| 1. |
- Andersson, Leif, et al.
(författare)
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ZBED6 : the birth of a new transcription factor in the common ancestor of placental mammals
- 2010
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Ingår i: Transcription. - : Informa UK Limited. - 2154-1272 .- 2154-1264. ; 1:3, s. 144-148
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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.
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| 2. |
- Ka, Sojeong, et al.
(författare)
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The expression of carnitine palmitoyl-CoA transferase-1B is influenced by a cis-acting eQTL in two chicken lines selected for high and low body weight
- 2013
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Ingår i: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 45:9, s. 367-376
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Tidskriftsartikel (refereegranskat)abstract
- Carnitine palmitoyl-CoA transferase-1B is a mitochondrial enzyme in the fatty acid oxidation pathway. In a previous study, CPT1B was identified as differentially expressed in the hypothalamus of two lines of chickens established by long-term selection for high (HWS) or low (LWS) body weight. Mammals have three paralogs (CPT1a, b and c) while non-mammalian vertebrates only have two (CPT1A, B). CPT1A is expressed in liver and CPT1B in muscle. CPT1c is expressed in hypothalamus, where it regulates feeding and energy expenditure. We identified an intronic length polymorphism, fixed for different alleles in the two populations and mapped the hitherto missing CPT1B locus in the chicken genome assembly, to the distal tip of chromosome 1p. Based on molecular phylogeny and gene synteny we suggest that chicken CPT1B is pro-orthologous of the mammalian CPT1c. Chicken CPT1B was differentially expressed in both muscle and hypothalamus but in opposite directions: higher levels in hypothalamus but lower levels in muscle in the HWS than in the LWS line. Using an advanced inter-cross population of the lines, CPT1B expression was found to be influenced by a cis-acting expression quantitative trait locus in muscle. The increased expression in hypothalamus and reduced expression in muscle is consistent with an increased food intake in the HWS line and at the same time reduced fatty acid oxidation in muscle yielding a net accumulation of energy intake and storage. The altered expression of CPT1B in hypothalamus and peripheral tissue is likely to be a mechanism contributing to the remarkable difference between lines.
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| 3. |
- Karlskov-Mortensen, Peter, et al.
(författare)
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Genome-wide identification of quantitative trait loci in a cross between Hampshire and Landrace I : carcass traits
- 2006
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Ingår i: Animal Genetics. - : Wiley. - 0268-9146 .- 1365-2052. ; 37:2, s. 156-162
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Tidskriftsartikel (refereegranskat)abstract
- We report the identification of quantitative trait loci (QTL) affecting carcass composition, carcass length, fat deposition and lean meat content using a genome scan across 462 animals from a combined intercross and backcross between Hampshire and Landrace pigs. Data were analysed using multiple linear regression fitting additive and dominance effects. This model was compared with a model including a parent-of-origin effect to spot evidence of imprinting. Several precisely defined muscle phenotypes were measured in order to dissect body composition in more detail. Three significant QTL were detected in the study at the 1% genome-wide level, and twelve significant QTL were detected at the 5% genome-wide level. These QTL comprise loci affecting fat deposition and lean meat content on SSC1, 4, 9, 10, 13 and 16, a locus on SSC2 affecting the ratio between weight of meat and bone in back and weight of meat and bone in ham and two loci affecting carcass length on SSC12 and 17. The well-defined phenotypes in this study enabled us to detect QTL for sizes of individual muscles and to obtain information of relevance for the description of the complexity underlying other carcass traits.
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| 4. |
- Korberg, Izabella Baranowska, et al.
(författare)
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WNT3 involvement in human bladder exstrophy and cloaca development in zebrafish
- 2015
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 24:18, s. 5069-5078
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Tidskriftsartikel (refereegranskat)abstract
- Bladder exstrophy, a severe congenital urological malformation when a child is born with an open urinary bladder, is the most common form of bladder exstrophy-epispadias complex (BEEC) with an incidence of 1: 30,000 children of Caucasian descent. Recent studies suggest that WNT genes may contribute to the etiology of bladder exstrophy. Here, we evaluated WNT-pathway genes in 20 bladder exstrophy patients using massively parallel sequencing. In total 13 variants were identified in WNT3, WNT6, WNT7A, WNT8B, WNT10A, WNT11, WNT16, FZD5, LRP1 and LRP10 genes and predicted as potentially disease causing, of which seven variants were novel. One variant, identified in a patient with a de novo nonsynonymous substitution in WNT3 (p.Cys91Arg), was further evaluated in zebrafish. Knock down of wnt3 in zebrafish showed cloaca malformations, including disorganization of the cloaca epithelium and expansion of the cloaca lumen. Our study suggests that the function of the WNT3 p.Cys91Arg variant was altered, since RNA overexpression of mutant Wnt3 RNA does not result in embryonic lethality as seen with wild-type WNT3 mRNA. Finally, we also mutation screened the WNT3 gene further in 410 DNA samples from BEEC cases and identified one additional mutation c.638G> A (p.Gly213Asp), which was paternally inherited. In aggregate our data support the involvement of WNT-pathway genes in BEEC and suggest that WNT3 in itself is a rare cause of BEEC.
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| 5. |
- Lundin, Johanna, et al.
(författare)
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Further support linking the 22q11.2 microduplication to an increased risk of bladder exstrophy and highlighting LZTR1 as a candidate gene
- 2019
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Ingår i: Molecular Genetics and Genomic Medicine. - : Wiley. - 2324-9269. ; 7:6
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Tidskriftsartikel (refereegranskat)abstract
- Background: The bladder exstrophy-epispadias complex (BEEC) is a congenital malformation of the bladder and urethra. The underlying causes of this malformation are still largely unknown; however, aside from environment, genetics is thought to play an essential role. The recurrent 22q11.2 microduplication is the most persistently detected genetic aberration found in BEEC cases. Methods: We performed array comparative genomic hybridization (array-CGH) analysis of 76 Swedish BEEC patients. Statistical analysis was performed on current dataset pooled with previously published data on the 22q11.2 microduplication in BEEC patients. We performed massive parallel sequencing (MPS) of the 22q11.2 region in 20 BEEC patients without the 22q11.2 microduplication followed by functional studies. Results: We identified three additional cases with the 22q11.2 microduplication. Pooling data from this study with previously published reports showed a statistically significant enrichment of the 22q11.2 microduplication in BEEC patients (2.61% in cases vs. 0.08% in controls; OR = 32.6; p = 8.7 × 10−4). MPS of the 22q11.2 region in 20 BEEC patients without the 22q11.2 microduplication identified a novel variant in LZTR1 (p.Ser698Phe) in one patient. Functional evaluation of the LZTR1 p.Ser698Phe variant in live NIH 3T3 cells showed that the concentration and cytoplasmic mobility differ between the Lztr1wt and Lztr1mut, indicating a potential functional effect of the LZTR1mut. Conclusion: Our study further emphasizes the involvement of the 22q11.2 region in BEEC development and highlights LZTR1 as a candidate gene underlying the urogenital malformation.
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| 6. |
- Markljung, Ellen, et al.
(författare)
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Genome-wide identification of quantitative trait loci in a cross between Hampshire and Landrace II : meat quality traits
- 2008
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Ingår i: BMC Genetics. - : Springer Science and Business Media LLC. - 1471-2156. ; 9, s. 22-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Meat quality traits are important in pig breeding programs, but they are difficult to include in a traditional selection program. Marker assisted selection (MAS) of meat quality traits is therefore of interest in breeding programs and a Quantitative Trait Locus (QTL) analysis is the key to identifying markers that can be used in MAS. In this study, Landrace and Hampshire intercross and backcross families were used to investigate meat quality traits. Hampshire pigs are commonly used as the sire line in commercial pig breeding. This is the first time a pedigree including Hampshire pigs has been used for a QTL analysis of meat quality traits. RESULTS: In total, we analyzed 39 meat quality traits and identified eight genome-wide significant QTL peaks in four regions: one on chromosome 3, two on chromosome 6 and one on chromosome 16. At least two of the QTLs do not appear to have been detected in previous studies. On chromosome 6 we identified QTLs for water content in M. longissimus dorsi (LD), drip loss in LD and post mortem pH decline in LD. On chromosomes 3 and 16 we identified previously undetected QTLs for protein content in LD and for freezing and cooking loss respectively. CONCLUSION: We identified at least two new meat quality trait QTLs at the genome-wide significance level. We detected two QTLs on chromosome 6 that possibly coincide with QTLs detected in other studies. We were also able to exclude the C1843T mutation in the ryanodine receptor (RYR1) as a causative mutation for one of the chromosome 6 QTLs in this cross.
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| 7. |
- Markljung, Ellen, 1978-
(författare)
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QTL Analysis in the Pig : From the Identification of Quantitative Trait Loci to the Understanding of Molecular Mechanisms
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Domestic pigs have become very different form the wild ancestors they originate from. Selection for muscle growth and meat quality has made the pig a good model for genetic studies of muscle development.The first part of this thesis presents a genome-wide scan for quantitative trait loci (QTL) in a cross between Landrace and Hampshire pigs. Traits such as body composition, fat deposition, body length, meat quality and weight measurements of individual muscles were investigated. In total we identified 15 different QTLs that reached genome-wide significance. The three most significant QTLs were for carcass length on chromosome 17 and two overlapping QTLs on chromosome 1 for body composition and weight of M. biceps femoris, respectively. A strong candidate gene for the body composition QTL is melanocortin 4 receptor (MC4R). We also identified several QTLs for sizes of different muscles, fat deposition and meat quality traits.In a previous study using a cross between the domestic Large White and wild boar, the mutation underlying a major QTL for muscle growth and fat deposition was identified as a single nucleotide substitution (QTN) in intron 3 of the IGF2 gene. The QTN disrupts the binding of a repressor affecting IGF2 mRNA expression. In the second part of this thesis, the identification of the repressor is presented. The repressor, named ZBED6, is a previously unknown mammalian member of the BED-domain protein family. We could show that Zbed6 specifically binds the wild-type but not the mutated sequence surrounding the QTN. Further studies of silenced Zbed6 in the mouse myoblast cell line C2C12 showed that it represses transcription in a luciferase reporter assay and affects Igf2 mRNA transcription and proliferation. ZBED6 shows very high sequence conservation and has a broad tissue distribution of expression suggesting that ZBED6 also has important biological function outside the muscle cell.
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| 8. |
- Markljung, Ellen, et al.
(författare)
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ZBED6, a novel transcription factor derived from a domesticated DNA transposon regulates IGF2 expression and muscle growth
- 2009
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Ingår i: PLoS biology. - : Public Library of Science (PLoS). - 1544-9173 .- 1545-7885. ; 7:12, s. e1000256-
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Tidskriftsartikel (refereegranskat)abstract
- A single nucleotide substitution in intron 3 of IGF2 in pigs abrogates a binding site for a repressor and leads to a 3-fold up-regulation of IGF2 in skeletal muscle. The mutation has major effects on muscle growth, size of the heart, and fat deposition. Here, we have identified the repressor and find that the protein, named ZBED6, is previously unknown, specific for placental mammals, and derived from an exapted DNA transposon. Silencing of Zbed6 in mouse C2C12 myoblasts affected Igf2 expression, cell proliferation, wound healing, and myotube formation. Chromatin immunoprecipitation (ChIP) sequencing using C2C12 cells identified about 2,500 ZBED6 binding sites in the genome, and the deduced consensus motif gave a perfect match with the established binding site in Igf2. Genes associated with ZBED6 binding sites showed a highly significant enrichment for certain Gene Ontology classifications, including development and transcriptional regulation. The phenotypic effects in mutant pigs and ZBED6-silenced C2C12 myoblasts, the extreme sequence conservation, its nucleolar localization, the broad tissue distribution, and the many target genes with essential biological functions suggest that ZBED6 is an important transcription factor in placental mammals, affecting development, cell proliferation, and growth.
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