| 1. |
- Mathioudaki, Argyri, Ph.D student, 1986-, et al.
(författare)
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The sex-stratified genetic architecture of ankylosing spondylitis
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Sexual dimorphism is an emerging feature of ankylosing spondylitis (AS), a chronic rheumatic condition affecting upto three times more men than women. Using 691 individuals from a Swedish case-control cohort, we revealed thatsex biases are also a hallmark of AS genetic predisposition, and that this multifactorial disease is in part driven byboth rare and common variants. We identified SNPs via the targeted re-sequencing of 7 270 coding and non-codingloci, and assessed novel patterns of association with both single marker and aggregate loci SKAT tests. The malespecific RUNX3 locus (including rs7414934, OR=2.58, p=1.7x10-5) and female specific MICB SKAT locus (27variants, p=1.2x10-6; rs3828903, OR=4.62, p=6.2x10-13) exceeded discovery thresholds. Multiple risk variants fromeach locus were shown to be functionally active in immune (Jurkat), skin (HaCat) and bone (SaOS-2) cell lines.Differential patterns of genetic predisposition may point to alternative disease mechanisms in male and femalepatients. Genetic and functional analyses demonstrated that risk alleles should not be considered in isolation and thatassociated variants would likely affect gene regulation across multiple tissues. This work illustrates the need toconsider the contribution of sex to the genetics of AS and the duality that individual loci may play in the key clinical outcomes of disease.
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| 2. |
- Artman, Henrik, 1968-, et al.
(författare)
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Effektiv miljötillsyn : slutrapport
- 2013
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Målsättningen har varit att ta fram ny kunskap inom miljötillsynen och därigenom uppnå en effektivare miljötillsyn samt att få in nya vetenskapliga perspektiv på miljötillsyn.I rapporten studeras metoder för inspektioner och det kommunikativa samspelet mellan inspektören och företrädare för den verksamhet som inspekteras, hur den institutionella ramen för inspektionsprocessen fungerar samt visar på möjligheter att mäta effekterna av inspektioner och tillsyn.Naturvårdsverket kommer att ha resultatet som ett kunskapsunderlag i fortsatt arbete med tillsynsvägledning och utveckling av hur tillsyn och tillsynsvägledning kan följas upp och utvärderas.
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| 3. |
- Axelsson, Erik, et al.
(författare)
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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
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 17:9
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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.
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| 4. |
- Bianchi, Matteo, et al.
(författare)
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Whole-genome genotyping and resequencing reveal the association of a deletion in the complex interferon alpha gene cluster with hypothyroidism in dogs
- 2020
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Ingår i: BMC Genomics. - : BMC. - 1471-2164. ; 21
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Tidskriftsartikel (refereegranskat)abstract
- Background: Hypothyroidism is a common complex endocrinopathy that typically has an autoimmune etiology, and it affects both humans and dogs. Genetic and environmental factors are both known to play important roles in the disease development. In this study, we sought to identify the genetic risk factors potentially involved in the susceptibility to the disease in the high-risk Giant Schnauzer dog breed.Results: By employing genome-wide association followed by fine-mapping (top variant p-value=5.7x10(-6)), integrated with whole-genome resequencing and copy number variation analysis, we detected a similar to 8.9 kbp deletion strongly associated (p-value=0.0001) with protection against development of hypothyroidism. The deletion is located between two predicted Interferon alpha (IFNA) genes and it may eliminate functional elements potentially involved in the transcriptional regulation of these genes. Remarkably, type I IFNs have been extensively associated to human autoimmune hypothyroidism and general autoimmunity. Nonetheless, the extreme genomic complexity of the associated region on CFA11 warrants further long-read sequencing and annotation efforts in order to ascribe functions to the identified deletion and to characterize the canine IFNA gene cluster in more detail.Conclusions: Our results expand the current knowledge on genetic determinants of canine hypothyroidism by revealing a significant link with the human counterpart disease, potentially translating into better diagnostic tools across species, and may contribute to improved canine breeding strategies.
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| 5. |
- Boschini, Anne, et al.
(författare)
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Gender and altruism in a random sample
- 2018
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Ingår i: Journal of Behavioral and Experimental Economics. - : Elsevier BV. - 2214-8043 .- 2214-8051. ; 77, s. 72-77
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Tidskriftsartikel (refereegranskat)abstract
- We study gender differences in altruism in a large random sample of the Swedish population using a standard dictator game. Beside a baseline treatment we implement a priming treatment where participants are reminded of their gender, and two treatments with known male and female counterpart respectively. We find suggestive evidence that women are more altruistic than men only in the priming treatment. A post-hoc analysis using data on interviewer gender to explore gender context effects indicates that priming affects behavior only in mixedgender contexts.
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| 6. |
- Boschini, Anne, et al.
(författare)
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Gender, risk preference and willingness to compete in a random sample of the Swedish population
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Working paper.Experimental results from student or other non-representative convenience samples often suggest that men, on average, are more risk-taking and competitive than women. Here we explore whether these gender preference gaps also exist in a simple random sample of the Swedish adult population. Our design comprises four different treatments to systematically explore how the experimental context may impact gender gaps; a baseline treatment, a treatment where participants are primed with their own gender, and a treatment where the participants know the gender of their counterpart (man or woman). We look at willingness to compete in two domains: a math task and a verbal task. We find no gender differences in risk preferences or in willingness to compete in the verbal task in this random sample. There is some support for men being more competitive than women in the math task, in particular in the pooled sample. The effect size is however considerably smaller than what is typically found. We further find no consistent impact of treatment on (the absence of) the gender gap in preferences.
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| 7. |
- Boschini, Anne, et al.
(författare)
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Gender, risk preferences and willingness to compete in a random sample of the Swedish population
- 2018
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Experimental results from student or other non-representative convenience samples often suggest that men, on average, are more risk-taking and competitive than women. Here we explore whether these gender preference gaps also exist in a simple random sample of the Swedish adult population. Our design comprises four different treatments to systematically explore how the experimental context may impact gender gaps; a baseline treatment, a treatment where participants are primed with their own gender, and a treatment where the participants know the gender of their counterpart (man or woman). We look at willingness to compete in two domains: a math task and a verbal task. We find no gender differences in risk preferences or in willingness to compete in the verbal task in this random sample. There is some support for men being more competitive than women in the math task, in particular in the pooled sample. The effect size is however considerably smaller than what is typically found. We further find no consistent impact of treatment on (the absence of) the gender gap in preferences.
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| 8. |
- Boschini, Anne, et al.
(författare)
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Gender, risk preferences and willingness to compete in a random sample of the Swedish population
- 2019
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Ingår i: Journal of Behavioral and Experimental Economics. - : Elsevier BV. - 2214-8043 .- 2214-8051. ; 83
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Tidskriftsartikel (refereegranskat)abstract
- Experimental results from student and other non-representative convenience samples often suggest that men, on average, are more risk taking and competitive than women. We explore whether these gender preference gaps also exist in incentivized tasks in a simple random sample of the Swedish adult population. Our design comprises four different conditions to systematically explore how the experimental context may impact gender gaps; a baseline condition, a condition where participants are primed with their own gender, and two conditions where the participants know the gender of their counterpart (man or woman). We further look at competitiveness in two domains: a math task and a verbal task. We find no gender gap in risk taking or competitiveness in the verbal task in this random sample. There is some support for men being more competitive than women in the math task in the pooled sample, but the effect size is small. We further find no consistent impact of the respective conditions on (the absence of) the gender gap in preferences.
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| 9. |
- Carlsson, Mattias, et al.
(författare)
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A Ham1p-Dependent Mechanism and Modulation of the Pyrimidine Biosynthetic Pathway can both Confer Resistance to 5-Fluorouracil in Yeast
- 2013
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:10, s. e52094-
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Tidskriftsartikel (refereegranskat)abstract
- 5-Fluorouracil (5-FU) is an anticancer drug and pyrimidine analogue. A problem in 5-FU therapy is acquired resistance to the drug. To find out more about the mechanisms of resistance, we screened a plasmid library in yeast for genes that confer 5-FU resistance when overexpressed. We cloned five genes: CPA1, CPA2, HMS1, YAE1 and YJL055W. CPA1 and CPA2 encode a carbamoyl phosphate synthase involved in arginine biosynthesis and HMS1 a helix-loop-helix transcription factor. Our results suggest that CPA1, CPA2, and HMS1 confer 5-FU resistance by stimulating pyrimidine biosynthesis. Thus, they are unable to confer 5-FU resistance in a ura2 mutant, and inhibit the uptake and incorporation into RNA of both uracil and 5-FU. In contrast, YAE1 and YJL055W confer 5-FU resistance in a ura2 mutant, and selectively inhibit incorporation into RNA of 5-FU but not uracil. YAE1 is the strongest resistance gene, but it partially depends on YJL055W for its function. This suggests that YAE1 and YJL055W function together in a novel mechanism for detoxification of 5-FU and other pyrimidine analogs. Yae1p belongs to a small protein family with only two members, which are conserved in all eukaryotes examined. One of the human homologs, TAOS1, is overexpressed in oral carcinomas.
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| 10. |
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| 11. |
- Dahlqvist, Johanna, 1979-, et al.
(författare)
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Identification and functional characterization of a novel susceptibility locus for small vessel vasculitis with MPO-ANCA
- 2022
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Ingår i: Rheumatology. - Oxford, United Kingdom : Oxford University Press (OUP). - 1462-0324 .- 1462-0332. ; 61:8, s. 3461-3470
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Tidskriftsartikel (refereegranskat)abstract
- Objective To identify and characterize genetic loci associated with the risk of developing ANCA-associated vasculitides (AAV). Methods Genetic association analyses were performed after Illumina sequencing of 1853 genes and subsequent replication with genotyping of selected single nucleotide polymorphisms in a total cohort of 1110 Scandinavian cases with granulomatosis with polyangiitis or microscopic polyangiitis, and 1589 controls. A novel AAV-associated single nucleotide polymorphism was analysed for allele-specific effects on gene expression using luciferase reporter assay. Results PR3-ANCA(+) AAV was significantly associated with two independent loci in the HLA-DPB1/HLA-DPA1 region [rs1042335, P = 6.3 x 10(-61), odds ratio (OR) 0.10; rs9277341, P = 1.5 x 10(-44), OR 0.22] and with rs28929474 in the SERPINA1 gene (P = 2.7 x 10(-10), OR 2.9). MPO-ANCA(+) AAV was significantly associated with the HLA-DQB1/HLA-DQA2 locus (rs9274619, P = 5.4 x 10(-25), OR 3.7) and with a rare variant in the BACH2 gene (rs78275221, P = 7.9 x 10(-7), OR 3.0), the latter a novel susceptibility locus for MPO-ANCA(+) granulomatosis with polyangiitis/microscopic polyangiitis. The rs78275221-A risk allele reduced luciferase gene expression in endothelial cells, specifically, as compared with the non-risk allele. Conclusion We identified a novel susceptibility locus for MPO-ANCA(+) AAV and propose that the associated variant is of mechanistic importance, exerting a regulatory function on gene expression in specific cell types.
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| 12. |
- Eriksson, D, et al.
(författare)
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Extended exome sequencing identifies BACH2 as a novel major risk locus for Addison's disease
- 2016
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 286:6, s. 595-608
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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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| 13. |
- Genereux, Diane P., et al.
(författare)
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A comparative genomics multitool for scientific discovery and conservation
- 2020
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Ingår i: Nature. - : NATURE RESEARCH. - 0028-0836 .- 1476-4687. ; 587:7833, s. 240-245
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Tidskriftsartikel (refereegranskat)abstract
- A whole-genome alignment of 240 phylogenetically diverse species of eutherian mammal-including 131 previously uncharacterized species-from the Zoonomia Project provides data that support biological discovery, medical research and conservation. The Zoonomia Project is investigating the genomics of shared and specialized traits in eutherian mammals. Here we provide genome assemblies for 131 species, of which all but 9 are previously uncharacterized, and describe a whole-genome alignment of 240 species of considerable phylogenetic diversity, comprising representatives from more than 80% of mammalian families. We find that regions of reduced genetic diversity are more abundant in species at a high risk of extinction, discern signals of evolutionary selection at high resolution and provide insights from individual reference genomes. By prioritizing phylogenetic diversity and making data available quickly and without restriction, the Zoonomia Project aims to support biological discovery, medical research and the conservation of biodiversity.
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| 14. |
- Gustavsson, Marie, et al.
(författare)
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Functional genomics of monensin sensitivity in yeast : Implications for post-Golgi traffic and vacuolar H+-ATPase function
- 2008
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Ingår i: Molecular Genetics and Genomics. - : Springer Science and Business Media LLC. - 1617-4615 .- 1617-4623. ; 280:3, s. 233-248
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Tidskriftsartikel (refereegranskat)abstract
- We have screened a complete collection of yeast knockout mutants for sensitivity to monensin, an ionophore that interferes with intracellular transport. A total of 63 sensitive strains were found. Most of the strains were deleted for genes involved in post-Golgi traffic, with an emphasis on vacuolar biogenesis. A high correlation was thus seen with VPS and VAM genes, but there were also significant differences between the three sets of genes. A weaker correlation was seen with sensitivity to NaCl, in particular rate of growth effects. Interestingly, all 14 genes encoding subunits of the vacuolar H(+)-ATPase (V-ATPase) were absent in our screen, even though they appeared in the VPS or VAM screens. All monensin-sensitive mutants that could be tested interact synthetically with a deletion of the A subunit of the V-ATPase, Vma1. Synthetic lethality was limited to mutations affecting endocytosis or retrograde transport to Golgi. In addition, vma1 was epistatic over the monensin sensitivity of vacuolar transport mutants, but not endocytosis mutants. Deletions of the two isoforms of the V-ATPase a subunit, Vph1 and Stv1 had opposite effects on the monensin sensitivity of a ypt7 mutant. These findings are consistent with a model where monensin inhibits growth by interfering with the maintenance of an acidic pH in the late secretory pathway. The synthetic lethality of vma1 with mutations affecting retrograde transport to the Golgi further suggests that it is in the late Golgi that a low pH must be maintained.
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| 15. |
- Ivansson, Emma L., et al.
(författare)
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Variants within the SP110 nuclear body protein modify risk of canine degenerative myelopathy
- 2016
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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. ; 113:22, s. E3091-E3100
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Tidskriftsartikel (refereegranskat)abstract
- Canine degenerative myelopathy (DM) is a naturally occurring neurodegenerative disease with similarities to some forms of amyotrophic lateral sclerosis (ALS). Most dogs that develop DM are homozygous for a common superoxide dismutase 1 gene (SOD1) mutation. However, not all dogs homozygous for this mutation develop disease. We performed a genome-wide association analysis in the Pembroke Welsh Corgi (PWC) breed comparing DM-affected and -unaffected dogs homozygous for the SOD1 mutation. The analysis revealed a modifier locus on canine chromosome 25. A haplotype within the SP110 nuclear body protein (SP110) was present in 40% of affected compared with 4% of unaffected dogs (P = 1.5 x 10(-5)), and was associated with increased probability of developing DM (P = 4.8 x 10(-6)) and earlier onset of disease (P = 1.7 x 10(-5)). SP110 is a nuclear body protein involved in the regulation of gene transcription. Our findings suggest that variations in SP110-mediated gene transcription may underlie, at least in part, the variability in risk for developing DM among PWCs that are homozygous for the disease-related SOD1 mutation. Further studies are warranted to clarify the effect of this modifier across dog breeds.
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| 16. |
- Mathioudaki, Argyri, Ph.D student, 1986-, et al.
(författare)
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Replication and fine mapping of ankylosing spondylitis replicated loci in the Swedish population reveal different CCHCR1 protective haplotypes
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background: The genetics of ankylosing spondylitis (AS) derives mainly from studies performed in large cohorts of British origin. However, within Europe, disease prevalence is higher in Sweden, and so we investigated the reproducibility of known AS susceptibility patterns in a homogeneous Swedish cohort.Methods: The replication power of the Swedish cohort was examined and a set of published SNP associations intersected with genotypes from an existing targeted sequencing study using these individuals (381 controls; 310 AS cases). To elucidate whether replication patterns derived from population subsampling or genetic similarity, allele frequency data from additional British and Swedish control populations were examined for genetic differentiation (FST). Replicated loci were fine mapped to investigate associations in more detail, and signals were dissected with haplotype analysis and functional annotation.Results: The study had 80% power to find variants of strong effect (Odds ratio, OR>2) given a wide range of risk allele frequencies (0.2-3), tagging HLA-B,CCHCR1and IL23R. The replication pattern was not due to European population genetic distance and fine mapping revealed genome-wide repositioned associations in HLA-Band CCHCR1, independent from the published associations (p-value < 2 x10-8, r2 < 0.3). The CCHCR1 locus showed two protective haplotype blocks (B1-1 and B2-1), independent from HLA-B signals (B1-1: r2 = 0.39, B2-2:r2=0.07), where 74% of controls were carrying 2 copies of the protective haplotypes (B1-1 and B2-1: OR=0.3, p-value = 1.2 x 10-45). Interestingly, while both haplotypes span CCHCR1, the effect of each haplotype is likely in cis, with eQTL evidence pointing to the regulation of TCF19(B1-1) and POU5F1(B1-2).Conclusions: Both European populations share key disease loci, but the Swedish cohort revealed fine-scale genetic differences, that may point to gene regulation. This study utilized a different variant resolution, and by doing so demonstrated that smaller populations have the potential to reveal new AS pathogenesis mechanisms and that further study of the Swedish population is warranted.
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| 17. |
- Mathioudaki, Argyri, Ph.D student, 1986-, et al.
(författare)
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Targeted sequencing reveals the somatic mutation landscape in a Swedish breast cancer cohort
- 2020
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Breast cancer (BC) is a genetically heterogeneous disease with high prevalence in Northern Europe. However, there has been no detailed investigation into the Scandinavian somatic landscape. Here, in a homogeneous Swedish cohort, we describe the somatic events underlying BC, leveraging a targeted next-generation sequencing approach. We designed a 20.5 Mb array targeting coding and regulatory regions of genes with a known role in BC (n = 765). The selected genes were either from human BC studies (n = 294) or from within canine mammary tumor associated regions (n = 471). A set of predominantly estrogen receptor positive tumors (ER + 85%) and their normal tissue counterparts (n = 61) were sequenced to ~ 140 × and 85 × mean target coverage, respectively. MuTect2 and VarScan2 were employed to detect single nucleotide variants (SNVs) and copy number aberrations (CNAs), while MutSigCV (SNVs) and GISTIC (CNAs) algorithms estimated the significance of recurrent somatic events. The significantly mutated genes (q ≤ 0.01) were PIK3CA (28% of patients), TP53 (21%) and CDH1 (11%). However, histone modifying genes contained the largest number of variants (KMT2C and ARID1A, together 28%). Mutations in KMT2C were mutually exclusive with PI3KCA mutations (p ≤ 0. 001) and half of these affect the formation of a functional PHD domain. The tumor suppressor CDK10 was deleted in 80% of the cohort while the oncogene MDM4 was amplified. Mutational signature analyses pointed towards APOBEC deaminase activity (COSMIC signature 2) and DNA mismatch repair (COSMIC signature 6). We noticed two significantly distinct patterns related to patient age; TP53 being more mutated in the younger group (29% vs 9% of patients) and CDH23 mutations were absent from the older group. The increased somatic mutation prevalence in the histone modifying genes KMT2C and ARID1A distinguishes the Swedish cohort from previous studies. KMT2C regulates enhancer activation and assists tumor proliferation in a hormone-rich environment, possibly pointing to a role in ER + BC, especially in older cases. Finally, age of onset appears to affect the mutational landscape suggesting that a larger age-diverse population incorporating more molecular subtypes should be studied to elucidate the underlying mechanisms.
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| 18. |
- Melin, Malin, et al.
(författare)
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Genome-Wide Analysis Identifies Germ-Line Risk Factors Associated with Canine Mammary Tumours
- 2016
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 12:5
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Tidskriftsartikel (refereegranskat)abstract
- Canine mammary tumours (CMT) are the most common neoplasia in unspayed female dogs. CMTs are suitable naturally occurring models for human breast cancer and share many characteristics, indicating that the genetic causes could also be shared. We have performed a genome-wide association study (GWAS) in English Springer Spaniel dogs and identified a genome-wide significant locus on chromosome 11 (p(raw) = 5.6x10(-7), p(perm) = 0.019). The most associated haplotype spans a 446 kb region overlapping the CDK5RAP2 gene. The CDK5RAP2 protein has a function in cell cycle regulation and could potentially have an impact on response to chemotherapy treatment. Two additional loci, both on chromosome 27, were nominally associated (p(raw) = 1.97x10(-5) and p(raw) = 8.30x10(-6)). The three loci explain 28.1 +/- 10.0% of the phenotypic variation seen in the cohort, whereas the top ten associated regions account for 38.2 +/- 10.8% of the risk. Furthermore, the ten GWAS loci and regions with reduced genetic variability are significantly enriched for snoRNAs and tumour-associated antigen genes, suggesting a role for these genes in CMT development. We have identified several candidate genes associated with canine mammary tumours, including CDK5RAP2. Our findings enable further comparative studies to investigate the genes and pathways in human breast cancer patients.
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| 19. |
- Murén, Eva, et al.
(författare)
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Rescue and characterization of episomally replicating DNA from the moss Physcomitrella
- 2009
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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. ; 106:46, s. 19444-19449
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Tidskriftsartikel (refereegranskat)abstract
- The moss Physcomitrella is unique among plants in that it permits efficient gene targeting by homologous recombination. Furthermore, transformed DNA can replicate episomally in Physcomitrella. Here we show that episomally replicating DNA can berescued back into E. coli, and use such rescue to study the fate of the transformed DNA. Significantly, plasmids rescued from moss transformed with circular DNA are identical to the original plasmid, whereas plasmids rescued from moss transformed with linearized DNA frequently have deletions created by direct repeat recombination.These events are highly predictable in that they target the longest direct repeat on the plasmid, if this repeat is at least 12 bp. Episomal transformants obtained with linearized DNA show a more than 1000-fold amplification of the DNA whereas transformants obtained with circular DNA have much lower copy numbers. Most episomal transformants quickly lose the plasmid in the absence of selection, but a semi-stable type of transformant that loses the plasmid at a much lower frequency was also observed. The consistent rescue of the original plasmid, or of predictable derivatives thereof, suggests that molecular genetics methods which rely on shuttle plasmids are feasible in Physcomitrella
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| 20. |
- Nordin, Jessika, et al.
(författare)
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Association of Protective HLA-A With HLA-B∗27 Positive Ankylosing Spondylitis
- 2021
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Ingår i: Frontiers in Genetics. - Lausanne, Switzerland : Frontiers Media S.A.. - 1664-8021. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To further elucidate the role of the MHC in ankylosing spondylitis by typing 17 genes, searching for HLA-B∗27 independent associations and assessing the impact of sex on this male biased disease.Methods: High-confidence two-field resolution genotyping was performed on 310 cases and 2196 controls using an n-1 concordance method. Protein-coding variants were called from next-generation sequencing reads using up to four software programs and the consensus result recorded. Logistic regression tests were applied to the dataset as a whole, and also in stratified sets based on sex or HLA-B∗27 status. The amino acids driving association were also examined.Results: Twenty-five HLA protein-coding variants were significantly associated to disease in the population. Three novel protective associations were found in a HLA-B∗27 positive population, HLA-A∗24:02 (OR = 0.4, CI = 0.2–0.7), and HLA-A amino acids Leu95 and Gln156. We identified a key set of seven loci that were common to both sexes, and robust to change in sample size. Stratifying by sex uncovered three novel risk variants restricted to the female population (HLA-DQA1∗04.01, -DQB1∗04:02, -DRB1∗08:01; OR = 2.4–3.1). We also uncovered a set of neutral variants in the female population, which in turn conferred strong effects in the male set, highlighting how population composition can lead to the masking of true associations.Conclusion: Population stratification allowed for a nuanced investigation into the tightly linked MHC region, revealing novel HLA-B∗27 signals as well as replicating previous HLA-B∗27 dependent results. This dissection of signals may help to elucidate sex biased disease predisposition and clinical progression.
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| 21. |
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| 22. |
- Olsson, Mia, 1978-, et al.
(författare)
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Thorough investigation of a canine autoinflammatory disease (AID) syndrome confirms one main risk factor and suggests a modifier locus for amyloidosis
- 2013
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:10, s. e75242-
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Tidskriftsartikel (refereegranskat)abstract
- Autoinflammatory disease (AID) manifests from the dysregulation of the innate immune system and is characterised by systemic and persistent inflammation. Clinical heterogeneity leads to patients presenting with one or a spectrum of phenotypic signs, leading to difficult diagnoses in the absence of a clear genetic cause. We used separate genome-wide SNP analyses to investigate five signs of AID (recurrent fever, arthritis, breed specific secondary dermatitis, otitis and systemic reactive amyloidosis) in a canine comparative model, the pure bred Chinese Shar-Pei. Analysis of 255 DNA samples revealed a shared locus on chromosome 13 spanning two peaks of association. A three-marker haplotype based on the most significant SNP (p<2.6x10(-8)) from each analysis showed that one haplotypic pair (H13-11) was present in the majority of AID individuals, implicating this as a shared risk factor for all phenotypes. We also noted that a genetic signature (F-ST) distinguishing the phenotypic extremes of the breed specific Chinese Shar-Pei thick and wrinkled skin, flanked the chromosome 13 AID locus; suggesting that breed development and differentiation has played a parallel role in the genetics of breed fitness. Intriguingly, a potential modifier locus for amyloidosis was revealed on chromosome 14, and an investigation of candidate genes from both this and the chromosome 13 regions revealed significant (p<0.05) renal differential expression in four genes previously implicated in kidney or immune health (AOAH, ELMO1, HAS2 and IL6). These results illustrate that phenotypic heterogeneity need not be a reflection of genetic heterogeneity, and that genetic modifiers of disease could be masked if syndromes were not first considered as individual clinical signs and then as a sum of their component parts.
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| 23. |
- Orzechowski Westholm, Jakub, 1977-, et al.
(författare)
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Combinatorial control of gene expression by the three yeast repressors Mig1, Mig2 and Mig3
- 2008
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Ingår i: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 9, s. 601-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Expression of a large number of yeast genes is repressed by glucose. The zinc finger protein Mig1 is the main effector in glucose repression, but yeast also has two related proteins: Mig2 and Mig3. We have used microarrays to study global gene expression in all possible combinations of mig1, mig2 and mig3 deletion mutants. Results: Mig1 and Mig2 repress a largely overlapping set of genes on 2% glucose. Genes that are upregulated in a mig1 mig2 double mutant were grouped according to the contribution of Mig2. Most of them show partially redundant repression, with Mig1 being the major repressor, but some genes show complete redundancy, and some are repressed only by Mig1. Several redundantly repressed genes are involved in phosphate metabolism. The promoters of these genes are enriched for Pho4 sites, a novel GGGAGG motif, and a variant Mig1 site which is absent from genes repressed only by Mig1. Genes repressed only by Mig1 on 2% glucose include the hexose transporter gene HXT4, but Mig2 contributes to HXT4 repression on 10% glucose. HXT6 is one of the few genes that are more strongly repressed by Mig2. Mig3 does not seem to overlap in function with Mig1 and Mig2. Instead, Mig3 downregulates the SIR2 gene encoding a histone deacetylase involved in gene silencing and the control of aging. Conclusions: Mig2 fine-tunes glucose repression by targeting a subset of the Mig1-repressed genes, and by responding to higher glucose concentrations. Mig3 does not target the same genes as Mig1 and Mig2, but instead downregulates the SIR2 gene.
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| 24. |
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| 25. |
- Tengvall, Katarina, 1980-, et al.
(författare)
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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
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Ingår i: BMC Genetics. - : Springer Science and Business Media LLC. - 1471-2156. ; 17:1
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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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| 26. |
- Tronnersjö, Susanna, et al.
(författare)
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The jmjN and jmjC domains of the yeast zinc finger protein Gis1 interact with 19 proteins involved in transcription, sumoylation and DNA repair
- 2007
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Ingår i: Molecular Genetics and Genomics. - : Springer Science and Business Media LLC. - 1617-4615 .- 1617-4623. ; 277:1, s. 57-70
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Tidskriftsartikel (refereegranskat)abstract
- The jumonji domain is a highly conserved bipartite domain made up of two subdomains, jmjN and jmjC, which is found in many eukaryotic transcription factors. The jmjC domain was recently shown to possess the histone demethylase activity. Here we show that the jmjN and jmjC domains of the yeast zinc finger protein Gis1 interact in a two-hybrid system with 19 yeast proteins that include the RecQ helicase Sgs1, the silencing factors Esc1 and Sir4, the URI-type prefoldin Bud27 and the PIAS type SUMO ligase Nfi1/Siz2. Extensive interaction cross dependencies further suggest that the proteins form a larger complex. Consistent with this, 16 of the proteins also interact with a Bud27 two-hybrid bait, and three of them co-precipitate with TAP-tagged Gis1. The Gis1 jumonji domain can repress transcription when recruited to a promoter as a lexA fusion. This effect is dependent on both the jmjN and jmjC subdomains, as were all 19 two-hybrid interactions, indicating that the two subdomains form a single functional unit. The human Sgs1 homolog WRN also interacts with the Gis1 jumonji domain. Finally, we note that several jumonji domain interactors are related to proteins that are found in mammalian PML nuclear bodies.
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| 27. |
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| 28. |
- Truvé, Katarina, et al.
(författare)
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Utilizing the Dog Genome in the Search for Novel Candidate Genes Involved in Glioma Development-Genome Wide Association Mapping followed by Targeted Massive Parallel Sequencing Identifies a Strongly Associated Locus
- 2016
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Ingår i: Plos Genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 12:5
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Tidskriftsartikel (refereegranskat)abstract
- Gliomas are the most common form of malignant primary brain tumors in humans and second most common in dogs, occurring with similar frequencies in both species. Dogs are valuable spontaneous models of human complex diseases including cancers and may provide insight into disease susceptibility and oncogenesis. Several brachycephalic breeds such as Boxer, Bulldog and Boston Terrier have an elevated risk of developing glioma, but others, including Pug and Pekingese, are not at higher risk. To identify glioma-associated genetic susceptibility factors, an across-breed genome-wide association study (GWAS) was performed on 39 dog glioma cases and 141 controls from 25 dog breeds, identifying a genome-wide significant locus on canine chromosome (CFA) 26 (p = 2.8 x 10(-8)). Targeted re-sequencing of the 3.4 Mb candidate region was performed, followed by genotyping of the 56 SNVs that best fit the association pattern between the re-sequenced cases and controls. We identified three candidate genes that were highly associated with glioma susceptibility: CAMKK2, P2RX7 and DENR. CAMKK2 showed reduced expression in both canine and human brain tumors, and a non-synonymous variant in P2RX7, previously demonstrated to have a 50% decrease in receptor function, was also associated with disease. Thus, one or more of these genes appear to affect glioma susceptibility.
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