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1.
Methods Mol Biol ; 1418: 67-90, 2016.
Article in English | MEDLINE | ID: mdl-27008010

ABSTRACT

Annotation resources make up a significant proportion of the Bioconductor project (Huber et al., Nat Methods 12:115-121, 2015). And there are also a diverse set of online resources available which are accessed using specific packages. Here we describe the most popular of these resources and give some high level examples on how to use them.


Subject(s)
Computational Biology/methods , Genomics/methods , Molecular Sequence Annotation/methods , Software
2.
Nat Commun ; 3: 698, 2012 Feb 28.
Article in English | MEDLINE | ID: mdl-22426219

ABSTRACT

The Tyrolean Iceman, a 5,300-year-old Copper age individual, was discovered in 1991 on the Tisenjoch Pass in the Italian part of the Ötztal Alps. Here we report the complete genome sequence of the Iceman and show 100% concordance between the previously reported mitochondrial genome sequence and the consensus sequence generated from our genomic data. We present indications for recent common ancestry between the Iceman and present-day inhabitants of the Tyrrhenian Sea, that the Iceman probably had brown eyes, belonged to blood group O and was lactose intolerant. His genetic predisposition shows an increased risk for coronary heart disease and may have contributed to the development of previously reported vascular calcifications. Sequences corresponding to ~60% of the genome of Borrelia burgdorferi are indicative of the earliest human case of infection with the pathogen for Lyme borreliosis.


Subject(s)
Genome, Human , Genome, Mitochondrial , Mummies , Base Sequence , Borrelia burgdorferi/genetics , Chromosome Mapping , DNA, Mitochondrial/genetics , Genetic Predisposition to Disease , History, Ancient , Humans , Lyme Disease/history , Mitochondria/genetics , Mummies/microbiology , Paleontology , Phenotype , Sequence Analysis, DNA , Vascular Calcification
3.
Lab Invest ; 88(12): 1291-302, 2008 Dec.
Article in English | MEDLINE | ID: mdl-18838963

ABSTRACT

Ewing's family tumors (EFTs) are characterized by recurrent chromosomal translocations that produce chimeric fusions between the EWS gene and one of five ETS transcription factors. The expression of EWS/FLI1, the predominant fusion product in EFTs, is believed to deregulate downstream target genes in an undefined tissue type and leads to development of EFTs. Attempts to generate model systems that represent EFTs have been hampered by an unexpected toxicity of the fusion gene. In the present study, we used gene expression analysis to identify tissue types based on the similarity of their expression profiles to those of EWS/FLI1-modulated genes. The data obtained from this screen helped to identify IMR-90 cells, a human fetal fibroblast, that upon further manipulation can maintain stable EWS/FLI1 expression without the reported toxicity. In addition, gene expression profiling of these cells revealed a significant overlap of genes that have been previously reported to be targets of EWS/FLI1. Furthermore, we show, for the first time, a partial transformation of these human primary fibroblasts with EWS/FLI1 expression. The experiments presented here provide a solid foundation for generation of a new model system for studying Ewing's sarcoma biology.


Subject(s)
Mesoderm/pathology , Models, Biological , Oncogene Proteins, Fusion/genetics , Sarcoma, Ewing/genetics , Transcription Factors/genetics , Apoptosis , Blotting, Western , Cell Line , Gene Expression Profiling , Gene Silencing , Humans , Mesenchymal Stem Cells/pathology , Polymerase Chain Reaction , Proto-Oncogene Protein c-fli-1 , RNA-Binding Protein EWS
4.
Radiology ; 249(1): 268-77, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18796682

ABSTRACT

PURPOSE: To determine the difference in gene expression between completely versus incompletely enhancing glioblastoma multiforme (GBM). MATERIALS AND METHODS: Gene expression was determined for 52 newly diagnosed GBMs by using DNA microarrays, and the relationship to enhancement pattern and survival was analyzed. This study was approved by the institutional review board and was HIPAA compliant; informed consent was obtained. RESULTS: Thirty-eight percent (20 of 52) of GBMs were incompletely enhancing (IE). The expression of eight genes was increased more than twofold in IE GBM when compared with completely enhancing (CE) GBM. Among these were tight junction protein-2 (2.2-fold increase, P = .019), and the oligodendroglioma markers oligodendrocyte lineage transcription factor 2 (2.4-fold increase, P = .029) and Achaete-scute complex-like 1 (ASCL1; 2.7-fold increase, P = .023). The expression of 71 genes showed relative overexpression in CE when compared with IE GBM. These included several proangiogenic and edema-related genes, including vascular endothelial growth factor (2.1-fold, P = .005) and neuronal pentraxin-2 (3.0-fold, P = .029). Several genes associated with primary GBM were overexpressed in CE tumors, whereas ASCL1, which is associated with secondary GBM, was overexpressed in IE tumors. Many genes overexpressed in IE GBM were associated with longer survival, whereas several genes overexpressed in CE GBM correlated with shortened survival. CONCLUSION: The enhancement pattern divides GBM in two groups with differing prognoses. By comparing gene expression between IE and CE GBMs, it was possible to identify genes that may affect magnetic resonance imaging features of edema and enhancement, and genes whose expression levels are predictive of both improved and shortened survival.


Subject(s)
Brain Neoplasms/genetics , Gene Expression Regulation, Neoplastic , Glioblastoma/genetics , Magnetic Resonance Imaging , Oligonucleotide Array Sequence Analysis , Basic Helix-Loop-Helix Transcription Factors/genetics , Brain Neoplasms/mortality , C-Reactive Protein/genetics , Glioblastoma/mortality , Humans , Membrane Proteins/genetics , Nerve Tissue Proteins/genetics , Oligodendrocyte Transcription Factor 2 , Vascular Endothelial Growth Factor A/genetics , Zonula Occludens-2 Protein
5.
Genome Biol ; 8(6): R112, 2007.
Article in English | MEDLINE | ID: mdl-17570842

ABSTRACT

Celsius is a data warehousing system to aggregate Affymetrix CEL files and associated metadata. It provides mechanisms for importing, storing, querying, and exporting large volumes of primary and pre-processed microarray data. Celsius contains ten billion assay measurements and affiliated metadata. It is the largest publicly available source of Affymetrix microarray data, and through sheer volume it allows a sophisticated, broad view of transcription that has not previously been possible.


Subject(s)
Database Management Systems , Databases, Genetic , Oligonucleotide Array Sequence Analysis , Animals , Gene Expression Profiling , Humans
6.
Clin Cancer Res ; 13(9): 2592-8, 2007 May 01.
Article in English | MEDLINE | ID: mdl-17473188

ABSTRACT

PURPOSE: Vascular endothelial growth factor (VEGF) is a potent mediator of vascular permeability. VEGF inhibition reduces edema and tumor burden in some patients with malignant glioma, whereas others show no response. The role of VEGF expression in edema production and the relationship to survival is not well understood. EXPERIMENTAL DESIGN: Using DNA microarray analysis, we examined VEGF and related gene expression in 71 newly diagnosed malignant gliomas and analyzed the relationship to edema and survival. RESULTS AND CONCLUSIONS: VEGF expression was predictive of survival in tumors with little or no edema [Cox proportional hazard model, 6.88; 95% confidence interval (95% CI), 2.61-18.1; P<0.0001], but not in tumors with extensive edema. The expression of several proangiogenic genes, including adrenomedullin (correlation coefficient, 0.80), hypoxia-inducible factor-1A (0.51), and angiopoietin-2 (0.44), was correlated with VEGF expression (all with P<0.0001), whereas that of several antiangiogenic genes was inversely correlated. The expression of six genes was increased greater than 3-fold in edematous versus nonedematous tumors in the absence of increased VEGF expression. The most increased, neuronal pentraxin 2 (NPTX2, 7-fold change), was predictive of survival in tumors with the highest levels of edema, in contrast to VEGF (hazard ratio, 2.73; 95% CI, 1.49-5.02; P=0.049). NPTX2 was tightly correlated with expression of the water channel aquaporin-3 (0.74, P<0.0001). These results suggest that there are both VEGF-dependent and VEGF-independent pathways of edema production in gliomas and may explain why edema is not reduced in some patients following anti-VEGF treatment.


Subject(s)
Brain Edema/diagnosis , Brain Neoplasms/mortality , C-Reactive Protein/genetics , Glioma/mortality , Nerve Tissue Proteins/genetics , Vascular Endothelial Growth Factor A/genetics , Adrenomedullin/genetics , Angiopoietin-2/genetics , Aquaporin 3/genetics , Brain Edema/genetics , Brain Neoplasms/complications , Gene Expression , Glioma/complications , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Oligonucleotide Array Sequence Analysis , Prognosis , Survival
7.
BMC Genomics ; 7: 40, 2006 Mar 03.
Article in English | MEDLINE | ID: mdl-16515682

ABSTRACT

BACKGROUND: Genes and proteins are organized into functional modular networks in which the network context of a gene or protein has implications for cellular function. Highly connected hub proteins, largely responsible for maintaining network connectivity, have been found to be much more likely to be essential for yeast survival. RESULTS: Here we investigate the properties of weighted gene co-expression networks formed from multiple microarray datasets. The constructed networks approximate scale-free topology, but this is not universal across all datasets. We show strong positive correlations between gene connectivity within the whole network and gene essentiality as well as gene sequence conservation. We demonstrate the preservation of a modular structure of the networks formed, and demonstrate that, within some of these modules, it is possible to observe a strong correlation between connectivity and essentiality or between connectivity and conservation within the modules particularly within modules containing larger numbers of essential genes. CONCLUSION: Application of these techniques can allow a finer scale prediction of relative gene importance for a particular process within a group of similarly expressed genes.


Subject(s)
Fungal Proteins/genetics , Gene Expression Regulation, Fungal , Models, Genetic , Saccharomyces/genetics , Base Sequence , Cell Cycle/genetics , Conserved Sequence , DNA Damage , DNA, Fungal/chemistry , Fungal Proteins/physiology , Gene Expression Profiling , Genomics , Oligonucleotide Array Sequence Analysis , Saccharomyces/metabolism
8.
Invest Ophthalmol Vis Sci ; 46(10): 3604-15, 2005 Oct.
Article in English | MEDLINE | ID: mdl-16186340

ABSTRACT

PURPOSE: To identify proteinases and growth factors abnormally expressed in human corneas of donors with diabetic retinopathy (DR), additional to previously described matrix metalloproteinase (MMP)-10 and -3 and insulin-like growth factor (IGF)-I. METHODS: RNA was isolated from 35 normal, diabetic, and DR autopsy human corneas ex vivo or after organ culture. Amplified cRNA was analyzed using 22,000-gene microarrays (Agilent Technologies, Palo Alto, CA). Gene expression in each diabetic corneal cRNA was assessed against pooled cRNA from 7 to 9 normal corneas. Select differentially expressed genes were validated by quantitative real-time RT-PCR (QPCR) and immunohistochemistry. Organ cultures were treated with a cathepsin inhibitor, cystatin C, or MMP-10. RESULTS: More than 100 genes were upregulated and 2200 were downregulated in DR corneas. Expression of cathepsin F and hepatocyte growth factor (HGF) genes was increased in ex vivo and organ-cultured DR corneas compared with normal corneas. HGF receptor c-met, fibroblast growth factor (FGF)-3, its receptor FGFR3, tissue inhibitor of metalloproteinase (TIMP)-4, laminin alpha4 chain, and thymosin beta(4) genes were downregulated. The data were corroborated by QPCR and immunohistochemistry analyses; main changes of these components occurred in corneal epithelium. In organ-cultured DR corneas, cystatin C increased laminin-10 and integrin alpha(3)beta(1), whereas in normal corneas MMP-10 decreased laminin-10 and integrin alpha(3)beta(1) expression. CONCLUSIONS: Elevated cathepsin F and the ability of its inhibitor to produce a more normal phenotype in diabetic corneas suggest increased proteolysis in these corneas. Proteinase changes may result from abnormalities of growth factors, such as HGF and FGF-3, in DR corneas. Specific modulation of proteinases and growth factors could reduce diabetic corneal epitheliopathy.


Subject(s)
Cornea/metabolism , Corneal Diseases/genetics , Diabetic Retinopathy/genetics , Gene Expression Regulation , Growth Substances/genetics , Peptide Hydrolases/genetics , Aged , Corneal Diseases/enzymology , Diabetic Retinopathy/enzymology , Fluorescent Antibody Technique, Indirect , Gene Expression Profiling , Growth Substances/metabolism , Humans , Oligonucleotide Array Sequence Analysis , Organ Culture Techniques , Peptide Hydrolases/metabolism , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Tissue Donors , Up-Regulation
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