimmune aetiology resembling human T1D is as prevalent in dogs as previously reported. Methods  Sera from 121 diabetic dogs representing 38 different breeds were tested for islet cell antibodies (ICA) and GAD65 autoantibodies (GADA) and compared with sera from 133 healthy dogs from 40 breeds. ICA was detected by indirect immunofluorescence using both canine and human frozen sections. GADA was detected by in vitro transcription and translation (ITT) of human and canine GAD65, followed by immunoprecipitation. Results None of the canine sera analyzed tested positive for ICA on sections of frozen canine or human ICA pancreas. However, serum from one diabetic dog was weakly positive in the canine GADA assay and serum from one healthy dog was weakly positive in the human GADA assay. Conclusions/interpretations Based on sera from 121 diabetic dogs from 38 different breeds were tested for humoral autoreactivity using four different assays, contrary to previous observations, we find no support for an autoimmune aetiology  in canine diabetes.
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2.
  • Ahlgren, Kerstin M. (författare)
  • Immunological Studies using Human and Canine Model Disorders
  • 2011
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • The studies presented in this thesis focus on human and canine models for autoimmune disease, with the main aim to gain new knowledge about disease mechanisms and to further evaluate the dog as a model for autoimmune disease. Autoimmune Polyendocrine Syndrome type 1 (APS-1) is a hereditary human multiorgan disease caused by mutations in the autoimmune regulator (AIRE) gene. Hallmarks of APS-1 are chronic mucocutaneous candidiasis caused by Candida albicans, together with the autoimmune endocrine disorders hypoparathyroidism and adrenocortical failure. Many human diseases have an equivalent disease in dogs. Because humans share environment, and in part life style with the dogs they provide an interesting model for further genetic studies. Immune responses to Candida albicans in APS-1 patients displayed an increased secretion of the proinflammatory cytokine IL-17A and similar results were also found in AIRE deficient mice. Anticytokine autoantibodies to IL-17A, IL-17F and IL-22 were detected in APS-1 patients, and a radioligand binding assay for measuring these autoantibodies was developed and evaluated. In the canine studies we investigated whether canine diabetes mellitus could serve as a model for human autoimmune diabetes mellitus. Furthermore, we investigated type I IFN responses in Nova Scotia duck tolling retriever dogs with a systemic autoimmune disease resembling human SLE. Four assays were used in search for signs of humoral autoimmunity in diabetic dogs. However, no evidence for a type 1 diabetes-like phenotype in dogs was found. Sera from Nova Scotia duck tolling retrievers suffering from steroid-responsive meningitis arteritis elicited an increased expression of IFN-inducible genes in the canine MDCK cell line. This suggests that these dogs have an IFN signature, as seen in human SLE.
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3.
  • Ahlgren, Kerstin M, et al. (författare)
  • Lack of evidence for a role of islet autoimmunity in the aetiology of canine diabetes mellitus
  • 2014
  • Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:8, s. e105473-
  • Tidskriftsartikel (refereegranskat)abstract
    • AIMS/HYPOTHESIS:Diabetes mellitus is one of the most common endocrine disorders in dogs and is commonly proposed to be of autoimmune origin. Although the clinical presentation of human type 1 diabetes (T1D) and canine diabetes are similar, the aetiologies may differ. The aim of this study was to investigate if autoimmune aetiology resembling human T1D is as prevalent in dogs as previously reported.METHODS:Sera from 121 diabetic dogs representing 40 different breeds were tested for islet cell antibodies (ICA) and GAD65 autoantibodies (GADA) and compared with sera from 133 healthy dogs. ICA was detected by indirect immunofluorescence using both canine and human frozen sections. GADA was detected by in vitro transcription and translation (ITT) of human and canine GAD65, followed by immune precipitation. Sections of pancreata from five diabetic dogs and two control dogs were examined histopathologically including immunostaining for insulin, glucagon, somatostatin and pancreas polypeptide.RESULTS:None of the canine sera analysed tested positive for ICA on sections of frozen canine or human ICA pancreas. However, serum from one diabetic dog was weakly positive in the canine GADA assay and serum from one healthy dog was weakly positive in the human GADA assay. Histopathology showed marked degenerative changes in endocrine islets, including vacuolisation and variable loss of immune-staining for insulin. No sign of inflammation was noted.CONCLUSIONS/INTERPRETATIONS:Contrary to previous observations, based on results from tests for humoral autoreactivity towards islet proteins using four different assays, and histopathological examinations, we do not find any support for an islet autoimmune aetiology in canine diabetes mellitus.
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4.
  • Ahlgren, Kerstin, M., et al. (författare)
  • Type I Interferon signature in Nova Scotia duck tolling retriever dogs with steroid responsive meningitis-arteritis
  • Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
    • Objective: Dogs of the breed Nova Scotia duck tolling retriever (NSDTR) are prone to develop a disease complex in some aspects resembling human systemic lupus erythematosus (SLE). Peripheral blood mononuclear cells (PBMCs) from human SLE patients have an increased mRNA expression type I interferon (IFN) regulated genes. However, it is unknown whether diseased dogs also display the typical type I IFN signature. Methods: To test canine sera for their capacity to induce type I IFN response Mardin-Darby canine kidney (MDCK) cells were cultured with sera from healthy dogs (n=25),  immune-mediated rheumatic disease (IMRD) dogs with anti-nuclear antibodies (ANA+) (n=30) or dogs with steroid responsive meningitis-arteritis (SRMA) (n=25). mRNA expression of the genes MX1, IFIT1 and CXCL10 was measured by quantitative Real Time PCR. Results: A highly significant (p=0.0009) increase in mRNA expression of the type I IFN responsive gene MX1 was detected in cells stimulated by sera from dogs with SRMA, but not from IMRD ANA+ dogs. Expression of IFIT1 was twice as high in cells stimulated by sera from dogs with SRMA compared to both healthy dogs and ANA+ dogs. The mean expression of CXCL10 was nearly ten times higher in cells stimulated by sera from SRMA dogs than by ANA+ dogs and four times higher compared to cells stimulated by control dogs. Conclusion: Presence of type I IFN in sera from diseased NSDTR dogs was found in this study. This implies that this canine model can be used for identification of pathways of importance for autoimmune disorders in humans and for testing of novel therapeutic approaches. Our results can also be a step on the way towards personalized drugs in these dogs.
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5.
  • Ardesjö-Lundgren, Brita, et al. (författare)
  • Comparison of cellular location and expression of Plakophilin-2 in epidermal cells from nonlesional atopic skin and healthy skin in German shepherd dogs
  • 2017
  • Ingår i: Veterinary dermatology (Print). - : Wiley. - 0959-4493 .- 1365-3164. ; 28:4, s. 377-e88
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundCanine atopic dermatitis (CAD) is an inflammatory and pruritic allergic skin disease caused by interactions between genetic and environmental factors. Previously, a genome‐wide significant risk locus on canine chromosome 27 for CAD was identified in German shepherd dogs (GSDs) and Plakophilin‐2 (PKP2) was defined as the top candidate gene. PKP2 constitutes a crucial component of desmosomes and also is important in signalling, metabolic and transcriptional activities.ObjectivesThe main objective was to evaluate the role of PKP2 in CAD by investigating PKP2 expression and desmosome structure in nonlesional skin from CAD‐affected (carrying the top GWAS SNP risk allele) and healthy GSDs. We also aimed at defining the cell types in the skin that express PKP2 and its intracellular location.Animals/MethodsSkin biopsies were collected from nine CAD‐affected and five control GSDs. The biopsies were frozen for immunofluorescence and fixed for electron microscopy immunolabelling and morphology.ResultsWe observed the novel finding of PKP2 expression in dendritic cells and T cells in dog skin. Moreover, we detected that PKP2 was more evenly expressed within keratinocytes compared to its desmosomal binding‐partner plakoglobin. PKP2 protein was located in the nucleus and on keratin filaments attached to desmosomes. No difference in PKP2 abundance between CAD cases and controls was observed.ConclusionPlakophilin‐2 protein in dog skin is expressed in both epithelial and immune cells; based on its subcellular location its functional role is implicated in both nuclear and structural processes.
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6.
  • Brander, Gustaf, et al. (författare)
  • Multiple Genetic Loci Associated with Pug Dog Thoracolumbar Myelopathy
  • 2023
  • Ingår i: Genes. - : MDPI. - 2073-4425. ; 14:2
  • Tidskriftsartikel (refereegranskat)abstract
    • Pug dogs with thoracolumbar myelopathy (PDM) present with a specific clinical phenotype that includes progressive pelvic limb ataxia and paresis, commonly accompanied by incontinence. Vertebral column malformations and lesions, excessive scar tissue of the meninges, and central nervous system inflammation have been described. PDM has a late onset and affects more male than female dogs. The breed-specific presentation of the disorder suggests that genetic risk factors are involved in the disease development. To perform a genome-wide search for PDM-associated loci, we applied a Bayesian model adapted for mapping complex traits (BayesR) and a cross-population extended haplotype homozygosity test (XP-EHH) in 51 affected and 38 control pugs. Nineteen associated loci (harboring 67 genes in total, including 34 potential candidate genes) and three candidate regions under selection (with four genes within or next to the signal) were identified. The multiple candidate genes identified have implicated functions in bone homeostasis, fibrotic scar tissue, inflammatory responses, or the formation, regulation, and differentiation of cartilage, suggesting the potential relevance of these processes to the pathogenesis of PDM.
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7.
  • Eriksson, D, et al. (författare)
  • Extended exome sequencing identifies BACH2 as a novel major risk locus for Addison's disease
  • 2016
  • Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 286:6, s. 595-608
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Autoimmune disease is one of the leading causes of morbidity and mortality worldwide. In Addison's disease, the adrenal glands are targeted by destructive autoimmunity. Despite being the most common cause of primary adrenal failure, little is known about its aetiology.METHODS: To understand the genetic background of Addison's disease, we utilized the extensively characterized patients of the Swedish Addison Registry. We developed an extended exome capture array comprising a selected set of 1853 genes and their potential regulatory elements, for the purpose of sequencing 479 patients with Addison's disease and 1394 controls.RESULTS: We identified BACH2 (rs62408233-A, OR = 2.01 (1.71-2.37), P = 1.66 × 10(-15) , MAF 0.46/0.29 in cases/controls) as a novel gene associated with Addison's disease development. We also confirmed the previously known associations with the HLA complex.CONCLUSION: Whilst BACH2 has been previously reported to associate with organ-specific autoimmune diseases co-inherited with Addison's disease, we have identified BACH2 as a major risk locus in Addison's disease, independent of concomitant autoimmune diseases. Our results may enable future research towards preventive disease treatment.
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8.
  • Fall, Tove, 1979-, et al. (författare)
  • Diabetes Mellitus in Elkhounds Is Associated with Diestrus and Pregnancy
  • 2010
  • Ingår i: Journal of Veterinary Internal Medicine. - : Wiley. - 0891-6640 .- 1939-1676. ; 24:6, s. 1322-1328
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Female Elkhounds are shown to be at increased risk for diabetes mellitus, and occurrence of diabetes during pregnancy has been described in several cases. Hypothesis: Onset of diabetes mellitus in Elkhounds is associated with diestrus. Animals: Sixty-three Elkhounds with diabetes mellitus and 26 healthy controls. Methods: Medical records from 63 Elkhounds with diabetes were reviewed and owners were contacted for follow-up information. Blood samples from the day of diagnosis were available for 26 dogs. Glucose, fructosamine, C-peptide, growth hormone (GH), insulin-like growth factor-1, progesterone, and glutamate decarboxylase isoform 65-autoantibodies were analyzed and compared with 26 healthy dogs. Logistic models were used to evaluate the association of clinical variables with the probability of diabetes and with permanent diabetes mellitus after ovariohysterectomy (OHE). Results: All dogs in the study were intact females and 7 dogs (11%) were pregnant at diagnosis. The 1st clinical signs of diabetes mellitus occurred at a median of 30 days (interquartile range [IQR], 3-45) after estrus, and diagnosis was made at a median of 46 days (IQR, 27-62) after estrus. Diabetes was associated with higher concentrations of GH and lower concentrations of progesterone compared with controls matched for time after estrus. Forty-six percent of dogs that underwent OHE recovered from diabetes with a lower probability of remission in dogs with higher glucose concentrations (odds ratio [OR], 1.2; P = .03) at diagnosis and longer time (weeks) from diagnosis to surgery (OR, 1.5; P = .05). Conclusions: Diabetes mellitus in Elkhounds develops mainly during diestrus and pregnancy. Immediate OHE improves the prognosis for remission of diabetes.
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9.
  • Lawniczak, Mara K. N., et al. (författare)
  • Standards recommendations for the Earth BioGenome Project
  • 2022
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences (PNAS). - 0027-8424 .- 1091-6490. ; 119:4
  • Tidskriftsartikel (refereegranskat)abstract
    • A global international initiative, such as the Earth BioGenome Project (EBP), requires both agreement and coordination on standards to ensure that the collective effort generates rapid progress toward its goals. To this end, the EBP initiated five technical standards committees comprising volunteer members from the global genomics scientific community: Sample Collection and Processing, Sequencing and Assembly, Annotation, Analysis, and IT and Informatics. The current versions of the resulting standards documents are available on the EBP website, with the recognition that opportunities, technologies, and challenges may improve or change in the future, requiring flexibility for the EBP to meet its goals. Here, we describe some highlights from the proposed standards, and areas where additional challenges will need to be met.
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10.
  • Olsson, Mia, et al. (författare)
  • Genome-Wide Analyses Suggest Mechanisms Involving Early B-cell Development in Canine IgA Deficiency
  • 2015
  • Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:7
  • Tidskriftsartikel (refereegranskat)abstract
    • Immunoglobulin A deficiency (IgAD) is the most common primary immune deficiency disorder in both humans and dogs, characterized by recurrent mucosal tract infections and a predisposition for allergic and other immune mediated diseases. In several dog breeds, low IgA levels have been observed at a high frequency and with a clinical resemblance to human IgAD. In this study, we used genome-wide association studies (GWAS) to identify genomic regions associated with low IgA levels in dogs as a comparative model for human IgAD. We used a novel percentile groups-approach to establish breed-specific cut-offs and to perform analyses in a close to continuous manner. GWAS performed in four breeds prone to low IgA levels (German shepherd, Golden retriever, Labrador retriever and Shar-Pei) identified 35 genomic loci suggestively associated (p <0.0005) to IgA levels. In German shepherd, three genomic regions (candidate genes include KIRREL3 and SERPINA9) were genome-wide significantly associated (p <0.0002) with IgA levels. A ~20kb long haplotype on CFA28, significantly associated (p = 0.0005) to IgA levels in Shar-Pei, was positioned within the first intron of the gene SLIT1. Both KIRREL3 and SLIT1 are highly expressed in the central nervous system and in bone marrow and are potentially important during B-cell development. SERPINA9 expression is restricted to B-cells and peaks at the time-point when B-cells proliferate into antibody-producing plasma cells. The suggestively associated regions were enriched for genes in Gene Ontology gene sets involving inflammation and early immune cell development.
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11.
  • Olsson, Mia, et al. (författare)
  • The dog as a genetic model for immunoglobulin A (IgA) deficiency : Identification of several breeds with low serum IgA concentrations
  • 2014
  • Ingår i: Veterinary Immunology and Immunopathology. - : Elsevier BV. - 0165-2427 .- 1873-2534. ; 60:3-4, s. 255-259
  • Tidskriftsartikel (refereegranskat)abstract
    • Immunoglobulin A (IgA) serves as the basis of the secretory immune system by protecting the lining of mucosal sites from pathogens. In both humans and dogs, IgA deficiency (IgAD) is associated with recurrent infections of mucosal sites and immune-mediated diseases. Low concentrations of serum IgA have previously been reported to occur in a number of dog breeds but no generally accepted cut-off value has been established for canine IgAD. The current study represents the largest screening to date of IgA in dogs in terms of both number of dogs (n = 1267) and number of breeds studied (n = 22). Serum IgA concentrations were quantified by using capture ELISA and were found to vary widely between breeds. We also found IgA to be positively correlated with age (p < 0.0001). Apart from the two breeds previously reported as predisposed to low IgA (Shar-Pei and German shepherd), we identified six additional breeds in which > 10% of all tested dogs had very low (<0.07 g/l) IgA concentrations (Hovawart, Norwegian elkhound, Nova Scotia duck tolling retriever, Bullterrier, Golden retriever and Labrador retriever). In addition, we discovered low IgA concentrations to be significantly associated with canine atopic dermatitis (CAD, p < 0.0001) and pancreatic acinar atrophy (PAA, p = 0.04) in German shepherds.
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12.
  • Owczarek-Lipska, Marta, et al. (författare)
  • Two Loci on Chromosome 5 Are Associated with Serum IgE Levels in Labrador Retrievers
  • 2012
  • Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:6, s. e39176-
  • Tidskriftsartikel (refereegranskat)abstract
    • Crosslinking of immunoglobulin E antibodies (IgE) bound at the surface of mast cells and subsequent mediator release is considered the most important trigger for allergic reactions. Therefore, the genetic control of IgE levels is studied in the context of allergic diseases, such as asthma, atopic rhinitis, or atopic dermatitis (AD). We performed genome-wide association studies in 161 Labrador Retrievers with regard to total and allergen-specific immunoglobulin E (IgE) levels. We identified a genome-wide significant association on CFA 5 with the antigen-specific IgE responsiveness to Acarus siro. We detected a second genome-wide significant association with respect to the antigen-specific IgE responsiveness to Tyrophagus putrescentiae at a different locus on chromosome 5. A. siro and T. putrescentiae both belong to the family Acaridae and represent so-called storage or forage mites. These forage mites are discussed as major allergen sources in canine AD. No obvious candidate gene for the regulation of IgE levels is located under the two association signals. Therefore our studies offer a chance of identifying a novel mechanism controlling the host's IgE response.
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14.
  • Tengvall, Katarina, 1980-, et al. (författare)
  • Bayesian model and selection signature analyses reveal risk factors for canine atopic dermatitis
  • 2022
  • Ingår i: Communications Biology. - : Springer Nature. - 2399-3642. ; 5:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Canine atopic dermatitis is an inflammatory skin disease with clinical similarities to human atopic dermatitis. Several dog breeds are at increased risk for developing this disease but previous genetic associations are poorly defined. To identify additional genetic risk factors for canine atopic dermatitis, we here apply a Bayesian mixture model adapted for mapping complex traits and a cross-population extended haplotype test to search for disease-associated loci and selective sweeps in four dog breeds at risk for atopic dermatitis. We define 15 associated loci and eight candidate regions under selection by comparing cases with controls. One associated locus is syntenic to the major genetic risk locus (Filaggrin locus) in human atopic dermatitis. One selection signal in common type Labrador retriever cases positions across the TBC1D1 gene (body weight) and one signal of selection in working type German shepherd controls overlaps the LRP1B gene (brain), near the KYNU gene (psoriasis). In conclusion, we identify candidate genes, including genes belonging to the same biological pathways across multiple loci, with potential relevance to the pathogenesis of canine atopic dermatitis. The results show genetic similarities between dog and human atopic dermatitis, and future across-species genetic comparisons are hereby further motivated.
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15.
  • Tengvall, Katarina, et al. (författare)
  • Genome-Wide Analysis in German Shepherd Dogs Reveals Association of a Locus on CFA 27 with Atopic Dermatitis
  • 2013
  • Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 9:5, s. e1003475-
  • Tidskriftsartikel (refereegranskat)abstract
    • Humans and dogs are both affected by the allergic skin disease atopic dermatitis (AD), caused by an interaction between genetic and environmental factors. The German shepherd dog (GSD) is a high-risk breed for canine AD (CAD). In this study, we used a Swedish cohort of GSDs as a model for human AD. Serum IgA levels are known to be lower in GSDs compared to other breeds. We detected significantly lower IgA levels in the CAD cases compared to controls (p = 1.1x10(-5)) in our study population. We also detected a separation within the GSD cohort, where dogs could be grouped into two different subpopulations. Disease prevalence differed significantly between the subpopulations contributing to population stratification (lambda = 1.3), which was successfully corrected for using a mixed model approach. A genome-wide association analysis of CAD was performed (n(cases) = 91, n(controls) = 88). IgA levels were included in the model, due to the high correlation between CAD and low IgA levels. In addition, we detected a correlation between IgA levels and the age at the time of sampling (corr = 0.42, p = 3.0x10(-9)), thus age was included in the model. A genome-wide significant association was detected on chromosome 27 (p(raw) = 3.1x10(-7), p(genome) = 0.03). The total associated region was defined as a similar to 1.5-Mb-long haplotype including eight genes. Through targeted re-sequencing and additional genotyping of a subset of identified SNPs, we defined 11 smaller haplotype blocks within the associated region. Two blocks showed the strongest association to CAD. The similar to 209-kb region, defined by the two blocks, harbors only the PKP2 gene, encoding Plakophilin 2 expressed in the desmosomes and important for skin structure. Our results may yield further insight into the genetics behind both canine and human AD.
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16.
  • Tengvall, Katarina, 1980-, et al. (författare)
  • Multiple regulatory variants located in cell type-specific enhancers within the PKP2 locus form major risk and protective haplotypes for canine atopic dermatitis in German shepherd dogs
  • 2016
  • Ingår i: BMC Genetics. - : Springer Science and Business Media LLC. - 1471-2156. ; 17:1
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundCanine atopic dermatitis (CAD) is a chronic inflammatory skin disease triggered by allergic reactions involving IgE antibodies directed towards environmental allergens. We previously identified a ~1.5 Mb locus on canine chromosome 27 associated with CAD in German shepherd dogs (GSDs). Fine-mapping indicated association closest to the PKP2 gene encoding plakophilin 2.ResultsAdditional genotyping and association analyses in GSDs combined with control dogs from five breeds with low-risk for CAD revealed the top SNP 27:19,086,778 (p = 1.4 × 10−7) and a rare ~48 kb risk haplotype overlapping the PKP2 gene and shared only with other high-risk CAD breeds. We selected altogether nine SNPs (four top-associated in GSDs and five within the ~48 kb risk haplotype) that spanned ~280 kb forming one risk haplotype carried by 35 % of the GSD cases and 10 % of the GSD controls (OR = 5.1, p = 5.9 × 10−5), and another haplotype present in 85 % of the GSD cases and 98 % of the GSD controls and conferring a protective effect against CAD in GSDs (OR = 0.14, p = 0.0032). Eight of these SNPs were analyzed for transcriptional regulation using reporter assays where all tested regions exerted regulatory effects on transcription in epithelial and/or immune cell lines, and seven SNPs showed allelic differences. The DNA fragment with the top-associated SNP 27:19,086,778 displayed the highest activity in keratinocytes with 11-fold induction of transcription by the risk allele versus 8-fold by the control allele (pdifference = 0.003), and also mapped close (~3 kb) to an ENCODE skin-specific enhancer region.ConclusionsOur experiments indicate that multiple CAD-associated genetic variants located in cell type-specific enhancers are involved in gene regulation in different cells and tissues. No single causative variant alone, but rather multiple variants combined in a risk haplotype likely contribute to an altered expression of the PKP2 gene, and possibly nearby genes, in immune and epithelial cells, and predispose GSDs to CAD.
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17.
  • Tengvall, Katarina, 1980-, et al. (författare)
  • Transcriptomes from German shepherd dogs reveal differences in immune activity between atopic dermatitis affected and control skin
  • 2020
  • Ingår i: Immunogenetics. - : Springer Science and Business Media LLC. - 0093-7711 .- 1432-1211. ; 72:5, s. 315-323
  • Tidskriftsartikel (refereegranskat)abstract
    • Canine atopic dermatitis (CAD) is an inflammatory and pruritic allergic skin disease with both genetic and environmental risk factors described. We performed mRNA sequencing of non-lesional axillary skin biopsies from nine German shepherd dogs. Obtained RNA sequences were mapped to the dog genome (CanFam3.1) and a high-quality skin transcriptome was generated with 23,510 expressed gene transcripts. Differentially expressed genes (DEGs) were defined by comparing three controls to five treated CAD cases. Using a leave-one-out analysis, we identified seven DEGs: five known to encode proteins with functions related to an activated immune system (CD209, CLEC4G, LOC102156842 (lipopolysaccharide-binding protein-like), LOC480601 (regakine-1-like), LOC479668 (haptoglobin-like)), one (OBP) encoding an odorant-binding protein potentially connected to rhinitis, and the last (LOC607095) encoding a novel long non-coding RNA. Furthermore, high mRNA expression of inflammatory genes was found in axillary skin from an untreated mild CAD case compared with healthy skin. In conclusion, we define genes with different expression patterns in CAD case skin helping us understand post-treatment atopic skin. Further studies in larger sample sets are warranted to confirm and to transfer these results into clinical practice.
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18.
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19.
  • Adolfsson, Peter, 1963, et al. (författare)
  • Hormonal response during physical exercise of different intensities in adolescents with type 1 diabetes and healthy controls.
  • 2012
  • Ingår i: Pediatric Diabetes. - : Hindawi Limited. - 1399-543X .- 1399-5448. ; 13:8, s. 587-96
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Physical activity is a critical component in the care of diabetes. Although it offers health benefits it presents challenges. Objective To investigate differences between adolescent boys and girls with type 1 diabetes and healthy controls in terms of maximal work capacity (VO2 max) and hormonal response to physical exercise of different intensities. Subjects Twelve individuals (six boys and six girls; age 1419 yr, pubertal stage 45) with type 1 diabetes (duration, 6.3 +/- 4.4 yr; hemoglobin A1c, 63 +/- 10 mmol/mol) were compared with 12 healthy controls matched for age, sex, pubertal stage, body mass index standard deviation score, and amount of regular physical activity. Methods During consecutive days, three different workloads; maximal, endurance, and interval, were performed on an Ergometer cycle. During the tests, levels of lactate, glucose, insulin, and regulatory hormones [glucagon, cortisol, growth hormone (GH), adrenaline, and noradrenaline] were measured in blood. Subcutaneous glucose was measured continuously. Results VO2 max did not differ between the groups, diabetes 49.8 +/- 9.9 vs. control 50.7 +/- 12.0 mL/min/kg. Hormonal responses did not differ between the groups except for mean peak GH level during the interval test, diabetes 63.2 +/- 27.0 vs. control 33.8 +/- 20.9 mU/L, p
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20.
  • Agler, Caryline, et al. (författare)
  • Canine Hereditary Ataxia in Old English Sheepdogs and Gordon Setters Is Associated with a Defect in the Autophagy Gene Encoding RAB24
  • 2014
  • Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 10:2, s. e1003991-
  • Tidskriftsartikel (refereegranskat)abstract
    • Old English Sheepdogs and Gordon Setters suffer from a juvenile onset, autosomal recessive form of canine hereditary ataxia primarily affecting the Purkinje neuron of the cerebellar cortex. The clinical and histological characteristics are analogous to hereditary ataxias in humans. Linkage and genome-wide association studies on a cohort of related Old English Sheepdogs identified a region on CFA4 strongly associated with the disease phenotype. Targeted sequence capture and next generation sequencing of the region identified an A to C single nucleotide polymorphism (SNP) located at position 113 in exon 1 of an autophagy gene, RAB24, that segregated with the phenotype. Genotyping of six additional breeds of dogs affected with hereditary ataxia identified the same polymorphism in affected Gordon Setters that segregated perfectly with phenotype. The other breeds tested did not have the polymorphism. Genome-wide SNP genotyping of Gordon Setters identified a 1.9 MB region with an identical haplotype to affected Old English Sheepdogs. Histopathology, immunohistochemistry and ultrastructural evaluation of the brains of affected dogs from both breeds identified dramatic Purkinje neuron loss with axonal spheroids, accumulation of autophagosomes, ubiquitin positive inclusions and a diffuse increase in cytoplasmic neuronal ubiquitin staining. These findings recapitulate the changes reported in mice with induced neuron-specific autophagy defects. Taken together, our results suggest that a defect in RAB24, a gene associated with autophagy, is highly associated with and may contribute to canine hereditary ataxia in Old English Sheepdogs and Gordon Setters. This finding suggests that detailed investigation of autophagy pathways should be undertaken in human hereditary ataxia. Author Summary Neurodegenerative diseases are one of the most important causes of decline in an aging population. An important subset of these diseases are known as the hereditary ataxias, familial neurodegenerative diseases that affect the cerebellum causing progressive gait disturbance in both humans and dogs. We identified a mutation in RAB24, a gene associated with autophagy, in Old English Sheepdogs and Gordon Setters with hereditary ataxia. Autophagy is a process by which cell proteins and organelles are removed and recycled and its critical role in maintenance of the continued health of cells is becoming clear. We evaluated the brains of affected dogs and identified accumulations of autophagosomes within the cerebellum, suggesting a defect in the autophagy pathway. Our results suggest that a defect in the autophagy pathway results in neuronal death in a naturally occurring disease in dogs. The autophagy pathway should be investigated in human hereditary ataxia and may represent a therapeutic target in neurodegenerative diseases.
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21.
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22.
  • Alfoeldi, Jessica, et al. (författare)
  • Comparative genomics as a tool to understand evolution and disease
  • 2013
  • Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 23:7, s. 1063-1068
  • Tidskriftsartikel (refereegranskat)abstract
    • When the human genome project started, the major challenge was how to sequence a 3 billion letter code in an organized and cost-effective manner. When completed, the project had laid the foundation for a huge variety of biomedical fields through the production of a complete human genome sequence, but also had driven the development of laboratory and analytical methods that could produce large amounts of sequencing data cheaply. These technological developments made possible the sequencing of many more vertebrate genomes, which have been necessary for the interpretation of the human genome. They have also enabled large-scale studies of vertebrate genome evolution, as well as comparative and human medicine. In this review, we give examples of evolutionary analysis using a wide variety of time frames-from the comparison of populations within a species to the comparison of species separated by at least 300 million years. Furthermore, we anticipate discoveries related to evolutionary mechanisms, adaptation, and disease to quickly accelerate in the coming years.
  •  
23.
  • Alfoeldi, Jessica, et al. (författare)
  • The genome of the green anole lizard and a comparative analysis with birds and mammals
  • 2011
  • Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 477:7366, s. 587-591
  • Tidskriftsartikel (refereegranskat)abstract
    • The evolution of the amniotic egg was one of the great evolutionary innovations in the history of life, freeing vertebrates from an obligatory connection to water and thus permitting the conquest of terrestrial environments(1). Among amniotes, genome sequences are available for mammals and birds(2-4), but not for non-avian reptiles. Here we report the genome sequence of the North American green anole lizard, Anolis carolinensis. We find that A. carolinensis microchromosomes are highly syntenic with chicken microchromosomes, yet do not exhibit the high GC and low repeat content that are characteristic of avian microchromosomes(2). Also, A. carolinensis mobile elements are very young and diverse-more so than in any other sequenced amniote genome. The GC content of this lizard genome is also unusual in its homogeneity, unlike the regionally variable GC content found in mammals and birds(5). We describe and assign sequence to the previously unknown A. carolinensis X chromosome. Comparative gene analysis shows that amniote egg proteins have evolved significantly more rapidly than other proteins. An anole phylogeny resolves basal branches to illuminate the history of their repeated adaptive radiations.
  •  
24.
  • Amemiya, Chris T., et al. (författare)
  • The African coelacanth genome provides insights into tetrapod evolution
  • 2013
  • Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 496:7445, s. 311-316
  • Tidskriftsartikel (refereegranskat)abstract
    • The discovery of a living coelacanth specimen in 1938 was remarkable, as this lineage of lobe-finned fish was thought to have become extinct 70 million years ago. The modern coelacanth looks remarkably similar to many of its ancient relatives, and its evolutionary proximity to our own fish ancestors provides a glimpse of the fish that first walked on land. Here we report the genome sequence of the African coelacanth, Latimeria chalumnae. Through a phylogenomic analysis, we conclude that the lungfish, and not the coelacanth, is the closest living relative of tetrapods. Coelacanth protein-coding genes are significantly more slowly evolving than those of tetrapods, unlike other genomic features. Analyses of changes in genes and regulatory elements during the vertebrate adaptation to land highlight genes involved in immunity, nitrogen excretion and the development of fins, tail, ear, eye, brain and olfaction. Functional assays of enhancers involved in the fin-to-limb transition and in the emergence of extra-embryonic tissues show the importance of the coelacanth genome as a blueprint for understanding tetrapod evolution.
  •  
25.
  • Andersson, Leif, et al. (författare)
  • ZBED6 : the birth of a new transcription factor in the common ancestor of placental mammals
  • 2010
  • Ingår i: Transcription. - : Informa UK Limited. - 2154-1272 .- 2154-1264. ; 1:3, s. 144-148
  • Tidskriftsartikel (refereegranskat)abstract
    • A DNA transposon integrated into -the genome of a primitive mammal some 200 million years ago and, millions of years later, it evolved an essential function in the common ancestor of all placental mammals. This protein, now named ZBED6, was recently discovered because a mutation disrupting one of its binding sites, in an intron of the IGF2 gene, makes pigs grow more muscle. These findings have revealed a new mechanism for regulating muscle growth as well as a novel transcription factor that appears to be of major importance for transcriptional regulation in placental mammals.
  •  
26.
  • Andrews, Gregory, et al. (författare)
  • Mammalian evolution of human cis-regulatory elements and transcription factor binding sites
  • 2023
  • Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 380:6643
  • Tidskriftsartikel (refereegranskat)abstract
    • Understanding the regulatory landscape of the human genome is a long-standing objective of modern biology. Using the reference-free alignment across 241 mammalian genomes produced by the Zoonomia Consortium, we charted evolutionary trajectories for 0.92 million human candidate cis-regulatory elements (cCREs) and 15.6 million human transcription factor binding sites (TFBSs). We identified 439,461 cCREs and 2,024,062 TFBSs under evolutionary constraint. Genes near constrained elements perform fundamental cellular processes, whereas genes near primate-specific elements are involved in environmental interaction, including odor perception and immune response. About 20% of TFBSs are transposable element-derived and exhibit intricate patterns of gains and losses during primate evolution whereas sequence variants associated with complex traits are enriched in constrained TFBSs. Our annotations illuminate the regulatory functions of the human genome.
  •  
27.
  • Arendt, Maja, et al. (författare)
  • Amylase activity is associated with AMY2B copy numbers in dog : implications for dog domestication, diet and diabetes
  • 2014
  • Ingår i: Animal Genetics. - : Wiley. - 0268-9146 .- 1365-2052. ; 45:5, s. 716-722
  • Tidskriftsartikel (refereegranskat)abstract
    • High amylase activity in dogs is associated with a drastic increase in copy numbers of the gene coding for pancreatic amylase, AMY2B, that likely allowed dogs to thrive on a relatively starch-rich diet during early dog domestication. Although most dogs thus probably digest starch more efficiently than do wolves, AMY2B copy numbers vary widely within the dog population, and it is not clear how this variation affects the individual ability to handle starch nor how it affects dog health. In humans, copy numbers of the gene coding for salivary amylase, AMY1, correlate with both salivary amylase levels and enzyme activity, and high amylase activity is related to improved glycemic homeostasis and lower frequencies of metabolic syndrome. Here, we investigate the relationship between AMY2B copy numbers and serum amylase activity in dogs and show that amylase activity correlates with AMY2B copy numbers. We then describe how AMY2B copy numbers vary in individuals from 20 dog breeds and find strong breed-dependent patterns, indicating that the ability to digest starch varies both at the breed and individual level. Finally, to test whether AMY2B copy number is strongly associated with the risk of developing diabetes mellitus, we compare copy numbers in cases and controls as well as in breeds with varying diabetes susceptibility. Although we see no such association here, future studies using larger cohorts are needed before excluding a possible link between AMY2B and diabetes mellitus.
  •  
28.
  • Arendt, Maja Louise, et al. (författare)
  • Genome-Wide Association Study of Golden Retrievers Identifies Germ-Line Risk Factors Predisposing to Mast Cell Tumours
  • 2015
  • Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 11:11
  • Tidskriftsartikel (refereegranskat)abstract
    • Canine mast cell tumours (CMCT) are one of the most common skin tumours in dogs with a major impact on canine health. Certain breeds have a higher risk of developing mast cell tumours, suggesting that underlying predisposing germ-line genetic factors play a role in the development of this disease. The genetic risk factors are largely unknown, although somatic mutations in the oncogene C-KIT have been detected in a proportion of CMCT, making CMCT a comparative model for mastocytosis in humans where C-KIT mutations are frequent. We have performed a genome wide association study in golden retrievers from two continents and identified separate regions in the genome associated with risk of CMCT in the two populations. Sequence capture of associated regions and subsequent fine mapping in a larger cohort of dogs identified a SNP associated with development of CMCT in the GNAI2 gene (p = 2.2x10(-16)), introducing an alternative splice form of this gene resulting in a truncated protein. In addition, disease associated haplotypes harbouring the hyaluronidase genes HYAL1, HYAL2 and HYAL3 on cfa20 and HYAL4, SPAM1 and HYALP1 on cfa14 were identified as separate risk factors in European and US golden retrievers, respectively, suggesting that turnover of hyaluronan plays an important role in the development of CMCT.
  •  
29.
  • Arendt, Maja Louise, et al. (författare)
  • PIK3CA is recurrently mutated in canine mammary tumors, similarly to in human mammary neoplasia
  • 2023
  • Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 13
  • Tidskriftsartikel (refereegranskat)abstract
    • Biological features of neoplastic disease affecting mammary gland tissue are shared between canines and humans. Research performed in either species has translational value and early phase clinical trials performed in canines with spontaneous disease could be informative for human trials. The purpose of this study was to investigate the somatic genetic aberrations occurring in canine mammary neoplasia by exome capture and next generation sequencing. Based on 55 tumor-normal pairs we identified the PIK3CA gene as the most commonly mutated gene in canine mammary tumors, with 25% of samples carrying mutations in this gene. A recurrent missense mutation was identified, p.H1047R, which is homologous to the human PIK3CA hotspot mutation found in different types of breast neoplasia. Mutations homologous to other known human mutation hotspots such as the PIK3CA p.E545K and the KRAS p.G12V/D were also identified. We identified copy number aberrations affecting important tumor suppressor and oncogenic pathways including deletions affecting the PTEN tumor suppressor gene. We suggest that activation of the KRAS or PIK3CA oncogenes or loss of the PTEN suppressor gene may be important for mammary tumor development in dogs. This data endorses the conservation of cancer across species and the validity of studying cancer in non-human species.
  •  
30.
  • Arendt, Maja Louise, et al. (författare)
  • The ABCC4 gene is associated with pyometra in golden retriever dogs
  • 2021
  • Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 11
  • Tidskriftsartikel (refereegranskat)abstract
    • Pyometra is one of the most common diseases in female dogs, presenting as purulent inflammation and bacterial infection of the uterus. On average 20% of intact female dogs are affected before 10 years of age, a proportion that varies greatly between breeds (3-66%). The clear breed predisposition suggests that genetic risk factors are involved in disease development. To identify genetic risk factors associated with the disease, we performed a genome-wide association study (GWAS) in golden retrievers, a breed with increased risk of developing pyometra (risk ratio: 3.3). We applied a mixed model approach comparing 98 cases, and 96 healthy controls and identified an associated locus on chromosome 22 (p = 1.2 x 10(-6), passing Bonferroni corrected significance). This locus contained five significantly associated SNPs positioned within introns of the ATP-binding cassette transporter 4 (ABCC4) gene. This gene encodes a transmembrane transporter that is important for prostaglandin transport. Next generation sequencing and genotyping of cases and controls subsequently identified four missense SNPs within the ABCC4 gene. One missense SNP at chr22:45,893,198 (p.Met787Val) showed complete linkage disequilibrium with the associated GWAS SNPs suggesting a potential role in disease development. Another locus on chromosome 18 overlapping the TESMIN gene, is also potentially implicated in the development of the disease.
  •  
31.
  • Armstrong, Joel, et al. (författare)
  • Progressive Cactus is a multiple-genome aligner for the thousand-genome era
  • 2020
  • Ingår i: Nature. - : Springer Nature. - 0028-0836 .- 1476-4687. ; 587:7833, s. 246-251
  • Tidskriftsartikel (refereegranskat)abstract
    • New genome assemblies have been arriving at a rapidly increasing pace, thanks to decreases in sequencing costs and improvements in third-generation sequencing technologies(1-3). For example, the number of vertebrate genome assemblies currently in the NCBI (National Center for Biotechnology Information) database(4) increased by more than 50% to 1,485 assemblies in the year from July 2018 to July 2019. In addition to this influx of assemblies from different species, new human de novo assemblies(5) are being produced, which enable the analysis of not only small polymorphisms, but also complex, large-scale structural differences between human individuals and haplotypes. This coming era and its unprecedented amount of data offer the opportunity to uncover many insights into genome evolution but also present challenges in how to adapt current analysis methods to meet the increased scale. Cactus(6), a reference-free multiple genome alignment program, has been shown to be highly accurate, but the existing implementation scales poorly with increasing numbers of genomes, and struggles in regions of highly duplicated sequences. Here we describe progressive extensions to Cactus to create Progressive Cactus, which enables the reference-free alignment of tens to thousands of large vertebrate genomes while maintaining high alignment quality. We describe results from an alignment of more than 600 amniote genomes, which is to our knowledge the largest multiple vertebrate genome alignment created so far. The Progressive Cactus program can create reference-free alignments of hundreds of large vertebrate genomes efficiently, and is used for the alignment of more than 600 amniote genomes.
  •  
32.
  • Astrof, Sophie, et al. (författare)
  • Heart development in fibronectin-null mice is governed by a genetic modifier on chromosome four
  • 2007
  • Ingår i: Mechanisms of Development. - : Elsevier BV. - 0925-4773 .- 1872-6356. ; 124:7-8, s. 551-558
  • Tidskriftsartikel (refereegranskat)abstract
    • Absence of the fibronectin (FN) gene leads to early embryonic lethality in both 129S4 and C57BL/6J strains due to severe cardiovascular defects. However, heart development is arrested at different stages in these embryos depending on the genetic background. In the majority of 129S4 FN-null embryos, heart progenitors remain at their anterior bilateral positions and fail to fuse at the midline to form a heart tube. However, on the C57BL/6J genetic background, cardiac development progresses further and results in a centrally positioned and looped heart. To find factor(s) involved in embryonic heart formation and governing the extent of heart development in FN-null embryos in 129S4 and C57BL/6J strains, we performed genetic mapping and haplotype analyses. These analyses lead to identification of a significant linkage to a 1-Mbp interval on chromosome four. Microarray analysis and sequencing identified 21 genes in this region, including five that are differentially expressed between the strains, as potential modifiers. Since none of these genes was previously known to play a role in heart development, one or more of them is likely to be a novel modifier affecting cardiac development. Identification of the modifier would significantly enhance our understanding of the molecular underpinning of heart development and disease.
  •  
33.
  • Awano, Tomoyuki, et al. (författare)
  • Genome-wide association analysis reveals a SOD1 mutation in canine degenerative myelopathy that resembles amyotrophic lateral sclerosis
  • 2009
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 106:8, s. 2794-2799
  • Tidskriftsartikel (refereegranskat)abstract
    • Canine degenerative myelopathy (DM) is a fatal neurodegenerative disease prevalent in several dog breeds. Typically, the initial progressive upper motor neuron spastic and general proprioceptive ataxia in the pelvic limbs occurs at 8 years of age or older. If euthanasia is delayed, the clinical signs will ascend, causing flaccid tetraparesis and other lower motor neuron signs. DNA samples from 38 DM-affected Pembroke Welsh corgi cases and 17 related clinically normal controls were used for genome-wide association mapping, which produced the strongest associations with markers on CFA31 in a region containing the canine SOD1 gene. SOD1 was considered a regional candidate gene because mutations in human SOD1 can cause amyotrophic lateral sclerosis (ALS), an adult-onset fatal paralytic neurodegenerative disease with both upper and lower motor neuron involvement. The resequencing of SOD1 in normal and affected dogs revealed a G to A transition, resulting in an E40K missense mutation. Homozygosity for the A allele was associated with DM in 5 dog breeds: Pembroke Welsh corgi, Boxer, Rhodesian ridgeback, German Shepherd dog, and Chesapeake Bay retriever. Microscopic examination of spinal cords from affected dogs revealed myelin and axon loss affecting the lateral white matter and neuronal cytoplasmic inclusions that bind anti-superoxide dismutase 1 antibodies. These inclusions are similar to those seen in spinal cord sections from ALS patients with SOD1 mutations. Our findings identify canine DM to be the first recognized spontaneously occurring animal model for ALS.
  •  
34.
  • Axelsson, Erik, et al. (författare)
  • Death of PRDM9 coincides with stabilization of the recombination landscape in the dog genome
  • 2011
  • Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 22:1, s. 51-63
  • Tidskriftsartikel (refereegranskat)abstract
    • Analysis of diverse eukaryotes has revealed that recombination events cluster in discrete genomic locations known as hotspots. In humans, a zinc-finger protein, PRDM9, is believed to initiate recombination in >40% of hotspots by binding to a specific DNA sequence motif. However, the PRDM9 coding sequence is disrupted in the dog genome assembly, raising questions regarding the nature and control of recombination in dogs. By analyzing the sequences of PRDM9 orthologs in a number of dog breeds and several carnivores, we show here that this gene was inactivated early in canid evolution. We next use patterns of linkage disequilibrium using more than 170,000 SNP markers typed in almost 500 dogs to estimate the recombination rates in the dog genome using a coalescent-based approach. Broad-scale recombination rates show good correspondence with an existing linkage-based map. Significant variation in recombination rate is observed on the fine scale, and we are able to detect over 4000 recombination hotspots with high confidence. In contrast to human hotspots, 40% of canine hotspots are characterized by a distinct peak in GC content. A comparative genomic analysis indicates that these peaks are present also as weaker peaks in the panda, suggesting that the hotspots have been continually reinforced by accelerated and strongly GC biased nucleotide substitutions, consistent with the long-term action of biased gene conversion on the dog lineage. These results are consistent with the loss of PRDM9 in canids, resulting in a greater evolutionary stability of recombination hotspots. The genetic determinants of recombination hotspots in the dog genome may thus reflect a fundamental process of relevance to diverse animal species.
  •  
35.
  • Axelsson, Erik, et al. (författare)
  • The genetic consequences of dog breed formation-Accumulation of deleterious genetic variation and fixation of mutations associated with myxomatous mitral valve disease in cavalier King Charles spaniels
  • 2021
  • Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 17:9
  • Tidskriftsartikel (refereegranskat)abstract
    • Selective breeding for desirable traits in strictly controlled populations has generated an extraordinary diversity in canine morphology and behaviour, but has also led to loss of genetic variation and random entrapment of disease alleles. As a consequence, specific diseases are now prevalent in certain breeds, but whether the recent breeding practice led to an overall increase in genetic load remains unclear. Here we generate whole genome sequencing (WGS) data from 20 dogs per breed from eight breeds and document a similar to 10% rise in the number of derived alleles per genome at evolutionarily conserved sites in the heavily bottlenecked cavalier King Charles spaniel breed (cKCs) relative to in most breeds studied here. Our finding represents the first clear indication of a relative increase in levels of deleterious genetic variation in a specific breed, arguing that recent breeding practices probably were associated with an accumulation of genetic load in dogs. We then use the WGS data to identify candidate risk alleles for the most common cause for veterinary care in cKCs-the heart disease myxomatous mitral valve disease (MMVD). We verify a potential link to MMVD for candidate variants near the heart specific NEBL gene in a dachshund population and show that two of the NEBL candidate variants have regulatory potential in heartderived cell lines and are associated with reduced NEBL isoform nebulette expression in papillary muscle (but not in mitral valve, nor in left ventricular wall). Alleles linked to reduced nebulette expression may hence predispose cKCs and other breeds to MMVD via loss of papillary muscle integrity.
  •  
36.
  • Axelsson, Erik, et al. (författare)
  • The genomic signature of dog domestication reveals adaptation to a starch-rich diet
  • 2013
  • Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 495:7441, s. 360-364
  • Tidskriftsartikel (refereegranskat)abstract
    • The domestication of dogs. was an important episode in the development of human civilization. The precise timing and location of this event is debated(1-5) and little is known about the genetic changes that accompanied the transformation of ancient wolves into domestic dogs. Here we conduct whole-genome resequencimg of dogs and wolves to identify 3.8 million genetic variants used to identify 36 genomic regions that probably represent targets for selection during dog domestication. Nineteen of these regions contain genes important in brain function, eight of which belong to nervous system development pathways and potentially underlie behavioural changes central to dog domestication(6). Ten genes with key roles in starch digestion and fat metabolism also show signals of selection. We identify candidate mutations in key genes and provide functional support for an increased starch digestion in dogs relative to wolves. Our results indicate that novel adaptations allowing the early ancestors of modern dogs to thrive on a diet rich in starch, relative to the carnivorous diet of wolves, constituted a crucial step in the early domestication of dogs.
  •  
37.
  • Bafadhel, Mona, et al. (författare)
  • Acute Exacerbations of Chronic Obstructive Pulmonary Disease : Identification of Biologic Clusters and Their Biomarkers
  • 2011
  • Ingår i: American Journal of Respiratory and Critical Care Medicine. - 1073-449X .- 1535-4970. ; 184:6, s. 662-671
  • Tidskriftsartikel (refereegranskat)abstract
    • Rationale: Exacerbations of chronic obstructive pulmonary disease (COPD) are heterogeneous with respect to inflammation and etiology. Objectives: Investigate biomarker expression in COPD exacerbations to identify biologic clusters and determine biomarkers that recognize clinical COPD exacerbation phenotypes, namely those associated with bacteria, viruses, or eosinophilic airway inflammation. Methods: Patients with COPD were observed for 1 year at stable and exacerbation visits. Biomarkers were measured in sputum and serum. Viruses and selected bacteria were assessed in sputum by polymerase chain reaction and routine diagnostic bacterial culture. Biologic phenotypes were explored using unbiased cluster analysis and biomarkers that differentiated clinical exacerbation phenotypes were investigated. Measurements and Main Results: A total of 145 patients (101 men and 44 women) entered the study. A total of 182 exacerbations were captured from 86 patients. Four distinct biologic exacerbation clusters were identified. These were bacterial-, viral-, or eosinophilic-predominant, and a fourth associated with limited changes in the inflammatory profile termed "pauciinflammatory." Of all exacerbations, 55%, 29%, and 28% were associated with bacteria, virus, or a sputum eosinophilia. The biomarkers that best identified these clinical phenotypes were sputum IL-1 beta, 0.89 (area under receiver operating characteristic curve) (95% confidence interval [CI], 0.83-0.95); serum CXCL10, 0.83 (95% CI, 0.70-0.96); and percentage peripheral eosinophils, 0.85 (95% CI, 0.78-0.93), respectively. Conclusions: The heterogeneity of the biologic response of COPD exacerbations can be defined. Sputum IL-1 beta, serum CXCL10, and peripheral eosinophils are biomarkers of bacteria-, virus-, or eosinophil-associated exacerbations of COPD. Whether phenotype-specific biomarkers can be applied to direct therapy warrants further investigation.
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38.
  • Baker, Michelle L, et al. (författare)
  • Analysis of a set of Australian northern brown bandicoot expressed sequence tags with comparison to the genome sequence of the South American grey short tailed opossum
  • 2007
  • Ingår i: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 8, s. 50-
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Expressed sequence tags (ESTs) have been used for rapid gene discovery in a variety of organisms and provide a valuable resource for whole genome annotation. Although the genome of one marsupial, the opossum Monodelphis domestica, has now been sequenced, no EST datasets have been reported from any marsupial species. In this study we describe an EST dataset from the bandicoot, Isoodon macrourus, providing information on the transcriptional profile of the bandicoot thymus and the opportunity for a genome wide comparison between the bandicoot and opossum, two distantly related marsupial species. RESULTS: A set of 1319 ESTs was generated from sequencing randomly chosen clones from a bandicoot thymus cDNA library. The nucleic acid and deduced amino acid sequences were compared with sequences both in GenBank and the recently completed whole genome sequence of M. domestica. This study provides information on the transcriptional profile of the bandicoot thymus with the identification of genes involved in a broad range of activities including protein metabolism (24%), transcription and/or nucleic acid metabolism (10%), metabolism/energy pathways (9%), immunity (5%), signal transduction (5%), cell growth and maintenance (3%), transport (3%), cell cycle (0.7%) and apoptosis (0.5%) and a proportion of genes whose function is unknown (5.8%). Thirty four percent of the bandicoot ESTs found no match with annotated sequences in any of the public databases. Clustering and assembly of the 1319 bandicoot ESTs resulted in a set of 949 unique sequences of which 375 were unannotated ESTs. Of these, seventy one unannotated ESTs aligned to non-coding regions in the opossum, human, or both genomes, and were identified as strong non-coding RNA candidates. Eighty-four percent of the 949 assembled ESTs aligned with the M. domestica genome sequence indicating a high level of conservation between these two distantly related marsupials. CONCLUSION: This study is among the first reported marsupial EST datasets with a significant inter-species genome comparison between marsupials, providing a valuable resource for transcriptional analyses in marsupials and for future annotation of marsupial whole genome sequences.
  •  
39.
  • Bannasch, Danika, et al. (författare)
  • Localization of canine brachycephaly using an across breed mapping approach
  • 2010
  • Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 5:3, s. e9632-
  • Tidskriftsartikel (refereegranskat)abstract
    • The domestic dog, Canis familiaris, exhibits profound phenotypic diversity and is an ideal model organism for the genetic dissection of simple and complex traits. However, some of the most interesting phenotypes are fixed in particular breeds and are therefore less tractable to genetic analysis using classical segregation-based mapping approaches. We implemented an across breed mapping approach using a moderately dense SNP array, a low number of animals and breeds carefully selected for the phenotypes of interest to identify genetic variants responsible for breed-defining characteristics. Using a modest number of affected (10-30) and control (20-60) samples from multiple breeds, the correct chromosomal assignment was identified in a proof of concept experiment using three previously defined loci; hyperuricosuria, white spotting and chondrodysplasia. Genome-wide association was performed in a similar manner for one of the most striking morphological traits in dogs: brachycephalic head type. Although candidate gene approaches based on comparable phenotypes in mice and humans have been utilized for this trait, the causative gene has remained elusive using this method. Samples from nine affected breeds and thirteen control breeds identified strong genome-wide associations for brachycephalic head type on Cfa 1. Two independent datasets identified the same genomic region. Levels of relative heterozygosity in the associated region indicate that it has been subjected to a selective sweep, consistent with it being a breed defining morphological characteristic. Genotyping additional dogs in the region confirmed the association. To date, the genetic structure of dog breeds has primarily been exploited for genome wide association for segregating traits. These results demonstrate that non-segregating traits under strong selection are equally tractable to genetic analysis using small sample numbers.
  •  
40.
  • Baranowska Körberg, Izabella, et al. (författare)
  • A Simple Repeat Polymorphism in the MITF-M Promoter Is a Key Regulator of White Spotting in Dogs
  • 2014
  • Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:8, s. e104363-
  • Tidskriftsartikel (refereegranskat)abstract
    • The white spotting locus (S) in dogs is colocalized with the MITF (microphtalmia-associated transcription factor) gene. The phenotypic effects of the four S alleles range from solid colour (S) to extreme white spotting (s(w)). We have investigated four candidate mutations associated with the s(w) allele, a SINE insertion, a SNP at a conserved site and a simple repeat polymorphism all associated with the MITF-M promoter as well as a 12 base pair deletion in exon 1B. The variants associated with white spotting at all four loci were also found among wolves and we conclude that none of these could be a sole causal mutation, at least not for extreme white spotting. We propose that the three canine white spotting alleles are not caused by three independent mutations but represent haplotype effects due to different combinations of causal polymorphisms. The simple repeat polymorphism showed extensive diversity both in dogs and wolves, and allele-sharing was common between wolves and white spotted dogs but was non-existent between solid and spotted dogs as well as between wolves and solid dogs. This finding was unexpected as Solid is assumed to be the wild-type allele. The data indicate that the simple repeat polymorphism has been a target for selection during dog domestication and breed formation. We also evaluated the significance of the three MITF-M associated polymorphisms with a Luciferase assay, and found conclusive evidence that the simple repeat polymorphism affects promoter activity. Three alleles associated with white spotting gave consistently lower promoter activity compared with the allele associated with solid colour. We propose that the simple repeat polymorphism affects cooperativity between transcription factors binding on either flanking sides of the repeat. Thus, both genetic and functional evidence show that the simple repeat polymorphism is a key regulator of white spotting in dogs.
  •  
41.
  • Beichman, Annabel C, et al. (författare)
  • Aquatic Adaptation and Depleted Diversity : A Deep Dive into the Genomes of the Sea Otter and Giant Otter.
  • 2019
  • Ingår i: Molecular biology and evolution. - : Oxford University Press (OUP). - 0737-4038 .- 1537-1719. ; 36:12, s. 2631-2655
  • Tidskriftsartikel (refereegranskat)abstract
    • Despite its recent invasion into the marine realm, the sea otter (Enhydra lutris) has evolved a suite of adaptations for life in cold coastal waters, including limb modifications and dense insulating fur. This uniquely dense coat led to the near-extinction of sea otters during the 18th-20th century fur trade and an extreme population bottleneck. We used the de novo genome of the southern sea otter (E. l. nereis) to reconstruct its evolutionary history, identify genes influencing aquatic adaptation, and detect signals of population bottlenecks. We compared the genome of the southern sea otter with the tropical freshwater-living giant otter (Pteronura brasiliensis) to assess common and divergent genomic trends between otter species, and with the closely related northern sea otter (E. l. kenyoni) to uncover population-level trends. We found signals of positive selection in genes related to aquatic adaptations, particularly limb development and polygenic selection on genes related to hair follicle development. We found extensive pseudogenization of olfactory receptor genes in both the sea otter and giant otter lineages, consistent with patterns of sensory gene loss in other aquatic mammals. At the population level, the southern sea otter and the northern sea otter showed extremely low genomic diversity, signals of recent inbreeding, and demographic histories marked by population declines. These declines may predate the fur trade and appear to have resulted in an increase in putatively deleterious variants that could impact the future recovery of the sea otter.
  •  
42.
  • Bellone, Rebecca R, et al. (författare)
  • Fine-mapping and mutation analysis of TRPM1 : a candidate gene for leopard complex (LP) spotting and congenital stationary night blindness in horses
  • 2010
  • Ingår i: Briefings in Functional Genomics & Proteomics. - : Oxford University Press (OUP). - 1473-9550 .- 1477-4062 .- 2041-2649 .- 2041-2657. ; 9:3, s. 193-207
  • Tidskriftsartikel (refereegranskat)abstract
    • Leopard Complex spotting occurs in several breeds of horses and is caused by an incompletely dominant allele (LP). Homozygosity for LP is also associated with congenital stationary night blindness (CSNB) in Appaloosa horses. Previously, LP was mapped to a 6 cm region on ECA1 containing the candidate gene TRPM1 (Transient Receptor Potential Cation Channel, Subfamily M, Member 1) and decreased expression of this gene, measured by qRT-PCR, was identified as the likely cause of both spotting and ocular phenotypes. This study describes investigations for a mutation causing or associated with the Leopard Complex and CSNB phenotype in horses. Re-sequencing of the gene and associated splice sites within the 105 624 bp genomic region of TRPM1 led to the discovery of 18 SNPs. Most of the SNPs did not have a predictive value for the presence of LP. However, one SNP (ECA1:108,249,293 C>T) found within intron 11 had a strong (P < 0.0005), but not complete, association with LP and CSNB and thus is a good marker but unlikely to be causative. To further localize the association, 70 SNPs spanning over two Mb including the TRPM1 gene were genotyped in 192 horses from three different breeds segregating for LP. A single 173 kb haplotype associated with LP and CSNB (ECA1: 108,197,355- 108,370,150) was identified. Illumina sequencing of 300 kb surrounding this haplotype revealed 57 SNP variants. Based on their localization within expressed sequences or regions of high sequence conservation across mammals, six of these SNPs were considered to be the most likely candidate mutations. While the precise function of TRPM1 remains to be elucidated, this work solidifies its functional role in both pigmentation and night vision. Further, this work has identified several potential regulatory elements of the TRPM1 gene that should be investigated further in this and other species.
  •  
43.
  • Berglund, Jonas, 1983- (författare)
  • Meiotic Recombination in Human and Dog : Targets, Consequences and Implications for Genome Evolution
  • 2014
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Understanding the mechanism of recombination has important implications for genome evolution and genomic variability. The work presented in this thesis studies the properties of recombination by investigating the effects it has on genome evolution in humans and dogs.Using alignments of human genes with chimpanzee and macaque orthologues we studied substitution patterns along the human lineage and scanned for evidence of positive selection. The properties mirror the situation in human non-coding sequences with the fixation bias ‘GC-biased gene conversion’ (gBGC) as a driving force in the most rapidly evolving regions. By assigning candidate genes to distinct classes of evolutionary forces we quantified the extent of those genes affected by gBGC to 20%. This suggests that human-specific characters can be prompted by the fixation bias of gBGC, which can be mistaken for selection.The gene PRDM9 controls recombination in most mammals, but is lacking in dogs. Using whole-genome alignments of dog with related species we examined the effects of PRDM9 inactivation. Additionally, we analyzed genomic variation in the genomes of several dog breeds. We identified that non-allelic homologous recombination (NAHR) via sequence identity, often GC-rich, creates structural variants of genomic regions. We show that these regions, which are also found in dog recombination hotspots, are a subset of unmethylated CpG-islands (CGIs). We inferred that CGIs have experienced a drastic increase in biased substitution rates, concurrent with a shift of recombination to target these regions. This enables recurrent episodes of gBGC to shape their distribution.The work presented in this thesis demonstrates the importance of meiotic recombination on patterns of molecular evolution and genomic variability in humans and dogs. Bioinformatic analyses identified mechanisms that regulate genome composition. gBGC is presented as an alternative to positive selection and is revealed as a major factor affecting allele configuration and the emergence of accelerated evolution on the human lineage. Characterization of recombination-induced sequence patterns highlights the potential of non-methylation and establishes unmethylated CGIs as targets of meiotic recombination in dogs. These observations describe recombination as an interesting process in genome evolution and provide further insights into the mechanisms of genomic variability.
  •  
44.
  • Berglund, Jonas, et al. (författare)
  • Novel origins of copy number variation in the dog genome
  • 2012
  • Ingår i: Genome Biology. - : Springer Science and Business Media LLC. - 1465-6906 .- 1474-760X .- 1474-7596. ; 13:8, s. R73-
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Copy number variants (CNVs) account for substantial variation between genomes and are a major source of normal and pathogenic phenotypic differences. The dog is an ideal model to investigate mutational mechanisms that generate CNVs as its genome lacks a functional ortholog of the PRDM9 gene implicated in recombination and CNV formation in humans. Here we comprehensively assay CNVs using high-density array comparative genomic hybridization in 50 dogs from 17 dog breeds and 3 gray wolves. RESULTS: We use a stringent new method to identify a total of 430 high-confidence CNV loci, which range in size from 9 kb to 1.6 Mb and span 26.4 Mb, or 1.08%, of the assayed dog genome, overlapping 413 annotated genes. Of CNVs observed in each breed, 98% are also observed in multiple breeds. CNVs predicted to disrupt gene function are significantly less common than expected by chance. We identify a significant overrepresentation of peaks of GC content, previously shown to be enriched in dog recombination hotspots, in the vicinity of CNV breakpoints. CONCLUSIONS: A number of the CNVs identified by this study are candidates for generating breed-specific phenotypes. Purifying selection seems to be a major factor shaping structural variation in the dog genome, suggesting that many CNVs are deleterious. Localized peaks of GC content appear to be novel sites of CNV formation in the dog genome by non-allelic homologous recombination, potentially activated by the loss of PRDM9. These sequence features may have driven genome instability and chromosomal rearrangements throughout canid evolution.
  •  
45.
  • Bergqvist, Kerstin, 1944-, et al. (författare)
  • Introduktion och forskningsöversikt
  • 2001. - 1
  • Ingår i: Interaktion i pedagogiska sammanhang. - Stockholm : Liber. - 9147049839 - 9789147049837 ; , s. 9-35
  • Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
    • Hur går det till när barn leker eller när ungdomar samtalar i skolan, och vad betyder leken och samtalen för deras lärande, socialisation och identitetsskapande? Författarna till Interaktion i pedagogiska sammanhang presenterar ett perspektiv för att svara på sådana frågor, och visar i sex undersökande kapitel hur perspektivet kan användas. Bokens utgångspunkt är konstruktionistisk. Det innebär att socialisation och lärande ses som något skapat i interaktion. Med den utgångspunkten är det nödvändigt att i detalj analysera barn och ungdomars interaktion - med varandra och med vuxna - för att förstå vilka erfarenheter de gör i olika pedagogiska sammanhang.
  •  
46.
  • Bergström, Staffan, et al. (författare)
  • Utred självvalt livsslut
  • 2016
  • Ingår i: Läkartidningen. - 0023-7205. ; 113:34-35
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
  •  
47.
  •  
48.
  • Bianchi, Matteo, et al. (författare)
  • A Multi-Breed Genome-Wide Association Analysis for Canine Hypothyroidism Identifies a Shared Major Risk Locus on CFA12
  • 2015
  • Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:8
  • Tidskriftsartikel (refereegranskat)abstract
    • Hypothyroidism is a complex clinical condition found in both humans and dogs, thought to be caused by a combination of genetic and environmental factors. In this study we present a multi-breed analysis of predisposing genetic risk factors for hypothyroidism in dogs using three high-risk breeds-the Gordon Setter, Hovawart and the Rhodesian Ridgeback. Using a genome-wide association approach and meta-analysis, we identified a major hypothyroidism risk locus shared by these breeds on chromosome 12 (p = 2.1x10(-11)). Further characterisation of the candidate region revealed a shared similar to 167 kb risk haplotype (4,915,018-5,081,823 bp), tagged by two SNPs in almost complete linkage disequilibrium. This breed-shared risk haplotype includes three genes (LHFPL5, SRPK1 and SLC26A8) and does not extend to the dog leukocyte antigen (DLA) class II gene cluster located in the vicinity. These three genes have not been identified as candidate genes for hypothyroid disease previously, but have functions that could potentially contribute to the development of the disease. Our results implicate the potential involvement of novel genes and pathways for the development of canine hypothyroidism, raising new possibilities for screening, breeding programmes and treatments in dogs. This study may also contribute to our understanding of the genetic etiology of human hypothyroid disease, which is one of the most common endocrine disorders in humans.
  •  
49.
  • Bianchi, Matteo, et al. (författare)
  • Contribution of rare genetic variation to disease susceptibility in a large Scandinavian myositis cohort
  • 2022
  • Ingår i: Arthritis & Rheumatology. - : John Wiley & Sons. - 2326-5191 .- 2326-5205. ; 74:2, s. 342-352
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of complex autoimmune conditions characterized by inflammation in skeletal muscle and extramuscular compartments, and interferon (IFN) system activation. We undertook this study to examine the contribution of genetic variation to disease susceptibility and to identify novel avenues for research in IIMs.Methods Targeted DNA sequencing was used to mine coding and potentially regulatory single nucleotide variants from ~1,900 immune-related genes in a Scandinavian case–control cohort of 454 IIM patients and 1,024 healthy controls. Gene-based aggregate testing, together with rare variant– and gene-level enrichment analyses, was implemented to explore genotype–phenotype relations.Results Gene-based aggregate tests of all variants, including rare variants, identified IFI35 as a potential genetic risk locus for IIMs, suggesting a genetic signature of type I IFN pathway activation. Functional annotation of the IFI35 locus highlighted a regulatory network linked to the skeletal muscle–specific gene PTGES3L, as a potential candidate for IIM pathogenesis. Aggregate genetic associations with AGER and PSMB8 in the major histocompatibility complex locus were detected in the antisynthetase syndrome subgroup, which also showed a less marked genetic signature of the type I IFN pathway. Enrichment analyses indicated a burden of synonymous and noncoding rare variants in IIM patients, suggesting increased disease predisposition associated with these classes of rare variants.Conclusion Our study suggests the contribution of rare genetic variation to disease susceptibility in IIM and specific patient subgroups, and pinpoints genetic associations consistent with previous findings by gene expression profiling. These features highlight genetic profiles that are potentially relevant to disease pathogenesis.
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50.
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