Genome Biology

Dosage compensation and the global re-balancing of aneuploid genomes.

Publication Date: 2010 Aug 26 PMID: 20804581
Authors: Prestel, M. - Feller, C. - Becker, P. B.
Journal: Genome Biol

ABSTRACT: Diploid genomes are exquisitely balanced systems of gene expression. The dosage-compensation systems that evolved along with monosomic sex chromosomes exemplify the intricacies of compensating for differences in gene copy number by transcriptional regulation.

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Elucidating the molecular characteristics of organogenesis in human embryos.

Publication Date: 2010 Aug 27 PMID: 20804579
Authors: Geng, X. - Oliver, G.
Journal: Genome Biol

ABSTRACT: A transcriptomic analysis of early human organogenesis reveals the molecular signature of these processes and provides a valuable resource for identifying and comparing crucial regulators of mammalian embryogenesis.

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An illuminated view of molecular biology.

Publication Date: 2010 Aug 26 PMID: 20804575
Authors: Barash, Y. - Wang, X.
Journal: Genome Biol

ABSTRACT: A report on the 18th Annual International Conference on Intelligent Systems for Molecular Biology (ISMB) and the 7th Special Interest Group meeting on Alternative Splicing, Boston, USA, 9-13 July 2010.

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The missing graphical user interface for genomics.

Publication Date: 2010 Aug 25 PMID: 20804568
Authors: Schatz, M. C.
Journal: Genome Biol

ABSTRACT: The Galaxy package empowers regular users to perform rich DNA sequence analysis through a much-needed and user-friendly graphical web interface.See research article http://genomebiology.com/2010/11/8/R86 RESEARCH HIGHLIGHT: With the advent of affordable and high-throughput DNA sequencing, sequencing is becoming an essential component in nearly every genetics lab. These data are being generated to probe sequence variations, to understand transcribed, regulated or methylated DNA elements, and to explore a host of other biological features across the tree of life and across a range of environments and conditions. Given this deluge of data, novices and experts alike are facing the daunting challenge of trying to analyze the raw sequence data computationally. With so many tools available and so many assays to analyze, how can one be expected to stay current with the state of the art? How can one be expected to learn to use each tool and construct robust end-to-end analysis pipelines, all while ensuring that input formats, command-line options, sequence databases and program libraries are set correctly? Finally, once the analysis is complete, how does one ensure the results are reproducible and transparent for others to scrutinize and study?In an article published in Genome Biology, Jeremy Goecks, Anton Nekrutenko, James Taylor and the rest of the Galaxy Team (Goecks et al. 1) make a great advance towards resolving these critical questions with the latest update to their Galaxy Project. The ambitious goal of Galaxy is to empower regular users to carry out their own computational analysis without having to be an expert in computational biology or computer science. Galaxy adds a desperately needed graphical user interface to genomics research, making data analysis universally accessible in a web browser, and freeing users from the minutiae of archaic command-line parameters, data formats and scripting languages. Data inputs and computational steps are selected from dynamic graphical menus, and the results are displayed in intuitive plots and summaries that encourage interactive workflows and the exploration of hypotheses. The underlying data analysis tools can be almost any piece of software, written in any language, but all their complexity is neatly hidden inside of Galaxy, allowing users to focus on scientific rather than technical questions.

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Comprehensive modeling of microRNA targets predicts functional non-conserved and non-canonical sites.

Publication Date: 2010 Aug 27 PMID: 20799968
Authors: Betel, D. - Koppal, A. - Agius, P. - Sander, C. - Leslie, C.
Journal: Genome Biol

ABSTRACT: MirSVR is a new machine learning method for ranking microRNA target sites by a down-regulation score. The algorithm trains a regression model on sequence and contextual features extracted from miRanda-predicted target sites. In a large-scale evaluation, miRanda-mirSVR is competitive with other target prediction methods in identifying target genes and predicting the extent of their downregulation at the mRNA or protein levels. Importantly, the method identifies a significant number of experimentally determined non-canonical and non-conserved sites.

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Genomic acquisition of a capsular polysaccharide virulence cluster by non-pathogenic Burkholderia isolates.

Publication Date: 2010 Aug 27 PMID: 20799932
Authors: Sim, B. M. - Chantratita, N. - Ooi, W. F. - Nandi, T. - Tewhey, R. - Wuthiekanun, V. - Thaipadungpanit, J. - Tumapa, S. - Ariyaratne, P. - Sung, W. K. - Sem, X. H. - Chua, H. H. - Ramnarayanan, K. - Lin, C. H. - Liu, Y. - Feil, E. J. - Glass, M. B. - Tan, G. - Peacock, S. J. - Tan, P.
Journal: Genome Biol

ABSTRACT: BACKGROUND: Burkholderia thailandensis is a non-pathogenic environmental saprophyte closely related to Burkholderia pseudomallei, the causative agent of the often fatal animal and human disease melioidosis. To study B. thailandensis genomic variation, we profiled 50 isolates using a pan-genome microarray comprising genomic elements from 28 Burkholderia strains and species. Of 39 genomic regions variably present across the B. thailandensis strains, 13 regions corresponded to known genomic islands, while 26 regions were novel. RESULTS: Variant B. thailandensis isolates exhibited isolated acquisition of a capsular polysaccharide biosynthesis gene cluster (B. pseudomallei-like capsular polysaccharide) closely resembling a similar cluster in B. pseudomallei that is essential for virulence in mammals; presence of this cluster was confirmed by whole genome sequencing of a representative variant strain (B. thailandensis E555). Both whole-genome microarray and multi-locus sequence typing analysis revealed that the variant strains formed part of a phylogenetic subgroup distinct from the ancestral B. thailandensis population and were associated with atypical isolation sources when compared to the majority of previously-described B. thailandensis strains. In functional assays, B. thailandensis E555 exhibited several B. pseudomallei-like phenotypes, including colony wrinkling, resistance to human complement binding, and intracellular macrophage survival. However, in murine infection assays, B. thailandensis E555 did not exhibit enhanced virulence relative to other B. thailandensis strains, suggesting that additional factors are required to successfully colonize and infect mammals. CONCLUSIONS: The discovery of such novel variant strains demonstrates how unbiased genomic surveys of non-pathogenic isolates can reveal insights on the development and emergence of new pathogenic species.

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The past is a foreign country.

Publication Date: 2010 Aug 29 PMID: 20796324
Authors:
Journal: Genome Biol

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Transcription, one allele at a time.

Publication Date: 2010 Aug 29 PMID: 20796323
Authors:
Journal: Genome Biol

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A standard variation file format for human genome sequences.

Publication Date: 2010 Aug 26 PMID: 20796305
Authors: Reese, M. G. - Moore, B. - Batchelor, C. - Salas, F. - Cunningham, F. - Marth, G. - Stein, L. - Flicek, P. - Yandell, M. - Eilbeck, K.
Journal: Genome Biol

ABSTRACT: Here we describe the Genome Variation Format (GVF) and the 10Gen dataset. GVF, an extension of Generic Feature Format version 3 (GFF3), is a simple tab-delimited format for DNA variant files, which uses Sequence Ontology to describe genome variation data. The 10Gen dataset, ten human genomes in GVF format, is freely available for community analysis from the Sequence Ontology website and from an Amazon elastic block storage (EBS) snapshot for use in Amazon's EC2 cloud computing environment.

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Strand-specific RNA sequencing reveals extensive regulated long antisense transcripts that are conserved across yeast species.

Publication Date: 2010 Aug 26 PMID: 20796282
Authors: Yassour, M. - Pfiffner, J. - Levin, J. Z. - Adiconis, X. - Gnirke, A. - Nusbaum, C. - Thompson, D. A. - Friedman, N. - Regev, A.
Journal: Genome Biol

ABSTRACT: BACKGROUND: Recent studies in budding yeast have shown that antisense transcription occurs at many loci. However, the functional role of antisense transcripts has been demonstrated only in a few cases and it has been suggested that most antisense transcripts may result from promiscuous bi-directional transcription in a dense genome. RESULTS: Here, we present data from the use of strand specific ribonucleic acid (RNA) sequencing in Saccharomyces cerevisiae. We detect 1103 putative antisense transcripts expressed in mid-log phase growth, ranging from 39 short transcripts covering only the 3'UTR of sense genes to 145 long transcripts covering the entire sense open reading frame. Many of these antisense transcripts overlap sense genes that are repressed in mid-log phase and are important in stationary phase, stress response, or meiosis. We validate the differential regulation of 67 antisense transcripts and their sense targets in relevant conditions, including nutrient limitation and environmental stresses. Moreover, we show that several antisense transcripts and, in some cases, their differential expression have been conserved across five species of yeast spanning 150 million years of evolution. Divergence in the regulation of antisense transcripts to two respiratory genes coincides with the evolution of respiro-fermentation. CONCLUSIONS: Our work provides support for a global and conserved role for antisense transcription in yeast gene regulation.

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Galaxy: a comprehensive approach for supporting accessible, reproducible, and transparent computational research in the life sciences.

Publication Date: 2010 Aug 25 PMID: 20738864
Authors: Goecks, J. - Nekrutenko, A. - Taylor, J. - Galaxy Team, T.
Journal: Genome Biol

ABSTRACT: Increased reliance on computational approaches in the life sciences has revealed grave concerns about how accessible and reproducible computation-reliant results truly are. Galaxy (http://usegalaxy.org), an open web-based platform for genomic research, addresses these problems. Galaxy automatically tracks and manages data provenance and provides support for capturing the context and intent of computational methods. Galaxy Pages are interactive, web-based documents that provide users with a medium to communicate a complete computational analysis.

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Digital expression profiling of novel diatom transcripts provides insight into their biological functions.

Publication Date: 2010 Aug 25 PMID: 20738856
Authors: Maheswari, U. - Jabbari, K. - Petit, J. L. - Porcel, B. M. - Allen, A. E. - Cadoret, J. P. - De Martino, A. - Heijde, M. - Kaas, R. - La Roche, J. - Lopez, P. J. - Martin-Jezequel, V. - Meichenin, A. - Mock, T. - Schnitzler Parker, M. - Vardi, A. - Armbrust, E. V. - Weissenbach, J. - Katinka, M. - Bowler, C.
Journal: Genome Biol

ABSTRACT: BACKGROUND: Diatoms represent the predominant group of eukaryotic phytoplankton in the oceans and are responsible for around 20% of global photosynthesis. Two whole genome sequences are now available. Notwithstanding, our knowledge of diatom biology remains limited because only around half of their genes can be ascribed a function based on homology-based methods. High throughput tools are needed therefore to associate functions to diatom-specific genes. RESULTS: We have performed a systematic analysis of 130,000 Expressed Sequence Tags (ESTs) derived from Phaeodactylum tricornutum cells grown in sixteen different conditions. These include different sources of nitrogen, different concentrations of carbon dioxide, silicate and iron, and abiotic stresses such as low temperature and low salinity. Based on unbiased statistical methods we have catalogued transcripts with similar expression profiles and identified transcripts differentially expressed in response to specific treatments. Functional annotation of these transcripts provides insights into expression patterns of genes involved in various metabolic and regulatory pathways and into the roles of novel genes with unknown functions. Specific growth conditions could be associated with enhanced gene diversity, known gene product functions, and over-representation of novel transcripts. Comparative analysis of data from the other sequenced diatom, Thalassiosira pseudonana, helped identify several unique diatom genes that are specifically regulated under particular conditions, thus facilitating studies of gene function, genome annotation and the molecular basis of species diversity. CONCLUSIONS: The digital gene expression database represents a new resource for identifying candidate diatom-specific genes involved in processes of major ecological relevance.

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Intronic motif pairs cooperate across exons to promote pre-mRNA splicing.

Publication Date: 2010 Aug 12 PMID: 20704715
Authors: Ke, S. - Chasin, L. A.
Journal: Genome Biol

ABSTRACT: BACKGROUND: A very early step in splice site recognition is exon definition, a process that is as yet poorly understood. Communication between the two ends of an exon is thought to be required for this step. We report genome-wide evidence for exons being defined through the combinatorial activity of motifs located in flanking intronic regions. RESULTS: Strongly co-occurring motifs were found to specifically reside in four intronic regions surrounding a large number of human exons. These paired motifs occur around constitutive and alternative exons but not pseudo exons. Most co-occurring motifs are limited to intronic regions within 100 nucleotides of the exon. They are preferentially associated with weaker exons. Their pairing is conserved in evolution and they exhibit a lower frequency of single nucleotide polymorphism when paired. Paired motifs display specificity with respect to distance from the exon borders and in constitutive versus alternative splicing. Many resemble binding sites for heterogeneous nuclear ribonucleoproteins. Specific pairs are associated with tissue-specific genes, the higher expression of which coincides with that of the pertinent RNA binding proteins. Tested pairs acted synergistically to enhance exon inclusion, and this enhancement was found to be exon-specific. CONCLUSIONS: The exon-flanking sequence pairs identified here by genomic analysis promote exon inclusion and may play a role in the exon definition step in pre- mRNA splicing. We propose a model in which multiple concerted interactions are required between exonic sequences and flanking intronic sequences to effect exon definition.

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Cloud-scale RNA-sequencing differential expression analysis with Myrna.

Publication Date: 2010 Aug 11 PMID: 20701754
Authors: Langmead, B. - Hansen, K. D. - Leek, J. T.
Journal: Genome Biol

ABSTRACT: As sequencing throughput approaches dozens of gigabases per day, there is a growing need for efficient software for analysis of transcriptome sequencing (RNA-Seq) data. Myrna is a cloud-computing pipeline for calculating differential gene expression in large RNA-Seq datasets. We apply Myrna to the analysis of publicly available data sets and assess the goodness of fit of standard statistical models. Myrna is available from http://bowtie-bio.sf.net/myrna.

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Evolution of an adenocarcinoma in response to selection by targeted kinase inhibitors.

Publication Date: 2010 Aug 9 PMID: 20696054
Authors: Jones, S. J. - Laskin, J. - Li, Y. Y. - Griffith, O. L. - An, J. - Bilenky, M. - Butterfield, Y. S. - Cezard, T. - Chuah, E. - Corbett, R. - Fejes, A. - Griffith, M. - Yee, J. - Martin, M. - Mayo, M. - Melnyk, N. - Morin, R. D. - Pugh, T. J. - Severson, T. - Shah, S. P. - Sutcliffe, M. - Tam, A. - Terry, J. - Thiessen, N. - Thomson, T. - Varhol, R. - Zeng, T. - Zhao, Y. - Moore, R. A. - Huntsman, D. G. - Birol, I. - Hirst, M. - Holt, R. A. - Marra, M. A.
Journal: Genome Biol

ABSTRACT: BACKGROUND: Adenocarcinomas of the tongue are rare and represent the minority (20-25%) of salivary gland tumors affecting the tongue. We investigated the utility of massively parallel sequencing to characterize an adenocarcinoma of the tongue, before and after treatment. RESULTS: In the pre-treatment tumor we identified 7,629 genes within regions of copy number gain. 1,078 genes exhibited increased expression relative to the blood and unrelated tumors and four genes contained somatic protein-coding mutations. Our analysis suggested the tumor cells were driven by the RET oncogene. Genes whose protein products are targeted by the RET inhibitors sunitinib and sorafenib correlated with being amplified and or highly expressed. Consistent with our observations administration of sunitinib was associated with stable disease lasting 4 months, after which the lung lesions began to grow. Administration of sorafenib and sulindac provided disease stabilization for an additional 3 months after which the cancer progressed and new lesions appeared. A recurring metastasis possessed 7,288 genes within copy number amplicons, 385 genes exhibiting increased expression relative to other tumours and 9 new somatic protein coding mutations. The observed mutations and amplifications were consistent with therapeutic resistance arising through activation of the MAPK and AKT pathways. CONCLUSIONS: We conclude that complete genomic characterization of a rare tumour has the potential to aid in clinical decision making and identifying therapeutic approaches where no established treatment protocols exist. These results also provide direct in-vivo genomic evidence for mutational evolution within a tumor under drug selection and potential mechanisms of drug resistance accrual.

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Multiple distinct small RNAs originate from the same microRNA precursors.

Publication Date: 2010 Aug 9 PMID: 20696037
Authors: Zhang, W. - Gao, S. - Zhou, X. - Xia, J. - Chellappan, P. - Zhou, X. - Zhang, X. - Jin, H.
Journal: Genome Biol

ABSTRACT: BACKGROUND: MicroRNAs (miRNAs), which originate from precursor transcripts with stem-loop structures, are essential gene expression regulators in eukaryotes. RESULTS: We report 19 miRNA precursors in Arabidopsis that can yield multiple distinct miRNA-like RNAs in addition to miRNAs and miRNA*s. These miRNA precursor-derived miRNA-like RNAs are often arranged in phase and form duplexes with an approximately two-nucleotide 3'-end overhang. Their production depends on the same biogenesis pathway as their sibling miRNAs and does not require RNA-dependent RNA polymerases or RNA polymerase IV. These miRNA-like RNAs are methylated, and many of them are associated with Argonaute proteins. Some of the miRNA-like RNAs are differentially expressed in response to bacterial challenges, and some are more abundant than the cognate miRNAs. Computational and expression analyses demonstrate that some of these miRNA-like RNAs are potentially functional and they target protein-coding genes for silencing. The function of some of these miRNA-like RNAs was further supported by their target cleavage products from the published small RNA degradome data. Our systematic examination of public small-RNA deep sequencing data from four additional plant species (Oryza sativa, Physcomitrella patens, Medicago truncatula and Populus trichocarpa) and four animals (Homo sapiens, Mus musculus, Caenorhabditis elegans and Drosophila) shows that such miRNA-like RNAs exist broadly in eukaryotes. CONCLUSIONS: We demonstrate that multiple miRNAs could derive from miRNA precursors by sequential processing of Dicer or Dicer-like proteins. Our results suggest that the pool of miRNAs is larger than was previously recognized, and miRNA-mediated gene regulation may be broader and more complex than previously thought.

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Comprehensive transcriptome analysis of mouse embryonic stem cell adipogenesis unravels new processes of adipocyte development.

Publication Date: 2010 Aug 3 PMID: 20678241
Authors: Billon, N. - Kolde, R. - Reimand, J. - Monteiro, M. C. - Kull, M. - Peterson, H. - Tretyakov, K. - Adler, P. - Wdziekonski, B. - Vilo, J. - Dani, C.
Journal: Genome Biol

ABSTRACT: BACKGROUND: The current epidemic of obesity has caused a surge of interest in the study of adipose tissue formation. While major progress has been made in defining the molecular networks that control adipocyte terminal differentiation, the early steps of adipocyte development and the embryonic origin of this lineage remain largely unknown. RESULTS: Here we performed genome-wide analysis of gene expression during adipogenesis of mouse embryonic stem cells (ESCs). We then pursued comprehensive bioinformatic analyses, including de novo functional annotation and curation of the generated data within the context of biological pathways, to uncover novel biological functions associated with the early steps of adipocyte development. By combining in-depth gene regulation studies and in silico analysis of transcription factor binding site enrichment, we also provide insights into the transcriptional networks that might govern these early steps. CONCLUSIONS: This study supports several biological findings: firstly, adipocyte development in mouse ESCs is coupled to blood vessel morphogenesis and neural development, just as it is during mouse development. Secondly, the early steps of adipocyte formation involve major changes in signaling and transcriptional networks. A large proportion of the transcription factors that we uncovered in mouse ESCs are also expressed in the mouse embryonic mesenchyme and in adipose tissues, demonstrating the power of our approach to probe for genes associated with early developmental processes on a genome-wide scale. Finally, we reveal a plethora of novel candidate genes for adipocyte development and present a unique resource that can be further explored in functional assays.

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