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A hidden reservoir of integrative elements is the major source of recently acquired foreign genes and ORFans in archaeal and bacterial genomes

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GENOME BIOLOGY 2009年第6期10卷 R65-R65页

作者： Cortez, Diego Forterre, Patrick Gribaldo, Simonetta Inst Pasteur Dept Microbiol Unite Biol Mol Gene Chez Extremophiles F-75724 Paris 15 France

Background: Archaeal and bacterial genomes contain a number of genes of foreign origin that arose from recent horizontal gene transfer, but the role of integrative elements (IEs), such as viruses, plasmids, and transposable elements, in this process has not been extensively quantified. Moreover, it is not known whether IEs play an important role in the origin of ORFans (open reading frames without matches in current sequence databases), whose proportion remains stable despite the growing number of complete sequenced genomes. Results: We have performed a large-scale survey of potential recently acquired IEs in 119 archaeal and bacterial genomes. We developed an accurate in silico Markov model-based strategy to identify clusters of genes that show atypical sequence composition (clusters of atypical genes or CAGs) and are thus likely to be recently integrated foreign elements, including IEs. Our method identified a high number of new CAGs. Probabilistic analysis of gene content indicates that 56% of these new CAGs are likely IEs, whereas only 7% likely originated via horizontal gene transfer from distant cellular sources. Thirty-four percent of CAGs remain unassigned, what may reflect a still poor sampling of IEs associated with bacterial and archaeal diversity. Moreover, our study contributes to the issue of the origin of ORFans, because 39% of these are found inside CAGs, many of which likely represent recently acquired IEs. Conclusions: Our results strongly indicate that archaeal and bacterial genomes contain an impressive proportion of recently acquired foreign genes (including ORFans) coming from a still largely unexplored reservoir of IEs.

关键词： additional data file tRNA Gene Bacterial Genome Core Gene Viral Origin

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GC- and AT-rich chromatin domains differ in conformation and histone modification status and are differentially modulated by Rpd3p

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GENOME BIOLOGY 2007年第6期8卷 R116-R116页

作者： Dekker, Job Univ Massachusetts Sch Med Program Gene Funct & Express Worcester MA 01605 USA Univ Massachusetts Sch Med Dept Biochem & Mol Pharmacol Worcester MA 01605 USA

Background: Base-composition varies throughout the genome and is related to organization of chromosomes in distinct domains (isochores). Isochore domains differ in gene expression levels, replication timing, levels of meiotic recombination and chromatin structure. The molecular basis for these differences is poorly understood. Results: We have compared GC- and AT-rich isochores of yeast with respect to chromatin conformation, histone modification status and transcription. Using 3C analysis we show that, along chromosome III, GC- rich isochores have a chromatin structure that is characterized by lower chromatin interaction frequencies compared to AT-rich isochores, which may point to a more extended chromatin conformation. In addition, we find that throughout the genome, GC- rich and AT-rich genes display distinct levels of histone modifications. Interestingly, elimination of the histone deacetylase Rpd3p differentially affects conformation of GC- and AT-rich domains. Further, deletion of RPD3 activates expression of GC- rich genes more strongly than AT-rich genes. Analyses of effects of the histone deacetylase inhibitor trichostatin A, global patterns of Rpd3p binding and effects of deletion of RPD3 on histone H4 acetylation confirmed that conformation and activity of GC- rich chromatin are more sensitive to Rpd3p-mediated deacetylation than AT-rich chromatin. Conclusion: We find that GC- rich and AT-rich chromatin domains display distinct chromatin conformations and are marked by distinct patterns of histone modifications. We identified the histone deacetylase Rpd3p as an attenuator of these base composition-dependent differences in chromatin status. We propose that GC- rich chromatin domains tend to occur in a more active conformation and that Rpd3p activity represses this propensity throughout the genome.

关键词： additional data file Interaction Frequency Chromatin Fiber Chromatin Conformation Histone Deacetylase Inhibitor Trichostatin

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A catalog of human cDNA expression clones and its application to structural genomics -: art. no. R71

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GENOME BIOLOGY 2004年第9期5卷 1-8页

作者： Büssow, K Quedenau, C Sievert, V Tischer, J Scheich, C Seitz, H Hieke, B Niesen, FH Götz, F Harttig, U Lehrach, H Prot Struct Factory D-14059 Berlin Germany Max Planck Inst Mol Genet D-14195 Berlin Germany Charite Univ Med Berlin Inst Med Phys & Biophys D-10117 Berlin Germany Alpha Bioverfahrenstech GmbH D-14532 Kleinmachnow Germany Genome Res GmbH RZPD German Resource Ctr D-14059 Berlin Germany

We describe here a systematic approach to the identification of human proteins and protein fragments that can be expressed as soluble proteins in Escherichia coli. A cDNA expression library of 10,825 clones was screened by small-scale expression and purification and 2,746 clones were identified. Sequence and protein-expression data were entered into a public database. A set of 163 clones was selected for structural analysis and 17 proteins were prepared for crystallization, leading to three new structures.

关键词： additional data file Expression Product cDNA Insert Expression Clone Ensembl database

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Tandem repeat copy-number variation in protein-coding regions of human genes

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GENOME BIOLOGY 2005年第8期6卷 R69-R69页

作者： O'Dushlaine, CT Edwards, RJ Park, SD Shields, DC Royal Coll Surgeons Ireland Dept Clin Pharmacol Bioinformat Core Dublin 2 Ireland Royal Coll Surgeons Ireland Inst Biopharmaceut Sci Dublin 2 Ireland

Background: Tandem repeat variation in protein-coding regions will alter protein length and may introduce frameshifts. Tandem repeat variants are associated with variation in pathogenicity in bacteria and with human disease. We characterized tandem repeat polymorphism in human proteins, using the UniGene database, and tested whether these were associated with host defense roles. Results: Protein-coding tandem repeat copy-number polymorphisms were detected in 249 tandem repeats found in 218 UniGene clusters;observed length differences ranged from 2 to 144 nucleotides, with unit copy lengths ranging from 2 to 57. This corresponded to 1.59% ( 218/13,749) of proteins investigated carrying detectable polymorphisms in the copy-number of protein-coding tandem repeats. We found no evidence that tandem repeat copy-number polymorphism was significantly elevated in defense-response proteins ( p = 0.882). An association with the Gene Ontology term 'protein-binding' remained significant after covariate adjustment and correction for multiple testing. Combining this analysis with previous experimental evaluations of tandem repeat polymorphism, we estimate the approximate mean frequency of tandem repeat polymorphisms in human proteins to be 6%. Because 13.9% of the polymorphisms were not a multiple of three nucleotides, up to 1% of proteins may contain frameshifting tandem repeat polymorphisms. Conclusion: Around 1 in 20 human proteins are likely to contain tandem repeat copy-number polymorphisms within coding regions. Such polymorphisms are not more frequent among defense-response proteins;their prevalence among protein-binding proteins may reflect lower selective constraints on their structural modification. The impact of frameshifting and longer copy-number variants on protein function and disease merits further investigation.

关键词： Gene Ontology Tandem Repeat additional data file Repeat Polymorphism UniGene Cluster

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Identification of secondary targets of N-containing bisphosphonates in mammalian cells via parallel competition analysis of the barcoded yeast deletion collection

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GENOME BIOLOGY 2009年第9期10卷 R93-R93页

作者： Bivi, Nicoletta Romanello, Milena Harrison, Richard Clarke, Ian Hoyle, David C. Moro, Luigi Ortolani, Fulvia Bonetti, Antonella Quadrifoglio, Franco Tell, Gianluca Delneri, Daniela Univ Manchester Fac Life Sci Manchester M13 9PT Lancs England Univ Udine Dept Biomed Sci & Technol I-33100 Udine Italy Inst Evolutionary Biol Sch Biol Sci Edinburgh EH9 3JT Midlothian Scotland Ctr Study Metab Bone Dis I-34170 Gorizia Italy Univ Udine Dept Med & Morphol Res I-33100 Udine Italy

Background: Nitrogen-containing bisphosphonates are the elected drugs for the treatment of diseases in which excessive bone resorption occurs, for example, osteoporosis and cancer-induced bone diseases. The only known target of nitrogen-containing bisphosphonates is farnesyl pyrophosphate synthase, which ensures prenylation of prosurvival proteins, such as Ras. However, it is likely that the action of nitrogen-containing bisphosphonates involves additional unknown mechanisms. To identify novel targets of nitrogen-containing bisphosphonates, we used a genome-wide high-throughput screening in which 5,936 Saccharomyces cerevisiae heterozygote barcoded mutants were grown competitively in the presence of sub-lethal doses of three nitrogen-containing bisphosphonates (risedronate, alendronate and ibandronate). Strains carrying deletions in genes encoding potential drug targets show a variation of the intensity of their corresponding barcodes on the hybridization array over the time. Results: With this approach, we identified novel targets of nitrogen-containing bisphosphonates, such as tubulin cofactor B and ASK/DBF4 (Activator of S-phase kinase). The up-regulation of tubulin cofactor B may explain some previously unknown effects of nitrogen-containing bisphosphonates on microtubule dynamics and organization. As nitrogen-containing bisphosphonates induce extensive DNA damage, we also document the role of DBF4 as a key player in nitrogen-containing bisphosphonate-induced cytotoxicity, thus explaining the effects on the cell-cycle. Conclusions: The dataset obtained from the yeast screen was validated in a mammalian system, allowing the discovery of new biological processes involved in the cellular response to nitrogen-containing bisphosphonates and opening up opportunities for development of new anticancer drugs.

关键词： Alendronate Zoledronic Acid additional data file Ibandronate Geranylgeranyl Pyrophosphate

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Hominoid chromosomal rearrangements on 17q map to complex regions of segmental duplication

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GENOME BIOLOGY 2008年第2期9卷 R28-R28页

作者： Cardone, Maria Francesca Jiang, Zhaoshi D'Addabbo, Pietro Archidiacono, Nicoletta Rocchi, Mariano Eichler, Evan E. Ventura, Mario Univ Bari Dept Genet & Microbiol I-70126 Bari Italy Univ Washington Sch Med Dept Genome Sci Seattle WA 98195 USA Univ Washington Howard Hughes Med Inst Seattle WA 98195 USA

Background: Chromosomal rearrangements, such as translocations and inversions, are recurrent phenomena during evolution, and both of them are involved in reproductive isolation and speciation. To better understand the molecular basis of chromosome rearrangements and their part in karyotype evolution, we have investigated the history of human chromosome 17 by comparative fluorescence in situ hybridization (FISH) and sequence analysis. Results: Human bacterial artificial chromosome/pI artificial chromosome probes spanning the length of chromosome 17 were used in FISH experiments on great apes, Old World monkeys and New World monkeys to study the evolutionary history of this chromosome. We observed that the macaque marker order represents the ancestral organization. Human, chimpanzee and gorilla homologous chromosomes differ by a paracentric inversion that occurred specifically in the Homo sapiens/Pan troglodytes/Gorilla gorilla ancestor. Detailed analyses of the paracentric inversion revealed that the breakpoints mapped to two regions syntenic to human 17q12/21 and 17q23, both rich in segmental duplications. Conclusion: Sequence analyses of the human and macaque organization suggest that the duplication events occurred in the catarrhine ancestor with the duplication blocks continuing to duplicate or undergo gene conversion during evolution of the hominoid lineage. We propose that the presence of these duplicons has mediated the inversion in the H. sapiens/P. troglodytes/G. gorilla ancestor. Recently, the same duplication blocks have been shown to be polymorphic in the human population and to be involved in triggering microdeletion and duplication in human. These results further support a model where genomic architecture has a direct role in both rearrangement involved in karyotype evolution and genomic instability in human.

关键词： Bacterial Artificial Chromosome additional data file Bacterial Artificial Chromosome Clone Segmental Duplication World Monkey

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Exploratory differential gene expression analysis in microarray experiments with no or limited replication

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GENOME BIOLOGY 2004年第3期5卷 1-33页

作者： Loguinov, AV Mian, IS Vulpe, CD Univ Calif Berkeley Dept Nutr Sci & Toxicol Berkeley CA 94720 USA Univ Calif Berkeley Lawrence Berkeley Lab Div Life Sci Berkeley CA 94720 USA

We describe an exploratory, data-oriented approach for identifying candidates for differential gene expression in cDNA microarray experiments in terms of alpha-outliers and outlier regions, using simultaneous tolerance intervals relative to the line of equivalence (Cy5=Cy3). We demonstrate the improved performance of our approach over existing single-slide methods using public datasets and simulation studies.

关键词： additional data file Tolerance Interval Scale Estimator Regular Observation Bivariate Normality

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Did an ancient chlamydial endosymbiosis facilitate the establishment of primary plastids?

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GENOME BIOLOGY 2007年第6期8卷 R99-R99页

作者： Huang, Jinling Gogarten, Johann Peter E Carolina Univ Dept Biol Greenville NC 27858 USA Marine Biol Lab NASA Astrobiol Inst Woods Hole MA 02543 USA Univ Connecticut Dept Mol & Cell Biol Storrs CT 06269 USA

Background: Ancient endosymbioses are responsible for the origins of mitochondria and plastids, and they contribute to the divergence of several major eukaryotic groups. Although chlamydiae, a group of obligate intracellular bacteria, are not found in plants, an unexpected number of chlamydial genes are most similar to plant homologs, which, interestingly, often contain a plastid-targeting signal. This observation has prompted several hypotheses, including gene transfer between chlamydiae and plant-related groups and an ancestral relationship between chlamydiae and cyanobacteria. Results: We conducted phylogenomic analyses of the red alga Cyanidioschyzon merolae to identify genes specifically related to chlamydial homologs. We show that at least 21 genes were transferred between chlamydiae and primary photosynthetic eukaryotes, with the donor most similar to the environmental Protochlamydia. Such an unusually high number of transferred genes suggests an ancient chlamydial endosymbiosis with the ancestral primary photosynthetic eukaryote. We hypothesize that three organisms were involved in establishing the primary photosynthetic lineage: the eukaryotic host cell, the cyanobacterial endosymbiont that provided photosynthetic capability, and a chlamydial endosymbiont or parasite that facilitated the establishment of the cyanobacterial endosymbiont. Conclusion: Our findings provide a glimpse into the complex interactions that were necessary to establish the primary endosymbiotic relationship between plastid and host cytoplasms, and thereby explain the rarity with which long-term successful endosymbiotic relationships between heterotrophs and photoautotrophs were established. Our data also provide strong and independent support for a common origin of all primary photosynthetic eukaryotes and of the plastids they harbor.

关键词： additional data file Green Plant Phylogenomic Analysis Photosynthetic Eukaryote Obligate Intracellular Bacterium

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A draft annotation and overview of the human genome

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GENOME BIOLOGY 2001年第7期2卷 1-39页

作者： Wright, Fred A. Lemon, William J. Zhao, Wei D. Sears, Russell Zhuo, Degen Wang, Jian-Ping Yang, Hee-Yung Baer, Troy Stredney, Don Spitzner, Joe Stutz, Al Krahe, Ralf Yuan, Bo Ohio State Univ Div Human Canc Genet Columbus OH 43210 USA LabBook Com Columbus OH 43229 USA OSC Columbus OH 43212 USA Ohio State Univ Dept Comp & Informat Sci Columbus OH 43210 USA

Background: The recent draft assembly of the human genome provides a unified basis for describing genomic structure and function. The draft is sufficiently accurate to provide useful annotation, enabling direct observations of previously inferred biological phenomena. Results: We report here a functionally annotated human gene index placed directly on the genome. The index is based on the integration of public transcript, protein, and mapping information, supplemented with computational prediction. We describe numerous global features of the genome and examine the relationship of various genetic maps with the assembly. In addition, initial sequence analysis reveals highly ordered chromosomal landscapes associated with paralogous gene clusters and distinct functional compartments. Finally, these annotation data were synthesized to produce observations of gene density and number that accord well with historical estimates. Such a global approach had previously been described only for chromosomes 21 and 22, which together account for 2.2% of the genome. Conclusions: We estimate that the genome contains 65,000-75,000 transcriptional units, with exon sequences comprising 4%. The creation of a comprehensive gene index requires the synthesis of all available computational and experimental evidence.

关键词： Bacterial Artificial Chromosome additional data file Genomic Clone Radiation Hybrid Transcriptional Unit

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Identification of signaling components required for the prediction of cytokine release in RAW 264.7 macrophages

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GENOME BIOLOGY 2006年第2期7卷 R11-R11页

作者： Pradervand, S Maurya, MR Subramaniam, S Univ Calif San Diego San Diego Supercomp Ctr Alliance Cellular Signaling Bioinformat & Data Coordinat Lab La Jolla CA 92093 USA Univ Calif San Diego Dept Bioengn La Jolla CA 92093 USA Univ Calif San Diego Dept Chem & Biochem La Jolla CA 92093 USA

Background: Release of immuno-regulatory cytokines and chemokines during inflammatory response is mediated by a complex signaling network. Multiple stimuli produce different signals that generate different cytokine responses. Current knowledge does not provide a complete picture of these signaling pathways. However, using specific markers of signaling pathways, such as signaling proteins, it is possible to develop a 'coarse-grained network' map that can help understand common regulatory modules for various cytokine responses and help differentiate between the causes of their release. Results: Using a systematic profiling of signaling responses and cytokine release in RAW 264.7 macrophages made available by the Alliance for Cellular Signaling, an analysis strategy is presented that integrates principal component regression and exhaustive search-based model reduction to identify required signaling factors necessary and sufficient to predict the release of seven cytokines (G-CSF, IL-1 alpha, IL-6, IL-10, MIP-1 alpha, RANTES, and TNF alpha) in response to selected ligands. This study provides a model-based quantitative estimate of cytokine release and identifies ten signaling components involved in cytokine production. The models identified capture many of the known signaling pathways involved in cytokine release and predict potentially important novel signaling components, like p38 MAPK for G-CSF release, IFN gamma- and IL-4-specific pathways for IL-1a release, and an M-CSF-specific pathway for TNF alpha release. Conclusion: Using an integrative approach, we have identified the pathways responsible for the differential regulation of cytokine release in RAW 264.7 macrophages. Our results demonstrate the power of using heterogeneous cellular data to qualitatively and quantitatively map intermediate cellular phenotypes.

关键词： Minimal Model additional data file Cytokine Release Interferon Regulatory Factor RANTES Promoter

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