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Characterization of the yeast ionome:: a genome-wide analysis of nutrient mineral and trace element homeostasis in Saccharomyces cerevisiae -: art. no. R77

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GENOME BIOLOGY 2005年第9期6卷 1-13页

作者： Eide, DJ Clark, S Nair, TM Gehl, M Gribskov, M Guerinot, ML Harper, JF Univ Wisconsin Dept Nutr Sci Madison WI 53706 USA Univ Calif San Diego San Diego Supercomp Ctr La Jolla CA 92903 USA Univ Nevada Dept Biochem Reno NV 89557 USA Dartmouth Coll Dept Biol Sci Hanover NH 03755 USA

Background: Nutrient minerals are essential yet potentially toxic, and homeostatic mechanisms are required to regulate their intracellular levels. We describe here a genome-wide screen for genes involved in the homeostasis of minerals in Saccharomyces cerevisiae. Using inductively coupled plasma-atomic emission spectroscopy (ICP-AES), we assayed 4,385 mutant strains for the accumulation of 13 elements (dcalcium, cobalt, copper, iron, potassium, magnesium, manganese, nickel, phosphorus, selenium, sodium, sulfur, and zinc). We refer to the resulting accumulation profile as the yeast 'ionome'. Results: We identified 212 strains that showed altered ionome profiles when grown on a rich growth medium. Surprisingly few of these mutants (four strains) were affected for only one element. Rather, levels of multiple elements were altered in most mutants. It was also remarkable that only six genes previously shown to be involved in the uptake and utilization of minerals were identified here, indicating that homeostasis is robust under these replete conditions. Many mutants identified affected either mitochondrial or vacuolar function and these groups showed similar effects on the accumulation of many different elements. In addition, intriguing positive and negative correlations among different elements were observed. Finally, ionome profile data allowed us to correctly predict a function for a previously uncharacterized gene, YDR065W. We show that this gene is required for vacuolar acidification. Conclusion: Our results indicate the power of ionomics to identify new aspects of mineral homeostasis and how these data can be used to develop hypotheses regarding the functions of previously uncharacterized genes.

关键词： Selenium additional data file Yeast Gene AdoMet Mineral Homeostasis

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A computational model of gene expression reveals early transcriptional events at the subtelomeric regions of the malaria parasite, Plasmodium falciparum

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GENOME BIOLOGY 2008年第5期9卷 R88-R88页

作者： Scholz, Matthias Fraunholz, Martin J. Univ Greifswald Competence Ctr Funct Genom D-17487 Greifswald Germany

Background: The malaria parasite, Plasmodium falciparum, replicates asexually in a well-defined infection cycle within human erythrocytes (red blood cells). The intra-erythrocytic developmental cycle (IDC) proceeds with a 48 hour periodicity. Results: Based on available malaria microarray data, which monitored gene expression over one complete IDC in one-hour time intervals, we built a mathematical model of the IDC using a circular variant of non-linear principal component analysis. This model enables us to identify rates of expression change within the data and reveals early transcriptional events at the subtelomeres of the parasite's nuclear chromosomes. Conclusion: A delay between subtelomeric and central gene activities suggests that key events of the IDC are initiated at the subtelomeric regions of the P. falciparum nuclear chromosomes.

关键词： Malaria additional data file Subtelomeric Region Standard Principal Component Analysis Infected RBCs

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Comparative genomics of mutualistic viruses of Glyptapanteles parasitic wasps

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GENOME BIOLOGY 2008年第12期9卷 R183-R183页

作者： Desjardins, Christopher A. Gundersen-Rindal, Dawn E. Hostetler, Jessica B. Tallon, Luke J. Fadrosh, Douglas W. Fuester, Roger W. Pedroni, Monica J. Haas, Brian J. Schatz, Michael C. Jones, Kristine M. Crabtree, Jonathan Forberger, Heather Nene, Vishvanath USDA ARS Invas Insect Biocontrol & Behavior Lab Beltsville MD 20705 USA USDA ARS Beneficial Insect Intro Res Lab Newark DE 19713 USA Univ Maryland Ctr Bioinformat & Computat Biol College Pk MD 20742 USA Univ Maryland Sch Med Inst Genome Sci Baltimore MD 21201 USA Univ Maryland Sch Med Dept Microbiol & Immunol Baltimore MD 21201 USA J Craig Venter Inst Rockville MD 20850 USA

Background: Polydnaviruses, double-stranded DNA viruses with segmented genomes, have evolved as obligate endosymbionts of parasitoid wasps. Virus particles are replication deficient and produced by female wasps from proviral sequences integrated into the wasp genome. These particles are co-injected with eggs into caterpillar hosts, where viral gene expression facilitates parasitoid survival and, thereby, survival of proviral DNA. Here we characterize and compare the encapsidated viral genome sequences of bracoviruses in the family Polydnaviridae associated with Glyptapanteles gypsy moth parasitoids, along with near complete proviral sequences from which both viral genomes are derived. Results: The encapsidated Glyptapanteles indiensis and Glyptapanteles flavicoxis bracoviral genomes, each composed of 29 different size segments, total approximately 517 and 594 kbp, respectively. They are generated from a minimum of seven distinct loci in the wasp genome. Annotation of these sequences revealed numerous novel features for polydnaviruses, including insect-like sugar transporter genes and transposable elements. Evolutionary analyses suggest that positive selection is widespread among bracoviral genes. Conclusions: The structure and organization of G. indiensis and G. flavicoxis bracovirus proviral segments as multiple loci containing one to many viral segments, flanked and separated by wasp gene-encoding DNA, is confirmed. Rapid evolution of bracovirus genes supports the hypothesis of bracovirus genes in an 'arms race' between bracovirus and caterpillar. Phylogenetic analyses of the bracoviral genes encoding sugar transporters provides the first robust evidence of a wasp origin for some polydnavirus genes. We hypothesize transposable elements, such as those described here, could facilitate transfer of genes between proviral segments and host DNA.

关键词： Bacterial Artificial Chromosome additional data file Bacterial Artificial Chromosome Clone Gypsy Moth Bacterial Artificial Chromosome Library

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Breaking the waves: improved detection of copy number variation from microarray-based comparative genomic hybridization

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GENOME BIOLOGY 2007年第10期8卷 R228-R228页

作者： Marioni, John C. Thorne, Natalie P. Valsesia, Armand Fitzgerald, Tomas Redon, Richard Fiegler, Heike Andrews, T. Daniel Stranger, Barbara E. Lynch, Andrew G. Dermitzakis, Emmanouil T. Carter, Nigel P. Tavare, Simon Hurles, Matthew E. Wellcome Trust Sanger Inst Cambridge CB10 1SA England Univ Cambridge Ctr Math Sci Dept Appl Math & Theoret Phys Computat Biol Grp Cambridge CB3 0RE England Univ Cambridge Canc Res UK Cambridge Res Inst Computat Biol Grp Cambridge CB2 0RE England

Background: Large-scale high throughput studies using microarray technology have established that copy number variation ( CNV) throughout the genome is more frequent than previously thought. Such variation is known to play an important role in the presence and development of phenotypes such as HIV-1 infection and Alzheimer's disease. However, methods for analyzing the complex data produced and identifying regions of CNV are still being refined. Results: We describe the presence of a genome-wide technical artifact, spatial autocorrelation or 'wave', which occurs in a large dataset used to determine the location of CNV across the genome. By removing this artifact we are able to obtain both a more biologically meaningful clustering of the data and an increase in the number of CNVs identified by current calling methods without a major increase in the number of false positives detected. Moreover, removing this artifact is critical for the development of a novel model-based CNV calling algorithm - CNVmix - that uses cross-sample information to identify regions of the genome where CNVs occur. For regions of CNV that are identified by both CNVmix and current methods, we demonstrate that CNVmix is better able to categorize samples into groups that represent copy number gains or losses. Conclusion: Removing artifactual 'waves' ( which appear to be a general feature of array comparative genomic hybridization ( aCGH) datasets) and using cross-sample information when identifying CNVs enables more biological information to be extracted from aCGH experiments designed to investigate copy number variation in normal individuals.

关键词： Copy Number Variation additional data file Log2 Ratio Copy Number Variable Region aCGH data

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Do Alu repeats drive the evolution of the primate transcriptome?

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GENOME BIOLOGY 2008年第2期9卷 R25-R25页

作者： Urrutia, Araxi O. Balladares Ocana, Leandro Hurst, Laurence D. Univ Bath Dept Biol & Biochem Bath BA4 7AY Avon England IPN Ctr Res Comp Mexico City 07738 DF Mexico Univ Calif Santa Cruz Dept Comp Engn Santa Cruz CA 95064 USA

Background: Of all repetitive elements in the human genome, Alus are unusual in being enriched near to genes that are expressed across a broad range of tissues. This has led to the proposal that Alus might be modifying the expression breadth of neighboring genes, possibly by providing CpG islands, modifying transcription factor binding, or altering chromatin structure. Here we consider whether Alus have increased expression breadth of genes in their vicinity. Results: Contrary to the modification hypothesis, we find that those genes that have always had broad expression are richest in Alus, whereas those that are more likely to have become more broadly expressed have lower enrichment. This finding is consistent with a model in which Alus accumulate near broadly expressed genes but do not affect their expression breadth. Furthermore, this model is consistent with the finding that expression breadth of mouse genes predicts Alu density near their human orthologs. However, Alus were found to be related to some alternative measures of transcription profile divergence, although evidence is contradictory as to whether Alus associate with lowly or highly diverged genes. If Alu have any effect it is not by provision of CpG islands, because they are especially rare near to transcriptional start sites. Previously reported Alu enrichment for genes serving certain cellular functions, suggested to be evidence of functional importance of Alus, appears to be partly a byproduct of the association with broadly expressed genes. Conclusion: The abundance of Alu near broadly expressed genes is better explained by their preferential preservation near to housekeeping genes rather than by a modifying effect on expression of genes.

关键词： Housekeeping Gene Flank Region additional data file Repetitive Element Peak Expression

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Ancient genomic architecture for mammalian olfactory receptor clusters

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GENOME BIOLOGY 2006年第10期7卷 R88-R88页

作者： Aloni, Ronny Olender, Tsviya Lancet, Doron Weizmann Inst Sci Dept Mol Genet IL-76100 Rehovot Israel Weizmann Inst Sci Crown Human Genome Ctr IL-76100 Rehovot Israel

Background: Mammalian olfactory receptor (OR) genes reside in numerous genomic clusters of up to several dozen genes. Whole-genome sequence alignment nets of five mammals allow their comprehensive comparison, aimed at reconstructing the ancestral olfactory subgenome. Results: We developed a new and general tool for genome-wide definition of genomic gene clusters conserved in multiple species. Syntenic orthologs, defined as gene pairs showing conservation of both genomic location and coding sequence, were subjected to a graph theory algorithm for discovering CLICs (clusters in conservation). When applied to ORs in five mammals, including the marsupial opossum, more than 90% of the OR genes were found within a framework of 48 multi-species CLICs, invoking a general conservation of gene order and composition. A detailed analysis of individual CLICs revealed multiple differences among species, interpretable through species-specific genomic rearrangements and reflecting complex mammalian evolutionary dynamics. One significant instance involves CLIC #1, which lacks a human member, implying the human-specific deletion of an OR cluster, whose mouse counterpart has been tentatively associated with isovaleric acid odorant detection. Conclusion: The identified multi-species CLICs demonstrate that most of the mammalian OR clusters have a common ancestry, preceding the split between marsupials and placental mammals. However, only two of these CLICs were capable of incorporating chicken OR genes, parsimoniously implying that all other CLICs emerged subsequent to the avian-mammalian divergence.

关键词： additional data file Olfactory Receptor Repertoire Size Isovaleric Acid Genomic Cluster

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Developmental roles of 21 Drosophila transcription factors are determined by quantitative differences in binding to an overlapping set of thousands of genomic regions

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GENOME BIOLOGY 2009年第7期10卷 R80-R80页

作者： MacArthur, Stewart Li, Xiao-Yong Li, Jingyi Brown, James B. Chu, Hou Cheng Zeng, Lucy Grondona, Brandi P. Hechmer, Aaron Simirenko, Lisa Keraenen, Soile V. E. Knowles, David W. Stapleton, Mark Bickel, Peter Biggin, Mark D. Eisen, Michael B. Univ Calif Berkeley Lawrence Berkeley Lab Genom Div Berkeley CA 94720 USA Univ Calif Berkeley Howard Hughes Med Inst Berkeley CA 94720 USA Univ Calif Berkeley Dept Stat Berkeley CA 94720 USA Univ Calif Berkeley Lawrence Berkeley Lab Div Life Sci Berkeley CA 94720 USA Univ Calif Berkeley Dept Mol & Cell Biol Berkeley CA 94720 USA

Background: We previously established that six sequence-specific transcription factors that initiate anterior/posterior patterning in Drosophila bind to overlapping sets of thousands of genomic regions in blastoderm embryos. While regions bound at high levels include known and probable functional targets, more poorly bound regions are preferentially associated with housekeeping genes and/or genes not transcribed in the blastoderm, and are frequently found in protein coding sequences or in less conserved non-coding DNA, suggesting that many are likely non-functional. Results: Here we show that an additional 15 transcription factors that regulate other aspects of embryo patterning show a similar quantitative continuum of function and binding to thousands of genomic regions in vivo. Collectively, the 21 regulators show a surprisingly high overlap in the regions they bind given that they belong to 11 DNA binding domain families, specify distinct developmental fates, and can act via different cis-regulatory modules. We demonstrate, however, that quantitative differences in relative levels of binding to shared targets correlate with the known biological and transcriptional regulatory specificities of these factors. Conclusions: It is likely that the overlap in binding of biochemically and functionally unrelated transcription factors arises from the high concentrations of these proteins in nuclei, which, coupled with their broad DNA binding specificities, directs them to regions of open chromatin. We suggest that most animal transcription factors will be found to show a similar broad overlapping pattern of binding in vivo, with specificity achieved by modulating the amount, rather than the identity, of bound factor.

关键词： Gene Ontology False Discovery Rate additional data file Functional Target Regulatory Classis

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Genome adaptation to chemical stress: clues from comparative transcriptomics in Saccharomyces cerevisiae and Candida glabrata

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GENOME BIOLOGY 2008年第11期9卷 R164-R164页

作者： Lelandais, Gaaelle Tanty, Veronique Geneix, Colette Etchebest, Catherine Jacq, Claude Devaux, Frederic Univ Paris 07 INSERM Equipe Bioinformat Genom & Mol UMR S726INTS F-75015 Paris France Ecole Normale Super CNRS Mol Genet Lab UMR 8541 F-75230 Paris 05 France Ecole Normale Super Plate Forme Transcriptome IFR 36 F-75230 Paris 05 France

Background Recent technical and methodological advances have placed microbial models at the forefront of evolutionary and environmental genomics. To better understand the logic of genetic network evolution, we combined comparative transcriptomics, a differential clustering algorithm and promoter analyses in a study of the evolution of transcriptional networks responding to an antifungal agent in two yeast species: the free-living model organism Saccharomyces cerevisiae and the human pathogen Candida glabrata. Results We found that, although the gene expression patterns characterizing the response to drugs were remarkably conserved between the two species, part of the underlying regulatory networks differed. In particular, the roles of the oxidative stress response transcription factors ScYap1p (in S. cerevisiae) and Cgap1p (in C. glabrata) had diverged. The sets of genes, whose benomyl response depend on these factors, are significantly different. Also, the DNA motifs targeted by ScYap1p and Cgap1p are differently represented in the promoters of these genes, suggesting that the DNA binding properties of the two proteins are slightly different. Experimental assays of ScYap1p and Cgap1p activities in vivo were in accordance with this last observation. Conclusions Based on these results and recently published data, we suggest that the robustness of environmental stress responses among related species contrasts with the rapid evolution of regulatory sequences, and depends both on the coevolution of transcription factor binding properties and on the versatility of regulatory associations within transcriptional networks.

关键词： additional data file Orthologous Gene Yeast Species Benomyl Oxidative Stress Response

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Insights into the regulation of intrinsically disordered proteins in the human proteome by analyzing sequence and gene expression data

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GENOME BIOLOGY 2009年第5期10卷 R50-R50页

作者： Edwards, Yvonne J. K. Lobley, Anna E. Pentony, Melissa M. Jones, David T. UCL Dept Comp Sci Bioinformat Grp London WC1E 6BT England

Background: Disordered proteins need to be expressed to carry out specified functions;however, their accumulation in the cell can potentially cause major problems through protein misfolding and aggregation. Gene expression levels, mRNA decay rates, microRNA (miRNA) targeting and ubiquitination have critical roles in the degradation and disposal of human proteins and transcripts. Here, we describe a study examining these features to gain insights into the regulation of disordered proteins. Results: In comparison with ordered proteins, disordered proteins have a greater proportion of predicted ubiquitination sites. The transcripts encoding disordered proteins also have higher proportions of predicted miRNA target sites and higher mRNA decay rates, both of which are indicative of the observed lower gene expression levels. The results suggest that the disordered proteins and their transcripts are present in the cell at low levels and/or for a short time before being targeted for disposal. Surprisingly, we find that for a significant proportion of highly disordered proteins, all four of these trends are reversed. Predicted estimates for miRNA targets, ubiquitination and mRNA decay rate are low in the highly disordered proteins that are constitutively and/or highly expressed. Conclusions: Mechanisms are in place to protect the cell from these potentially dangerous proteins. The evidence suggests that the enrichment of signals for miRNA targeting and ubiquitination may help prevent the accumulation of disordered proteins in the cell. Our data also provide evidence for a mechanism by which a significant proportion of highly disordered proteins (with high expression levels) can escape rapid degradation to allow them to successfully carry out their function.

关键词： additional data file miRNA Target Human Proteome miRNA Target Site Protein Code Transcript

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Functions, structure, and read-through alternative splicing of feline APOBEC3 genes

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GENOME BIOLOGY 2008年第3期9卷 R48-R48页

作者： Muenk, Carsten Beck, Thomas Zielonka, Joerg Hotz-Wagenblatt, Agnes Chareza, Sarah Battenberg, Marion Thielebein, Jens Cichutek, Klaus Bravo, Ignacio G. O'Brien, Stephen J. Loechelt, Martin Yuhki, Naoya Paul Ehrlich Inst Div Med Biotechnol D-63225 Langen Germany SAIC Frederick Inc NCI Lab Genom Divers Frederick MD 21702 USA German Canc Res Ctr Dept Mol Biophys Res Program Struct & Funct Genom D-69120 Heidelberg Germany German Canc Res Ctr Dept Genome Modificat & Carcinogenesis Res Program Infect & Canc D-69120 Heidelberg Germany Univ Halle Wittenberg Inst Agr & Nutr Sci D-06108 Halle Germany Univ Munster Inst Evolut & Biodivers D-48143 Munster Germany NCI Lab Genom Divers Frederick MD 21702 USA

Background: Over the past years a variety of host restriction genes have been identified in human and mammals that modulate retrovirus infectivity, replication, assembly, and/or cross-species transmission. Among these host-encoded restriction factors, the APOBEC3 (A3;apolipoprotein B mRNA-editing catalytic polypeptide 3) proteins are potent inhibitors of retroviruses and retrotransposons. While primates encode seven of these genes (A3A to A3H), rodents carry only a single A3 gene. Results: Here we identified and characterized several A3 genes in the genome of domestic cat (Felis catus) by analyzing the genomic A3 locus. The cat genome presents one A3H gene and three very similar A3C genes (a-c), probably generated after two consecutive gene duplications. In addition to these four one-domain A3 proteins, a fifth A3, designated A3CH, is expressed by readthrough alternative splicing. Specific feline A3 proteins selectively inactivated only defined genera of feline retroviruses: Bet-deficient feline foamy virus was mainly inactivated by feA3Ca, feA3Cb, and feA3Cc, while feA3H and feA3CH were only weakly active. The infectivity of Vif-deficient feline immunodeficiency virus and feline leukemia virus was reduced only by feA3H and feA3CH, but not by any of the feA3Cs. Within Felidae, A3C sequences show significant adaptive selection, but unexpectedly, the A3H sequences present more sites that are under purifying selection. Conclusion: Our data support a complex evolutionary history of expansion, divergence, selection and individual extinction of antiviral A3 genes that parallels the early evolution of Placentalia, becoming more intricate in taxa in which the arms race between host and retroviruses is harsher.

关键词： additional data file Simian Immunodeficiency Virus Feline Immunodeficiency Virus Whole Genome Shotgun Feline Immunodeficiency Virus Infection

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