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| 2. |
- Bannasch, Danika, et al.
(författare)
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Localization of canine brachycephaly using an across breed mapping approach
- 2010
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 5:3, s. e9632-
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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.
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| 3. |
- Downs, Louise M., et al.
(författare)
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A Frameshift Mutation in Golden Retriever Dogs with Progressive Retinal Atrophy Endorses SLC4A3 as a Candidate Gene for Human Retinal Degenerations
- 2011
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Ingår i: PLoS one. - : Public Library of Science (PLoS). - 1932-6203. ; 6:6, s. e21452-
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Tidskriftsartikel (refereegranskat)abstract
- Progressive retinal atrophy (PRA) in dogs, the canine equivalent of retinitis pigmentosa (RP) in humans, is characterised by vision loss due to degeneration of the photoreceptor cells in the retina, eventually leading to complete blindness. It affects more than 100 dog breeds, and is caused by numerous mutations. RP affects 1 in 4000 people in the Western world and 70% of causal mutations remain unknown. Canine diseases are natural models for the study of human diseases and are becoming increasingly useful for the development of therapies in humans. One variant, prcd-PRA, only accounts for a small proportion of PRA cases in the Golden Retriever (GR) breed. Using genome-wide association with 27 cases and 19 controls we identified a novel PRA locus on CFA37 (p(raw) = 1.94x10(-10), p(genome) = 1.0x10(-5)), where a 644 kb region was homozygous within cases. A frameshift mutation was identified in a solute carrier anion exchanger gene (SLC4A3) located within this region. This variant was present in 56% of PRA cases and 87% of obligate carriers, and displayed a recessive mode of inheritance with full penetrance within those lineages in which it segregated. Allele frequencies are approximately 4% in the UK, 6% in Sweden and 2% in France, but the variant has not been found in GRs from the US. A large proportion of cases (approximately 44%) remain unexplained, indicating that PRA in this breed is genetically heterogeneous and caused by at least three mutations. SLC4A3 is important for retinal function and has not previously been associated with spontaneously occurring retinal degenerations in any other species, including humans.
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| 4. |
- Einarsdottir, Berglind Osk, 1979, et al.
(författare)
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Melanoma patient-derived xenografts accurately model the disease and develop fast enough to guide treatment decisions.
- 2014
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 5:20, s. 9609-18
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Tidskriftsartikel (refereegranskat)abstract
- The development of novel therapies against melanoma would benefit from individualized tumor models to ensure the rapid and accurate identification of biomarkers of therapy response. Previous studies have suggested that patient-derived xenografts (PDXes) could be useful. However, the utility of PDXes in guiding real-time treatment decisions has only been reported in anecdotal forms. Here tumor biopsies from patients with stage III and IV metastatic malignant melanoma were transplanted into immunocompromised mice to generate PDXes. 23/26 melanoma biopsies generated serially transplantable PDX models, and their histology, mutation status and expression profile resembled their corresponding patient biopsy. The potential treatment for one patient was revealed by an in vitro drug screen and treating PDXes with the MEK inhibitor trametinib. In another patient, the BRAF mutation predicted the response of both the patient and its corresponding PDXes to MAPK-targeted therapy. Importantly, in this unselected group of patients, the time from biopsy for generation of PDXes until death was significantly longer than the time required to reach the treatment phase of the PDXes. Thus, it could be clinically meaningful to use this type of platform for melanoma patients as a pre-selection tool in clinical trials.
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| 5. |
- Olsson, Mia, et al.
(författare)
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A Novel Unstable Duplication Upstream of HAS2 Predisposes to a Breed-Defining Skin Phenotype and a Periodic Fever Syndrome in Chinese Shar-Pei Dogs
- 2011
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 7:3, s. e1001332-
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Tidskriftsartikel (refereegranskat)abstract
- Hereditary periodic fever syndromes are characterized by recurrent episodes of fever and inflammation with no known pathogenic or autoimmune cause. In humans, several genes have been implicated in this group of diseases, but the majority of cases remain unexplained. A similar periodic fever syndrome is relatively frequent in the Chinese Shar-Pei breed of dogs. In the western world, Shar-Pei have been strongly selected for a distinctive thick and heavily folded skin. In this study, a mutation affecting both these traits was identified. Using genome-wide SNP analysis of Shar-Pei and other breeds, the strongest signal of a breed-specific selective sweep was located on chromosome 13. The same region also harbored the strongest genome-wide association (GWA) signal for susceptibility to the periodic fever syndrome (p(raw) = 2.3 x 10(-6), p(genome) = 0.01). Dense targeted resequencing revealed two partially overlapping duplications, 14.3 Kb and 16.1 Kb in size, unique to Shar-Pei and upstream of the Hyaluronic Acid Synthase 2 (HAS2) gene. HAS2 encodes the rate-limiting enzyme synthesizing hyaluronan (HA), a major component of the skin. HA is up-regulated and accumulates in the thickened skin of Shar-Pei. A high copy number of the 16.1 Kb duplication was associated with an increased expression of HAS2 as well as the periodic fever syndrome (p, < 0.0001). When fragmented, HA can act as a trigger of the innate immune system and stimulate sterile fever and inflammation. The strong selection for the skin phenotype therefore appears to enrich for a pleiotropic mutation predisposing these dogs to a periodic fever syndrome. The identification of HA as a major risk factor for this canine disease raises the potential of this glycosaminoglycan as a risk factor for human periodic fevers and as an important driver of chronic inflammation.
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| 6. |
- Truvé, Katarina
(författare)
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Bioinformatics mining for disease causing mutations : using the dog genome as a model for human disease
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Humans and dogs share many common diseases, and it has been shown that the identification of mutations that cause disease in dogs can help unravel the genetic basis for a similar disease in humans. Mapping of traits and disease in dogs is not a new idea, but the sequencing of the whole dog genome, the creation of a dense SNP maps followed by the development of SNP arrays for high throughput genotyping has led to new facilitated mapping procedures. Each dog breed can be seen as a genetic isolate and certain breeds are often predisposed to specific diseases. Because of the genomic structure of the dog genome and the availability of new resources for disease mapping, the dog has been proposed to be especially advantageous for the mapping of complex disease that is difficult to map in human outbred populations. In this thesis, the aim has been to identify disease-causing mutations for three complex diseases in dogs with the presence of similar conditions in humans. Emphasis has been on bioinformatics analyses of genome-wide SNP and large re-sequencing data. In the dog breed Nova Scotia duck tolling retriever it is common with an immune-mediated disease complex that resembles human systemic lupus erythematosus (SLE). In paper I we used a two-stage genome-wide association mapping method and successfully located several susceptibility loci in dogs for this disease complex. In paper II we identified a mutation that had been under selection in the Shar-Pei breed, causing both a breed-defining wrinkled skin phenotype and an autoinflammatory fever disease. Because the locus had been under selection we used an alternative mapping approach, called homozygosity mapping to identify the locus, followed by re-sequencing using next generation sequencing technologies. In paper III we report the development of a web-based tool that facilitates analyses and extraction of essential information from the large amount of data produced by next generation sequencing projects. In paper IV we used across-breed genome-wide association mapping to identify risk factors for glioma, a type of malignant brain tumor fatal to both human and dogs. For the three diseases excellent candidate genes have been identified, and continued research might has the potential to lead to better treatment options and thus benefit both dogs and humans.
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| 10. |
- Wilbe, Maria, et al.
(författare)
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Genome-wide association mapping identifies multiple loci for a canine SLE-related disease complex.
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:3, s. 250-254
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Tidskriftsartikel (refereegranskat)abstract
- The unique canine breed structure makes dogs an excellent model for studying genetic diseases. Within a dog breed, linkage disequilibrium is extensive, enabling genome-wide association (GWA) with only around 15,000 SNPs and fewer individuals than in human studies. Incidences of specific diseases are elevated in different breeds, indicating that a few genetic risk factors might have accumulated through drift or selective breeding. In this study, a GWA study with 81 affected dogs (cases) and 57 controls from the Nova Scotia duck tolling retriever breed identified five loci associated with a canine systemic lupus erythematosus (SLE)-related disease complex that includes both antinuclear antibody (ANA)-positive immune-mediated rheumatic disease (IMRD) and steroid-responsive meningitis-arteritis (SRMA). Fine mapping with twice as many dogs validated these loci. Our results indicate that the homogeneity of strong genetic risk factors within dog breeds allows multigenic disorders to be mapped with fewer than 100 cases and 100 controls, making dogs an excellent model in which to identify pathways involved in human complex diseases.
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