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  • 1.
    Andersen, Malin
    KTH, School of Biotechnology (BIO), Gene Technology.
    Computational and experimental approaches to regulatory genetic variation2007Doctoral thesis, comprehensive summary (Other scientific)
    Abstract [en]

    Genetic variation is a strong risk factor for many human diseases, including diabetes, cancer, cardiovascular disease, depression, autoimmunity and asthma. Most of the disease genes identified so far alter the amino acid sequences of encoded proteins. However, a significant number of genetic variants affecting complex diseases may alter the regulation of gene transcription. The map of the regulatory elements in the human genome is still to a large extent unknown, and it remains a challenge to separate the functional regulatory genetic variations from linked neutral variations.

    The objective of this thesis was to develop methods for the identification of genetic variation with a potential to affect the transcriptional regulation of human genes, and to analyze potential regulatory polymorphisms in the CD36 glycoprotein, a candidate gene for cardiovascular disease.

    An in silico tool for the prediction of regulatory polymorphisms in human genes was implemented and is available at www.cisreg.ca/RAVEN. The tool was evaluated using experimentally verified regulatory single nucleotide polymorphisms (SNPs) collected from the scientific literature, and tested in combination with experimental detection of allele specific expression of target genes (allelic imbalance). Regulatory SNPs were shown to be located in evolutionary conserved regions more often than background SNPs, but predicted transcription factor binding sites were unable to enrich for regulatory SNPs unless additional information linking transcription factors with the target genes were available.

    The in silico tool was applied to the CD36 glycoprotein, a candidate gene for cardiovascular disease. Potential regulatory SNPs in the alternative promoters of this gene were identified and evaluated in vitro and in vivo using a clinical study for coronary artery disease. We observed association to the plasma concentrations of inflammation markers (serum amyloid A protein and C-reactive protein) in myocardial infarction patients, which highlights the need for further analyses of potential regulatory polymorphisms in this gene.

    Taken together, this thesis describes an in silico approach to identify putative regulatory polymorphisms which can be useful for directing limited laboratory resources to the polymorphisms most likely to have a phenotypic effect.

  • 2.
    Andersen, Malin
    et al.
    KTH, School of Biotechnology (BIO), Gene Technology.
    Engström, Pär
    Lithwick, Stuart
    Arenillas, David
    Eriksson, Per
    Lenhard, Boris
    Wasserman, Wyeth
    Odeberg, Jacob
    KTH, School of Biotechnology (BIO), Gene Technology.
    In silico detection of sequence variations modifying transcriptional regulation2008In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 4, no 1, p. e5-Article in journal (Refereed)
    Abstract [en]

    Identification of functional genetic variation associated with increased susceptibility to complex diseases can elucidate genes and underlying biochemical mechanisms linked to disease onset and progression. For genes linked to genetic diseases, most identified causal mutations alter an encoded protein sequence. Technological advances for measuring RNA abundance suggest that a significant number of undiscovered causal mutations may alter the regulation of gene transcription. However, it remains a challenge to separate causal genetic variations from linked neutral variations. Here we present an in silico driven approach to identify possible genetic variation in regulatory sequences. The approach combines phylogenetic footprinting and transcription factor binding site prediction to identify variation in candidate cis-regulatory elements. The bioinformatics approach has been tested on a set of SNPs that are reported to have a regulatory function, as well as background SNPs. In the absence of additional information about an analyzed gene, the poor specificity of binding site prediction is prohibitive to its application. However, when additional data is available that can give guidance on which transcription factor is involved in the regulation of the gene, the in silico binding site prediction improves the selection of candidate regulatory polymorphisms for further analyses. The bioinformatics software generated for the analysis has been implemented as a Web-based application system entitled RAVEN ( regulatory analysis of variation in enhancers). The RAVEN system is available at http://www.cisreg.ca for all researchers interested in the detection and characterization of regulatory sequence variation.

  • 3.
    Andersen, Malin
    et al.
    KTH, School of Biotechnology (BIO), Gene Technology.
    Lenhard, Boris
    Whatling, Carl
    Eriksson, Per
    Odeberg, Jacob
    KTH, School of Biotechnology (BIO), Gene Technology.
    Alternative promoter usage of the membrane glycoprotein CD362006In: BMC Molecular Biology, ISSN 1471-2199, E-ISSN 1471-2199, Vol. 7, p. 8-Article in journal (Refereed)
    Abstract [en]

    Background: CD36 is a membrane glycoprotein involved in a variety of cellular processes such as lipid transport, immune regulation, hemostasis, adhesion, angiogenesis and atherosclerosis. It is expressed in many tissues and cell types, with a tissue specific expression pattern that is a result of a complex regulation for which the molecular mechanisms are not yet fully understood. There are several alternative mRNA isoforms described for the gene. We have investigated the expression patterns of five alternative first exons of the CD36 gene in several human tissues and cell types, to better understand the molecular details behind its regulation.

    Results: We have identified one novel alternative first exon of the CD36 gene, and confirmed the expression of four previously known alternative first exons of the gene. The alternative transcripts are all expressed in more than one human tissue and their expression patterns vary highly in skeletal muscle, heart, liver, adipose tissue, placenta, spinal cord, cerebrum and monocytes. All alternative first exons are upregulated in THP-1 macrophages in response to oxidized low density lipoproteins. The alternative promoters lack TATA-boxes and CpG islands. The upstream region of exon 1b contains several features common for house keeping gene and monocyte specific gene promoters.

    Conclusion: Tissue-specific expression patterns of the alternative first exons of CD36 suggest that the alternative first exons of the gene are regulated individually and tissue specifically. At the same time, the fact that all first exons are upregulated in THP-1 macrophages in response to oxidized low density lipoproteins may suggest that the alternative first exons are coregulated in this cell type and environmental condition. The molecular mechanisms regulating CD36 thus appear to be unusually complex, which might reflect the multifunctional role of the gene in different tissues and cellular conditions.

  • 4.
    Andrade, Jorge
    et al.
    KTH, School of Biotechnology (BIO), Gene Technology.
    Andersen, Malin
    KTH, School of Biotechnology (BIO), Gene Technology.
    Berglund, Lisa
    KTH, School of Biotechnology (BIO), Proteomics.
    Odeberg, Jacob
    KTH, School of Biotechnology (BIO), Gene Technology.
    Applications of grid computing in genetics and proteomics2007In: Applied Parallel Computing: State Of The Art In Scientific Computing / [ed] Kagstrom, B; Elmroth, E; Dongarra, J; Wasniewski, J, 2007, Vol. 4699, p. 791-798Conference paper (Refereed)
    Abstract [en]

    The potential for Grid technologies in applied bioinformatics is largely unexplored. We have developed a model for solving computationally demanding bioinformatics tasks in distributed Grid environments, designed to ease the usability for scientists unfamiliar with Grid computing. With a script-based implementation that uses a strategy of temporary installations of databases and existing executables on remote nodes at submission, we propose a generic solution that do not rely on predefined Grid runtime environments and that can easily be adapted to other bioinformatics tasks suitable for parallelization. This implementation has been successfully applied to whole proteome sequence similarity analyses and to genome-wide genotype simulations, where computation time was reduced from years to weeks. We conclude that computational Grid technology is a useful resource for solving high compute tasks in genetics and proteomics using existing algorithms.

  • 5.
    Andrade, Jorge
    et al.
    KTH, School of Biotechnology (BIO), Gene Technology.
    Andersen, Malin
    KTH, School of Biotechnology (BIO), Gene Technology.
    Sillén, Anna
    Graff, Caroline
    Odeberg, Jacob
    KTH, School of Biotechnology (BIO), Gene Technology.
    The use of grid computing to drive data-intensive genetic research2007In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 15, no 6, p. 694-702Article in journal (Refereed)
    Abstract [en]

    In genetics, with increasing data sizes and more advanced algorithms for mining complex data, a point is reached where increased computational capacity or alternative solutions becomes unavoidable. Most contemporary methods for linkage analysis are based on the Lander-Green hidden Markov model (HMM), which scales exponentially with the number of pedigree members. In whole genome linkage analysis, genotype simulations become prohibitively time consuming to perform on single computers. We have developed 'Grid-Allegro', a Grid aware implementation of the Allegro software, by which several thousands of genotype simulations can be performed in parallel in short time. With temporary installations of the Allegro executable and datasets on remote nodes at submission, the need of predefined Grid run-time environments is circumvented. We evaluated the performance, efficiency and scalability of this implementation in a genome scan on Swedish multiplex Alzheimer's disease families. We demonstrate that 'Grid-Allegro' allows for the full exploitation of the features available in Allegro for genome-wide linkage. The implementation of existing bioinformatics applications on Grids (Distributed Computing) represent a cost-effective alternative for addressing highly resource-demanding and data-intensive bioinformatics task, compared to acquiring and setting up clusters of computational hardware in house (Parallel Computing), a resource not available to most geneticists today.

  • 6. Cheung, Louisa
    et al.
    Andersen, Malin
    KTH, School of Biotechnology (BIO), Gene Technology.
    Gustavsson, Carolina
    Odeberg, Jacob
    KTH, School of Biotechnology (BIO), Biochemistry.
    Fernández-Pérez, Leandro
    Norsteds, Gunnar
    Tollet-Egnell, Petra
    Hormonal and nutritional regulation of alternative CD36 transcripts in rat liver: a role for growth hormone in alternative exon usage2007In: BMC Molecular Biology, ISSN 1471-2199, E-ISSN 1471-2199, Vol. 8, no 60, p. 12-Article in journal (Refereed)
    Abstract [en]

    Background: CD36 is a multiligand receptor involved in various metabolic pathways, including cellular uptake of long-chain fatty acids. Defect function or expression of CD36 can result in dyslipidemia or insulin resistance. We have previously shown that CD36 expression is female-predominant in rat liver. In the present study, hormonal and nutritional regulation of hepatic CD36 expression was examined in male and female rats. Since alternative transcription start sites have been described in murine and human Cd36, we investigated whether alternative CD36 transcripts are differentially regulated in rat liver during these conditions.

    Results: Sequence information of the rat Cd36 5'-UTR was extended, showing that the gene structure of Cd36 in rat is similar to that previously described in mouse with at least two alternative first exons. The rat Cd36 exon 1a promoter was sequenced and found to be highly similar to murine and human Cd36. We show that alternative first exon usage is involved in the female-predominant expression of CD36 in rat liver and during certain hormonal states that induce CD36 mRNA abundance. Estrogen treatment or continuous infusion of growth hormone (GH) in male rats induced CD36 expression preferentially through the exon 1a promoter. Old age was associated with increased CD36 expression in male rats, albeit without any preferential first exon usage. Intermittent GH treatment in old male rats reversed this effect. Mild starvation (12 hours without food) reduced CD36 expression in female liver, whereas its expression was increased in skeletal muscle.

    Conclusion: The results obtained in this study confirm and extend our previous observation that GH is an important regulator of hepatic CD36, and depending on the mode of treatment (continuous or intermittent) the gene might be either induced or repressed. We suggest that the effects of continuous GH secretion in females (which is stimulatory) and intermittent GH secretion in males (which is inhibitory) explains the sex-different expression of this gene. Furthermore, a female-specific repression of hepatic CD36 in response to food deprivation was found, which was in contrast to a stimulatory effect in skeletal muscle. This demonstrates a tissue-specific regulation of Cd36.

  • 7. Milani, Lili
    et al.
    Gupta, Manu
    Andersen, Malin
    KTH, School of Biotechnology (BIO), Gene Technology.
    Dhar, Sumeer
    Fryknäs, Mårten
    Isaksson, Anders
    Larsson, Rolf
    Syvänen, Ann-Christine
    Allelic imbalance in gene expression as a guide to cis-acting regulatory single nucleotide polymorphisms in cancer cells2007In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 35, no 5, p. E34-Article in journal (Refereed)
    Abstract [en]

    Using the relative expression levels of two SNIP alleles of a gene in the same sample is an effective approach for identifying cis-acting regulatory SNPs (rSNPs). In the current study, we established a process for systematic screening for cis-acting rSNPs using experimental detection of Al as an initial approach. We selected 160 expressed candidate genes that are involved in cancer and anticancer drug resistance for analysis of All in a panel of cell lines that represent different types of cancers and have been well characterized for their response patterns against anticancer drugs. Of these genes, 60 contained heterozygous SNPs in their coding regions, and 41 of the genes displayed imbalanced expression of the two cSNP alleles. Genes that displayed Al were subjected to bioinformatics-assisted identification of rSNPs that alter the strength of transcription factor binding. rSNPs in 15 genes were subjected to electrophoretic mobility shift assay, and in eight of these genes (APC, BCL2, CCND2, MLH1, PARP1, SLIT2, YES1, XRCC1) we identified differential protein binding from a nuclear extract between the SNIP alleles. The screening process allowed us to zoom in from 160 candidate genes to eight genes that may contain functional rSNPs in their promoter regions.

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