| 1. |
- Groenen, M. A., et al.
(författare)
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Analyses of pig genomes provide insight into porcine demography and evolution
- 2012
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 491:7424, s. 393-398
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Tidskriftsartikel (refereegranskat)abstract
- For 10,000 years pigs and humans have shared a close and complex relationship. From domestication to modern breeding practices, humans have shaped the genomes of domestic pigs. Here we present the assembly and analysis of the genome sequence of a female domestic Duroc pig (Sus scrofa) and a comparison with the genomes of wild and domestic pigs from Europe and Asia. Wild pigs emerged in South East Asia and subsequently spread across Eurasia. Our results reveal a deep phylogenetic split between European and Asian wild boars approximately 1 million years ago, and a selective sweep analysis indicates selection on genes involved in RNA processing and regulation. Genes associated with immune response and olfaction exhibit fast evolution. Pigs have the largest repertoire of functional olfactory receptor genes, reflecting the importance of smell in this scavenging animal. The pig genome sequence provides an important resource for further improvements of this important livestock species, and our identification of many putative disease-causing variants extends the potential of the pig as a biomedical model.
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| 2. |
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| 4. |
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| 5. |
- Rubin, Carl-Johan, et al.
(författare)
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Strong signatures of selection in the domestic pig genome
- 2012
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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. ; 109:48, s. 19529-19536
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Tidskriftsartikel (refereegranskat)abstract
- Domestication of wild boar (Sus scrofa) and subsequent selection have resulted in dramatic phenotypic changes in domestic pigs for a number of traits, including behavior, body composition, reproduction, and coat color. Here we have used whole-genome resequencing to reveal some of the loci that underlie phenotypic evolution in European domestic pigs. Selective sweep analyses revealed strong signatures of selection at three loci harboring quantitative trait loci that explain a considerable part of one of the most characteristic morphological changes in the domestic pig - the elongation of the back and an increased number of vertebrae. The three loci were associated with the NR6A1, PLAG1, and LCORL genes. The latter two have repeatedly been associated with loci controlling stature in other domestic animals and in humans. Most European domestic pigs are homozygous for the same haplotype at these three loci. We found an excess of derived nonsynonymous substitutions in domestic pigs, most likely reflecting both positive selection and relaxed purifying selection after domestication. Our analysis of structural variation revealed four duplications at the KIT locus that were exclusively present in white or white-spotted pigs, carrying the Dominant white, Patch, or Belt alleles. This discovery illustrates how structural changes have contributed to rapid phenotypic evolution in domestic animals and how alleles in domestic animals may evolve by the accumulation of multiple causative mutations as a response to strong directional selection.
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| 6. |
- Sjöstrand, Karin, et al.
(författare)
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Breed Differences in Natriuretic Peptides in Healthy Dogs
- 2014
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Ingår i: Journal of Veterinary Internal Medicine. - : Wiley. - 0891-6640 .- 1939-1676. ; 28:2, s. 451-457
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Tidskriftsartikel (refereegranskat)abstract
- Background Measurement of plasma concentration of natriuretic peptides (NPs) is suggested to be of value in diagnosis of cardiac disease in dogs, but many factors other than cardiac status may influence their concentrations. Dog breed potentially is 1 such factor. Objective To investigate breed variation in plasma concentrations of pro-atrial natriuretic peptide 31-67 (proANP 31-67) and N-terminal B-type natriuretic peptide (NT-proBNP) in healthy dogs. Animals 535 healthy, privately owned dogs of 9 breeds were examined at 5 centers as part of the European Union (EU) LUPA project. Methods Absence of cardiovascular disease or other clinically relevant organ-related or systemic disease was ensured by thorough clinical investigation. Plasma concentrations of proANP 31-67 and NT-proBNP were measured by commercially available ELISA assays. Results Overall significant breed differences were found in proANP 31-67 (P<.0001) and NT-proBNP (P<.0001) concentrations. Pair-wise comparisons between breeds differed in approximately 50% of comparisons for proANP 31-67 as well as NT-proBNP concentrations, both when including all centers and within each center. Interquartile range was large for many breeds, especially for NT-proBNP. Among included breeds, Labrador Retrievers and Newfoundlands had highest median NT-proBNP concentrations with concentrations 3 times as high as those of Dachshunds. German Shepherds and Cavalier King Charles Spaniels had the highest median proANP 31-67 concentrations, twice the median concentration in Doberman Pinschers. Conclusions and Clinical Importance Considerable interbreed variation in plasma NP concentrations was found in healthy dogs. Intrabreed variation was large in several breeds, especially for NT-proBNP. Additional studies are needed to establish breed-specific reference ranges.
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| 7. |
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| 8. |
- Ameen, Carly, et al.
(författare)
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Specialized sledge dogs accompanied Inuit dispersal across the North American Arctic
- 2019
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Ingår i: Proceedings of the Royal Society of London. Biological Sciences. - : The Royal Society. - 0962-8452 .- 1471-2954. ; 286:1916
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Tidskriftsartikel (refereegranskat)abstract
- Domestic dogs have been central to life in the North American Arctic for millennia. The ancestors of the Inuit were the first to introduce the widespread usage of dog sledge transportation technology to the Americas, but whether the Inuit adopted local Palaeo-Inuit dogs or introduced a new dog population to the region remains unknown. To test these hypotheses, we generated mitochondrial DNA and geometric morphometric data of skull and dental elements from a total of 922 North American Arctic dogs and wolves spanning over 4500 years. Our analyses revealed that dogs from Inuit sites dating from 2000 BP possess morphological and genetic signatures that distinguish them from earlier Palaeo-Inuit dogs, and identified a novel mitochondrial clade in eastern Siberia and Alaska. The genetic legacy of these Inuit dogs survives today in modern Arctic sledge dogs despite phenotypic differences between archaeological and modern Arctic dogs. Together, our data reveal that Inuit dogs derive from a secondary pre-contact migration of dogs distinct from Palaeo-Inuit dogs, and probably aided the Inuit expansion across the North American Arctic beginning around 1000 BP.
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| 11. |
- Fredholm, Simon, et al.
(författare)
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SATB1 in Malignant T Cells
- 2018
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Ingår i: Journal of Investigative Dermatology. - : Elsevier. - 0022-202X .- 1523-1747. ; 138:8, s. 1805-1815
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Tidskriftsartikel (refereegranskat)abstract
- Deficient expression of SATB1 hampers thymocyte development and results in inept T-cell lineages. Recent data implicate dysregulated SATB1 expression in the pathogenesis of mycosis fungoides, the most frequent variant of cutaneous T-cell lymphoma. Here, we report on a disease stage-associated decrease of SATB1 expression and an inverse expression of STAT5 and SATB1 in situ. STAT5 inhibited SATB1 expression through induction of microRNA-155. Decreased SATB1 expression triggered enhanced expression of IL-5 and IL-9 (but not IL-6 and IL-32), whereas increased SATB1 expression had the opposite effect, indicating that the microRNA-155 target SATB1 is a repressor of IL-5 and IL-9 in malignant T cells. In accordance, inhibition of STAT5 and its upstream activator JAK3 triggered increased SATB1 expression and a concomitant suppression of IL-5 and IL-9 expression in malignant T cells. In conclusion, we provide a mechanistic link between the proto-oncogenic JAK3/STAT5/microRNA-155 pathway, SATB1, and cytokines linked to CTCL severity and progression, indicating that SATB1 dysregulation is involved in cutaneous T-cell lymphoma pathogenesis.
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| 12. |
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| 14. |
- Höglund, Katja, et al.
(författare)
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Effect of Breed on Plasma Endothelin-1 Concentration, Plasma Renin Activity, and Serum Cortisol Concentration in Healthy Dogs
- 2016
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Ingår i: Journal of Veterinary Internal Medicine. - : Wiley. - 0891-6640 .- 1939-1676. ; 30:2, s. 566-573
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Tidskriftsartikel (refereegranskat)abstract
- Background: There are breed differences in several blood variables in healthy dogs.Objective: Investigate breed variation in plasma endothelin-1 (ET-1) concentration, plasma renin activity, and serum cortisol concentration.Animals: Five-hundred and thirty-one healthy dogs of 9 breeds examined at 5 centers (2-4 breeds/center).Methods: Prospective observational study. Circulating concentrations of ET-1 and cortisol, and renin activity, were measured using commercially available assays. Absence of organ-related or systemic disease was ensured by thorough clinical investigations, including blood pressure measurement, echocardiography, ECG, blood and urine analysis.Results: Median ET-1 concentration was 1.29 (interquartile range [IQR], 0.97-1.82) pg/mL, median cortisol concentration 46.0 (IQR, 29.0-80.8) nmol/L, and median renin activity 0.73 (IQR, 0.48-1.10) ng/mL/h in all dogs. Overall, breed differences were found in ET-1 and cortisol concentrations, and renin activity (P < .0001 for all). Pair-wise comparisons between breeds differed in 67% of comparisons for ET-1, 22% for cortisol, and 19% for renin activity, respectively. Within centers, breed differences were found at 5/5 centers for ET-1, 4/5 centers for cortisol, and 2/5 centers for renin activity. Newfoundlands had highest median ET-1 concentration, 3 times higher than Cavalier King Charles Spaniels, Doberman Pinschers, and Dachshunds. Median renin activity was highest in Dachshunds, twice the median value in Newfoundlands and Boxers. Median cortisol concentration was highest in Finnish Lapphunds, almost 3 times higher than in Boxers.Conclusions and Clinical Importance: Breed variation might be important to take into consideration when interpreting test results in clinical studies.
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| 15. |
- Jacobsen, M, et al.
(författare)
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Refined candidate region specified by haplotype sharing for Escherichia coli F4ab/F4ac susceptibility alleles in pigs
- 2010
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Ingår i: Animal Genetics. - : Wiley. - 0268-9146 .- 1365-2052. ; 41:1, s. 21-25
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Tidskriftsartikel (refereegranskat)abstract
- Infection of the small intestine by enterotoxigenic Escherichia coli F4ab/ac is a major welfare problem and financial burden for the pig industry. Natural resistance to this infection is inherited as a Mendelian recessive trait, and a polymorphism in the MUC4 gene segregating for susceptibility/resistance is presently used in a selection programme by the Danish pig breeding industry. To elucidate the genetic background involved in E. coli F4ab/ac susceptibility in pigs, a detailed haplotype map of the porcine candidate region was established. This region covers approximately 3.7 Mb. The material used for the study is a three generation family, where the founders are two Wild boars and eight Large White sows. All pigs have been phenotyped for susceptibility to F4ab/ac using an adhesion assay. Their haplotypes are known from segregation analysis using flanking markers. By a targeted approach, the candidate region was subjected to screening for polymorphisms, mainly focusing on intronic sequences. A total of 18 genes were partially sequenced, and polymorphisms were identified in GP5, CENTB2, APOD, PCYT1A, OSTalpha, ZDHHC19, TFRC, ACK1, MUC4, MUC20, KIAA0226, LRCH3 and MUC13. Overall, 227 polymorphisms were discovered in the founder generation. The analysis revealed a large haplotype block, spanning at least 1.5 Mb around MUC4, to be associated with F4ab/ac susceptibility.
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| 18. |
- Lindahl, Lise M., et al.
(författare)
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STAT5 induces miR-21 expression in cutaneous T cell lymphoma
- 2016
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:29, s. 45730-45744
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Tidskriftsartikel (refereegranskat)abstract
- In cutaneous T cell lymphomas (CTCL), miR-21 is aberrantly expressed in skin and peripheral blood and displays anti-apoptotic properties in malignant T cells. It is, however, unclear exactly which cells express miR-21 and what mechanisms regulate miR-21. Here, we demonstrate miR-21 expression in situ in both malignant and reactive lymphocytes as well as stromal cells. qRT-PCR analysis of 47 patients with mycosis fungoides (MF) and Sezary Syndrome (SS) confirmed an increased miR- 21 expression that correlated with progressive disease. In cultured malignant T cells miR-21 expression was inhibited by Tofacitinib (CP-690550), a clinical-grade JAK3 inhibitor. Chromatin immunoprecipitation (ChIP) analysis showed direct binding of STAT5 to the miR-21 promoter. Cytokine starvation ex vivo triggered a decrease in miR-21 expression, whereas IL-2 induced an increased miR-21 expression in primary SS T cells and cultured cytokine-dependent SS cells (SeAx). siRNA-mediated depletion of STAT5 inhibited constitutive- and IL-2- induced miR-21 expression in cytokine- independent and dependent T cell lines, respectively. IL-15 and IL-2 were more potent than IL-21 in inducing miR-21 expression in the cytokine-dependent T cells. In conclusion, we provide first evidence that miR-21 is expressed in situ in CTCL skin lesions, induced by IL-2 and IL-15 cytokines, and is regulated by STAT5 in malignant T cells. Thus, our data provide novel evidence for a pathological role of IL-2Rg cytokines in promoting expression of the oncogenic miR-21 in CTCL.
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| 19. |
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| 20. |
- Reimer, C., et al.
(författare)
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Analysis of porcine body size variation using re-sequencing data of miniature and large pigs
- 2018
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Ingår i: BMC Genomics. - : BMC. - 1471-2164. ; 19
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Tidskriftsartikel (refereegranskat)abstract
- Background: Domestication has led to substantial phenotypic and genetic variation in domestic animals. In pigs, the size of so called minipigs differs by one order of magnitude compared to breeds of large body size. We used biallelic SNPs identified from re-sequencing data to compare various publicly available wild and domestic populations against two minipig breeds to gain better understanding of the genetic background of the extensive body size variation. We combined two complementary measures, expected heterozygosity and the composite likelihood ratio test implemented in "SweepFinder", to identify signatures of selection in Minipigs. We intersected these sweep regions with a measure of differentiation, namely F-ST, to remove regions of low variation across pigs. An extraordinary large sweep between 52 and 61 Mb on chromosome X was separately analyzed based on SNP-array data of F-2 individuals from a cross of Goettingen Minipigs and large pigs. Results: Selective sweep analysis identified putative sweep regions for growth and subsequent gene annotation provided a comprehensive set of putative candidate genes. A long swept haplotype on chromosome X, descending from the Goettingen Minipig founders was associated with a reduction of adult body length by 3% in F-2 cross-breds. Conclusion: The resulting set of genes in putative sweep regions implies that the genetic background of body size variation in pigs is polygenic rather than mono-or oligogenic. Identified genes suggest alterations in metabolic functions and a possible insulin resistance to contribute to miniaturization. A size QTL located within the sweep on chromosome X, with an estimated effect of 3% on body length, is comparable to the largest known in pigs or other species. The androgen receptor AR, previously known to influence pig performance and carcass traits, is the most obvious potential candidate gene within this region.
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| 22. |
- Arslan, G, et al.
(författare)
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P2Y receptors contribute to ATP-induced increases in intracellular calcium in differentiated but not undifferentiated PC12 cells
- 2000
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Ingår i: Neuropharmacology. - 1873-7064 .- 0028-3908. ; 39:3, s. 482-496
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Tidskriftsartikel (refereegranskat)abstract
- ATP-induced Ca2+ transients were examined in individual PC12 cells of a well defined clone, before and after treatment with nerve growth factor (NGF) to induce a neurone-like phenotype. Using reverse transcriptase PCR these cells were found to express mRNA for several P2 receptors. In undifferentiated cells the ATP-induced Ca2+ response was entirely dependent on Ca2+ influx, could not be mimicked by UTP, alpha,beta-methylene ATP or dibenzoyl ATP or be blocked by pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS). ATP had no significant effect on levels of cyclic AMP or inositol 1,4,5-trisphosphate (InsP3). These results suggest that in undifferentiated PC12 cells ATP mainly acts on a P2X receptor, possibly the P2X4 subtype. After treatment with NGF for 7 days the ATP response was increased and partially sensitive to PPADS. A component of the ATP-induced Ca2+ increase was due to mobilisation of intracellular Ca2+ stores and another to capacitative Ca2+ entry. UTP caused an increase in intracellular Ca2+, and InsP3 formation could be stimulated by ATP and UTP. ATP also caused a small increase in cyclic AMP, but this was abolished in the presence of indomethacin. Thus, after NGF treatment ATP acts partially via a P2Y receptor, possibly the P2Y2 subtype.
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| 24. |
- Blumel, Edda, et al.
(författare)
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Staphylococcal alpha-toxin tilts the balance between malignant and non-malignant CD4+ T cells in cutaneous T-cell lymphoma
- 2019
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Ingår i: Oncoimmunology. - : Taylor & Francis. - 2162-4011 .- 2162-402X. ; 8:11
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Tidskriftsartikel (refereegranskat)abstract
- Staphylococcus aureus is implicated in disease progression in cutaneous T-cell lymphoma (CTCL). Here, we demonstrate that malignant T cell lines derived from CTCL patients as well as primary malignant CD4+ T cells from Sézary syndrome patients are considerably more resistant to alpha-toxin-induced cell death than their non-malignant counterparts. Thus, in a subset of Sézary syndrome patients the ratio between malignant and non-malignant CD4+ T cells increases significantly following exposure to alpha-toxin. Whereas toxin-induced cell death is ADAM10 dependent in healthy CD4+ T cells, resistance to alpha-toxin in malignant T cells involves both downregulation of ADAM10 as well as other resistance mechanisms. In conclusion, we provide first evidence that Staphylococcus aureus derived alpha-toxin can tilt the balance between malignant and non-malignant CD4+ T cells in CTCL patients. Consequently, alpha-toxin may promote disease progression through positive selection of malignant CD4+ T cells, identifying alpha-toxin as a putative drug target in CTCL.
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