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Boolean implication networks derived from large scale, whole genome microarray datasets

GENOME BIOLOGY 2008年第10期9卷 R157-R157页

作者： Sahoo, Debashis Dill, David L. Gentles, Andrew J. Tibshirani, Robert Plevritis, Sylvia K. Stanford Univ Dept Comp Sci Stanford CA 94305 USA Stanford Univ Dept Elect Engn Stanford CA 94305 USA Stanford Univ Dept Hlth Res & Policy Stanford CA 94305 USA Stanford Univ Dept Stat Stanford CA 94305 USA Stanford Univ Dept Radiol Stanford CA 94305 USA

We describe a method for extracting Boolean implications (if-then relationships) in very large amounts of gene expression microarray data. A meta-analysis of data from thousands of microarrays for humans, mice, and fruit flies finds millions of implication relationships between genes that would be missed by other methods. These relationships capture gender differences, tissue differences, development, and differentiation. New relationships are discovered that are preserved across all three species.

关键词： Bayesian Network Gene Pair additional data file Gene Expression Microarray data Boolean Circuit

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DNA signatures for detecting genetic engineering in bacteria

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GENOME BIOLOGY 2008年第3期9卷 R56-R56页

作者： Allen, Jonathan E. Gardner, Shea N. Slezak, Tom R. Lawrence Livermore Natl Lab Livermore CA 94550 USA

Using newly designed computational tools we show that, despite substantial shared sequences between natural plasmids and artificial vector sequences, a robust set of DNA oligomers can be identified that can differentiate artificial vector sequences from all available background viral and bacterial genomes and natural plasmids. We predict that these tools can achieve very high sensitivity and specificity rates for detecting new unsequenced vectors in microarray-based bioassays. Such DNA signatures could be important in detecting genetically engineered bacteria in environmental samples.

关键词： additional data file Hash Table Maximal Clique Vector Sequence Multiple Cloning Site

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Quantitative methods for genome-scale analysis of in situ hybridization and correlation with microarray data

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GENOME BIOLOGY 2008年第1期9卷 R23-R23页

作者： Lee, Chang-Kyu Sunkin, Susan M. Kuan, Chihchau Thompson, Carol L. Pathak, Sayan Ng, Lydia Lau, Chris Fischer, Shanna Mortrud, Marty Slaughterbeck, Cliff Jones, Allan Lein, Ed Hawrylycz, Michael Allen Inst Brain Sci Seattle WA 98103 USA

With the emergence of genome-wide colorimetric in situ hybridization (ISH) data sets such as the Allen Brain Atlas, it is important to understand the relationship between this gene expression modality and those derived from more quantitative based technologies. This study introduces a novel method for standardized relative quantification of colorimetric ISH signal that enables a large-scale cross-platform expression level comparison of ISH with two publicly available microarray brain data sources.

关键词： additional data file Massively Parallel Signature Sequencing Wolfram Syndrome Allen Brain Atlas Allen Brain Atlas data

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Cell death upon epigenetic genome methylation: a novel function of methyl-specific deoxyribonucleases

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GENOME BIOLOGY 2008年第11期9卷 R163-R163页

作者： Fukuda, Eri Kaminska, Katarzyna H. Bujnicki, Janusz M. Kobayashi, Ichizo Univ Tokyo Dept Med Genome Sci Lab Social Genome Sci Minato Ku Tokyo 1088639 Japan Univ Tokyo Grad Sch Sci Grad Program Biophys & Biochem Minato Ku Tokyo 1088639 Japan Int Inst Mol & Cell Biol PL-02109 Warsaw Poland Adam Mickiewicz Univ Fac Biol PL-61614 Poznan Poland Univ Tokyo Inst Med Sci Minato Ku Tokyo 1088639 Japan

Background Alteration in epigenetic methylation can affect gene expression and other processes. In Prokaryota, DNA methyltransferase genes frequently move between genomes and present a potential threat. A methyl-specific deoxyribonuclease, McrBC, of Escherichia coli cuts invading methylated DNAs. Here we examined whether McrBC competes with genome methylation systems through host killing by chromosome cleavage. Results McrBC inhibited the establishment of a plasmid carrying a PvuII methyltransferase gene but lacking its recognition sites, likely through the lethal cleavage of chromosomes that become methylated. Indeed, its phage-mediated transfer caused McrBC-dependent chromosome cleavage. Its induction led to cell death accompanied by chromosome methylation, cleavage and degradation. RecA/RecBCD functions affect the chromosome processing and, together with SOS response, reduce the lethality. Our evolutionary/genomic analyses of mcrBC homologs revealed (i) wide distribution in Prokaryota, (ii) frequent distant horizontal transfer and linkage with mobility-related genes, (iii) diversification in the DNA binding domain. In these features, McrBCs resemble Type II restriction-modification systems, which behave as selfish mobile elements maintaining their frequency by host killing. McrBCs are frequently found linked with a methyltransferase homolog, which suggests a functional association. Conclusions Our experiments indicate McrBC can respond to genome methylation systems by host killing. Combined with our evolutionary/genomic analyses, they support our hypothesis McrBCs have evolved as mobile elements competing with specific genome methylation systems through host killing. To our knowledge, this represents the first report of a defense system against epigenetic systems through cell death.

关键词： additional data file Methyltransferase Gene Genome Methylation Arabinose Concentration Intragenomic Conflict

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Segmentation-based detection of allelic imbalance and loss-of-heterozygosity in cancer cells using whole genome SNP arrays

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GENOME BIOLOGY 2008年第9期9卷 R136-R136页

作者： Staaf, Johan Lindgren, David Vallon-Christersson, Johan Isaksson, Anders Goransson, Hanna Juliusson, Gunnar Rosenquist, Richard Hoglund, Mattias Borg, Ake Ringner, Markus Lund Univ Dept Oncol SE-22185 Lund Sweden Lund Univ CREATE Hlth Strateg Ctr Clin Canc Res SE-22184 Lund Sweden Uppsala Univ Dept Med Sci Canc Pharmacol & Informat SE-75185 Uppsala Sweden Lund Univ Lund Strateg Res Ctr Stem Cell Biol & Cell Therap SE-22184 Lund Sweden Uppsala Univ Dept Genet & Pathol SE-75185 Uppsala Sweden

We present a strategy for detection of loss-of-heterozygosity and allelic imbalance in cancer cells from whole genome single nucleotide polymorphism genotyping data. Using a dilution series of a tumor cell line mixed with its paired normal cell line and data generated on Affymetrix and Illumina platforms, including paired tumor-normal samples and tumors characterized by fluorescent in situ hybridization, we demonstrate a high sensitivity and specificity of the strategy for detecting both minute and gross allelic imbalances in heterogeneous tumor samples.

关键词： additional data file Allelic Imbalance Segmentation Approach Copy Number Gain Segmentation Strategy

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Cross-kingdom patterns of alternative splicing and splice recognition

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GENOME BIOLOGY 2008年第3期9卷 R50-R50页

作者： McGuire, Abigail M. Pearson, Matthew D. Neafsey, Daniel E. Galagan, James E. MIT Broad Inst Cambridge MA 02142 USA Harvard Univ Cambridge Ctr Cambridge MA 02142 USA

Background: Variations in transcript splicing can reveal how eukaryotes recognize intronic splice sites. Retained introns (RIs) commonly appear when the intron definition (ID) mechanism of splice site recognition inconsistently identifies intron-exon boundaries, and cassette exons (CEs) are often caused by variable recognition of splice junctions by the exon definition (ED) mechanism. We have performed a comprehensive survey of alternative splicing across 42 eukaryotes to gain insight into how spliceosomal introns are recognized. Results: All eukaryotes we studied exhibit RIs, which appear more frequently than previously thought. CEs are also present in all kingdoms and most of the organisms in our analysis. We observe that the ratio of CEs to RIs varies substantially among kingdoms, while the ratio of competing 3' acceptor and competing 5' donor sites remains nearly constant. In addition, we find the ratio of CEs to RIs in each organism correlates with the length of its introns. In all 14 fungi we examined, as well as in most of the 9 protists, RIs far outnumber CEs. This differs from the trend seen in 13 multicellular animals, where CEs occur much more frequently than RIs. The six plants we analyzed exhibit intermediate proportions of CEs and RIs. Conclusion: Our results suggest that most extant eukaryotes are capable of recognizing splice sites via both ID and ED, although ED is most common in multicellular animals and ID predominates in fungi and most protists.

关键词： Splice Site Splice Variant additional data file Intron Retention Intron Length

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Whole proteome identification of plant candidate G-protein coupled receptors in Arabidopsis, rice, and poplar:: computational prediction and in-vivo protein coupling

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GENOME BIOLOGY 2008年第7期9卷 R120-R120页

作者： Gookin, Timothy E. Kim, Junhyong Assmann, Sarah M. Penn State Univ Dept Biol Mueller Lab University Pk PA 16802 USA Univ Penn Dept Biol Philadelphia PA 19104 USA Univ Penn Penn Genome Frontiers Inst Philadelphia PA 19104 USA

Background: The classic paradigm of heterotrimeric G-protein signaling describes a heptahelical, membrane-spanning G-protein coupled receptor that physically interacts with an intracellular G alpha subunit of the G-protein heterotrimer to transduce signals. G-protein coupled receptors comprise the largest protein superfamily in metazoa and are physiologically important as they sense highly diverse stimuli and play key roles in human disease. The heterotrimeric G-protein signaling mechanism is conserved across metazoa, and also readily identifiable in plants, but the low sequence conservation of G-protein coupled receptors hampers the identification of novel ones. Using diverse computational methods, we performed whole-proteome analyses of the three dominant model plant species, the herbaceous dicot Arabidopsis thaliana (mouse-eared cress), the monocot Oryza sativa (rice), and the woody dicot Populus trichocarpa (poplar), to identify plant protein sequences most likely to be GPCRs. Results: Our stringent bioinformatic pipeline allowed the high confidence identification of candidate G-protein coupled receptors within the Arabidopsis, Oryza, and Populus proteomes. We extended these computational results through actual wet-bench experiments where we tested over half of our highest ranking Arabidopsis candidate G-protein coupled receptors for the ability to physically couple with GPA1, the sole Ga in Arabidopsis. We found that seven out of eight tested candidate G-protein coupled receptors do in fact interact with GPA1. We show through G- protein coupled receptor classification and molecular evolutionary analyses that both individual G-protein coupled receptor candidates and candidate G- protein coupled receptor families are conserved across plant species and that, in some cases, this conservation extends to metazoans. Conclusion: Our computational and wet-bench results provide the first step toward understanding the diversity, conservation, and functional roles of plant

关键词： additional data file GPCR Family Signal Peptide Prediction Arabidopsis Proteome Intermediate Pool

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An improved method for detecting and delineating genomic regions with altered gene expression in cancer

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GENOME BIOLOGY 2008年第1期9卷 R13-R13页

作者： Nilsson, Bjorn Johansson, Mikael Heyden, Anders Nelander, Sven Fioretos, Thoas Univ Lund Hosp Dept Clin Genet SE-22185 Lund Sweden Univ Lund Hosp Dept Transfus Med SE-22185 Lund Sweden Harvard Univ Broad Inst Cambridge MA 02142 USA MIT Cambridge MA 02142 USA Royal Inst Technol Dept Automat Control SE-10044 Stockholm Sweden Malmo Univ Dept Appl Math SE-20506 Malmo Sweden Mem Sloan Kettering Canc Ctr Computat Biol Ctr New York NY 10021 USA

Genomic regions with altered gene expression are a characteristic feature of cancer cells. We present a novel method for identifying such regions in gene expression maps. This method is based on total variation minimization, a classical signal restoration technique. In systematic evaluations, we show that our method combines top-notch detection performance with an ability to delineate relevant regions without excessive over-segmentation, making it a significant advance over existing methods. Software (Rendersome) is provided.

关键词： Acute Lymphoblastic Leukemia additional data file Receiver Operating Characteristic Receiver Operating Characteristic Curve Relevant Region

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Gene expression response in target organ and whole blood varies as a function of target organ injury phenotype

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GENOME BIOLOGY 2008年第6期9卷 R100-R100页

作者： Lobenhofer, Edward K. Auman, J. Todd Blackshear, Pamela E. Boorman, Gary A. Bushel, Pierre R. Cunningham, Michael L. Fostel, Jennifer M. Gerrish, Kevin Heinloth, Alexandra N. Irwin, Richard D. Malarkey, David E. Merrick, B. Alex Sieber, Stella O. Tucker, Charles J. Ward, Sandra M. Wilson, Ralph E. Hurban, Patrick Tennant, Raymond W. Paules, Richard S. Cogenics Div Ciln Data Inc Morrisville NC 27560 USA NIEHS NIEHS Microarray Grp Natl Inst Hlth Res Triangle Pk NC 27709 USA Integrated Syst Lab Inc Res Triangle Pk NC 27709 USA NIEHS Natl Toxicol Program Natl Inst Hlth Res Triangle Pk NC 27709 USA NIEHS Biostat Branch Natl Inst Hlth Res Triangle Pk NC 27709 USA NIEHS Natl Ctr Toxicogenom Natl Inst Hlth Res Triangle Pk NC 27709 USA NIEHS Lab Resp Biol Natl Inst Hlth Res Triangle Pk NC 27709 USA NIEHS Lab Expt Pathol Natl Inst Hlth Res Triangle Pk NC 27709 USA NIEHS Canc Biol Grp Natl Inst Hlth Res Triangle Pk NC 27709 USA NIEHS Environm Stress & Canc Grp Natl Inst Hlth Res Triangle Pk NC 27709 USA

This report details the standardized experimental design and the different data streams that were collected (histopathology, clinical chemistry, hematology and gene expression from the target tissue (liver) and a bio-available tissue (blood)) after treatment with eight known hepatotoxicants (at multiple time points and doses with multiple biological replicates). The results of the study demonstrate the classification of histopathological differences, likely reflecting differences in mechanisms of cell-specific toxicity, using either liver tissue or blood transcriptomic data.

关键词： Support Vector Machine Gene Ontology Gene Expression data additional data file Galactosamine

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Membrane transporters and protein traffic networks differentially affecting metal tolerance: a genomic phenotyping study in yeast

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GENOME BIOLOGY 2008年第4期9卷 R67-R67页

作者： Ruotolo, Roberta Marchini, Gessica Ottonello, Simone Univ Parma Dept Biochem & Mol Biol I-43100 Parma Italy

Background: The cellular mechanisms that underlie metal toxicity and detoxification are rather variegated and incompletely understood. Genomic phenotyping was used to assess the roles played by all nonessential Saccharomyces cerevisiae proteins in modulating cell viability after exposure to cadmium, nickel, and other metals. Results: A number of novel genes and pathways that affect multimetal as well as metal-specific tolerance were discovered. Although the vacuole emerged as a major hot spot for metal detoxification, we also identified a number of pathways that play a more general, less direct role in promoting cell survival under stress conditions (for example, mRNA decay, nucleocytoplasmic transport, and iron acquisition) as well as proteins that are more proximally related to metal damage prevention or repair. Most prominent among the latter are various nutrient transporters previously not associated with metal toxicity. A strikingly differential effect was observed for a large set of deletions, the majority of which centered on the ESCRT (endosomal sorting complexes required for transport) and retromer complexes, which-by affecting transporter downregulation and intracellular protein traffic-cause cadmium sensitivity but nickel resistance. Conclusion: The data show that a previously underestimated variety of pathways are involved in cadmium and nickel tolerance in eukaryotic cells. As revealed by comparison with five additional metals, there is a good correlation between the chemical properties and the cellular toxicity signatures of various metals. However, many conserved pathways centered on membrane transporters and protein traffic affect cell viability with a surprisingly high degree of metal specificity.

关键词： Cadmium Gene Ontology additional data file Metal Tolerance Nuclear Pore Complex

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