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Genomic linkage map of the human blood fluke Schistosoma mansoni

GENOME BIOLOGY 2009年第6期10卷 R71-R71页

作者： Criscione, Charles D. Valentim, Claudia L. L. Hirai, Hirohisa LoVerde, Philip T. Anderson, Timothy J. C. Texas A&M Univ Dept Biol College Stn TX 77843 USA Univ Texas Hlth Sci Ctr San Antonio Dept Biochem San Antonio TX 78229 USA Univ Texas Hlth Sci Ctr San Antonio Dept Pathol San Antonio TX 78229 USA SW Fdn Biomed Res Dept Genet San Antonio TX 78245 USA Kyoto Univ Primate Res Inst Aichi 4848506 Japan

Background: Schistosoma mansoni is a blood fluke that infects approximately 90 million people. The complete life cycle of this parasite can be maintained in the laboratory, making this one of the few experimentally tractable human helminth infections, and a rich literature reveals heritable variation in important biomedical traits such as virulence, host-specificity, transmission and drug resistance. However, there is a current lack of tools needed to study S. mansoni's molecular, quantitative, and population genetics. Our goal was to construct a genetic linkage map for S. mansoni, and thus provide a new resource that will help stimulate research on this neglected pathogen. Results: We genotyped grandparents, parents and 88 progeny to construct a 5.6 cM linkage map containing 243 microsatellites positioned on 203 of the largest scaffolds in the genome sequence. The map allows 70% of the estimated 300 Mb genome to be ordered on chromosomes, and highlights where scaffolds have been incorrectly assembled. The markers fall into eight main linkage groups, consistent with seven pairs of autosomes and one pair of sex chromosomes, and we were able to anchor linkage groups to chromosomes using fluorescent in situ hybridization. The genome measures 1,228.6 cM. Marker segregation reveals higher female recombination, confirms ZW inheritance patterns, and identifies recombination hotspots and regions of segregation distortion. Conclusions: The genetic linkage map presented here is the first for S. mansoni and the first for a species in the phylum Platyhelminthes. The map provides the critical tool necessary for quantitative genetic analysis, aids genome assembly, and furnishes a framework for comparative flatworm genomics and field-based molecular epidemiological studies.

关键词： Linkage Group Genome Assembly additional data file Segregation Distortion Pseudoautosomal Region

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Multiple effects govern endogenous retrovirus survival patterns in human gene introns

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GENOME BIOLOGY 2006年第9期7卷 R86-R86页

作者： van de Lagemaat, Louie N. Medstrand, Patrik Mager, Dixie L. British Columbia Canc Res Ctr Terry Fox Lab Vancouver BC V5Z 1L3 Canada Univ British Columbia Dept Med Genet Vancouver BC V6T 1Z3 Canada Lund Univ Dept Expt Med Sci S-22184 Lund Sweden

Background: Endogenous retroviruses ( ERVs) and solitary long terminal repeats ( LTRs) have a significant antisense bias when located in gene introns, suggesting strong negative selective pressure on such elements oriented in the same transcriptional direction as the enclosing gene. It has been assumed that this bias reflects the presence of strong transcriptional regulatory signals within LTRs but little work has been done to investigate this phenomenon further. Results: In the analysis reported here, we found significant differences between individual human ERV families in their prevalence within genes and degree of antisense bias and show that, regardless of orientation, ERVs of most families are less likely to be found in introns than in intergenic regions. Examination of density profiles of ERVs across transcriptional units and the transcription signals present in the consensus ERVs suggests the importance of splice acceptor sites, in conjunction with splice donor and polyadenylation signals, as the major targets for selection against most families of ERVs/LTRs. Furthermore, analysis of annotated human mRNA splicing events involving ERV sequence revealed that the relatively young human ERVs ( HERVs), HERV9 and HERV-K ( HML-2), are involved in no human mRNA splicing events at all when oriented antisense to gene transcription, while elements in the sense direction in transcribed regions show considerable bias for use of strong splice sites. Conclusion: Our observations suggest suppression of splicing among young intronic ERVs oriented antisense to gene transcription, which may account for their reduced mutagenicity and higher fixation rate in gene introns.

关键词： Splice Site additional data file Polyadenylation Signal Splice Signal Orientation Bias

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Early and long-standing rheumatoid arthritis: distinct molecular signatures identified by gene-expression profiling in synovia

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ARTHRITIS RESEARCH & THERAPY 2009年第3期11卷 1-8页

作者： Lequerre, Thierry Bansard, Carine Vittecoq, Olivier Derambure, Celine Hiron, Martine Daveau, Maryvonne Tron, Francois Ayral, Xavier Biga, Norman Auquit-Auckbur, Isabelle Chiocchia, Gilles Le Loet, Xavier Salier, Jean-Philippe Univ Rouen Fac Med Pharm Inst Federatif Rech Multidisciplinaire Peptides 2 Inst Biomed ResINSERMU905 Rouen France Univ Rouen Inserm 905 F-76031 Rouen France Univ Rouen Rouen Univ Hosp Dept Rheumatol Rouen France Univ Paris 05 AP HP Cochin Hosp Dept Rheumatol F-75679 Paris 14 France Rouen Univ Hosp Dept Orthoped & Traumatol F-76031 Rouen France Rouen Univ Hosp Dept Plast & Reconstruct Surg F-76031 Rouen France Univ Paris 05 Inst Cochin INSERM CNRSU567UMR8104 Paris France

Introduction Rheumatoid arthritis (RA) is a heterogeneous disease and its underlying molecular mechanisms are still poorly understood. Because previous microarray studies have only focused on long-standing (LS) RA compared to osteoarthritis, we aimed to compare the molecular profiles of early and LS RA versus control synovia. Methods Synovial biopsies were obtained by arthroscopy from 15 patients (4 early untreated RA, 4 treated LS RA and 7 controls, who had traumatic or mechanical lesions). Extracted mRNAs were used for large-scale gene-expression profiling. The different gene-expression combinations identified by comparison of profiles of early, LS RA and healthy synovia were linked to the biological processes involved in each situation. Results Three combinations of 719, 116 and 52 transcripts discriminated, respectively, early from LS RA, and early or LS RA from healthy synovia. We identified several gene clusters and distinct molecular signatures specifically expressed during early or LS RA, thereby suggesting the involvement of different pathophysiological mechanisms during the course of RA. Conclusions Early and LS RA have distinct molecular signatures with different biological processes participating at different times during the course of the disease. These results suggest that better knowledge of the main biological processes involved at a given RA stage might help to choose the most appropriate treatment.

关键词： Rheumatoid Arthritis Rheumatoid Arthritis Patient additional data file Early Rheumatoid Arthritis Synovial Biopsy

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Origins of chromosomal rearrangement hotspots in the human genome:: evidence from the AZFa deletion hotspots -: art. no. R55

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GENOME BIOLOGY 2004年第8期5卷 1-19页

作者： Hurles, ME Willey, D Matthews, L Hussain, SS Univ Cambridge McDonald Inst Archaeol Res Mol Genet Lab Cambridge CB2 3ER England Wellcome Trust Sanger Inst Cambridge CB10 1SA England

Background: The origins of the recombination hotspots that are a common feature of both allelic and non-allelic homologous recombination in the human genome are poorly understood. We have investigated, by comparative sequencing, the evolution of two hotspots of non-allelic homologous recombination on the Y chromosome that lie within paralogous sequences known to sponsor deletions resulting in male infertility. Results: These recombination hotspots are characterized by signatures of concerted evolution, which indicate that gene conversion between paralogs has been predominant in shaping their recent evolution. By contrast, the paralogous sequences that surround the hotspots exhibit little evidence of gene conversion. A second feature of these rearrangement hotspots is the extreme interspecific sequence divergence (around 2.5%) that places them among the most divergent orthologous sequences between humans and chimpanzees. Conclusions: Several hominid-specific gene conversion events have rendered these hotspots better substrates for chromosomal rearrangements in humans than in chimpanzees or gorillas. Monte Carlo simulations of sequence evolution suggest that extreme sequence divergence is a direct consequence of gene conversion between paralogs. We propose that the coincidence of signatures of concerted evolution and recurrent breakpoints of chromosomal rearrangement (mapped at the sequence level) may enable the identification of putative rearrangement hotspots from analysis of comparative sequences from great apes.

关键词： additional data file Gene Conversion Segmental Duplication Concerted Evolution Phylogenetic Network

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Egr1 regulates the coordinated expression of numerous EGF receptor target genes as identified by ChIP on chip

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GENOME BIOLOGY 2008年第11期9卷 R166-R166页

作者： Arora, Shilpi Wang, Yipeng Jia, Zhenyu Vardar-Sengul, Saynur Munawar, Ayla Doctor, Kutbuddin S. Birrer, Michael McClelland, Michael Adamson, Eileen Mercola, Dan Univ Calif Irvine Dept Pathol & Lab Med Irvine CA 92697 USA Sidney Kimmel Canc Ctr San Diego CA 92121 USA Ege Univ Sch Dent Dept Periodontol TR-35100 Izmir Turkey Burnham Inst Med Res La Jolla CA 92037 USA NCI NIH Cell & Canc Biol Res Bethesda MD 20892 USA

Background: UV irradiation activates the EGF receptor, induces Egr1 expression and promotes apoptosis in a variety of cell types. We examined the hypothesis that Egr1 regulates genes that mediate this process by use of a chip-on-chip protocol in human tumorigenic prostate M12 cells. Results: UV irradiation led to significant binding of 288 gene promoters by Egr1. A major functional subgroup consisted of apoptosis related genes. The largest subgroup of 24 genes;belong to the EGFR-signal transduction pathway. Egr1 promoter binding had a significant impact on gene expression of target genes. Conventional ChIP and qRTPCR were used to validate promoter binding and expression changes. siRNA experiments were used to demonstrate the specific role of Egr1 in gene regulation. UV-stimulation promotes growth arrest and apoptosis of M12 cells and our data clearly show that downstream target of EGFR, namely Egr1, mediates this apoptotic response. Our study also identified numerous previously unknown targets of Egr1. These include FasL, MAX and RRAS2, which may play a role in the apoptotic response/growth arrest. Conclusion: Our results indicate that M12 cells undergo Egr1-dependent apoptotic response upon UV-stimulation and led to the identification of downstream targets of Egr1, which mediate EGFR function.

关键词： Epidermal Growth Factor Receptor Prostate Cancer Cell additional data file Suramin Epidermal Growth Factor Receptor Expression

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Determining promoter location based on DNA structure first-principles calculations

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GENOME BIOLOGY 2007年第12期8卷 R263-R263页

作者： Goni, J. Ramon Perez, Alberto Torrents, David Orozco, Modesto Inst Biomed Res Barcelona 08028 Spain Univ Barcelona Fac Biol Dept Bioquim & Biol Mol E-08028 Barcelona Spain Univ Vic Laura Dept Biol Sistemes Grp Recerca Bioinformat & Estadist Med VIC 08500 Spain Barcelona Supercomp Ctr Computat Bioinformat Unit Barcelona 08028 Spain ICREA Barcelona 08010 Spain Struct Bioinformat Unit Inst Nacl Bioinformat Barcelona 08028 Spain

A new method for the prediction of promoter regions based on atomic molecular dynamics simulations of small oligonucleotides has been developed. The method works independently of gene structure conservation and orthology and of the presence of detectable sequence features. Results obtained with our method confirm the existence of a hidden physical code that modulates genome expression.

关键词： additional data file ProStar Encode Region Dinucleotide Step Base Step Pair

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At-TAX:: a whole genome tiling array resource for developmental expression analysis and transcript identification in Arabidopsis thaliana

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GENOME BIOLOGY 2008年第7期9卷 R112-R112页

作者： Laubinger, Sascha Zeller, Georg Henz, Stefan R. Sachsenberg, Timo Widmer, Christian K. Naouar, Naira Vuylsteke, Marnik Schoelkopf, Bernhard Raetsch, Gunnar Weigel, Detlef Max Planck Inst Dev Biol Dept Mol Biol D-72076 Tubingen Germany Max Planck Gesell Friedrich Miescher Lab D-72076 Tubingen Germany Univ Ghent VIB Dept Plant Syst Biol B-9052 Ghent Belgium Univ Ghent Dept Mol Genet B-9052 Ghent Belgium Max Planck Inst Biol Cybernet Dept Empir Inference D-72076 Tubingen Germany

Gene expression maps for model organisms, including Arabidopsis thaliana, have typically been created using gene-centric expression arrays. Here, we describe a comprehensive expression atlas, Arabidopsis thaliana Tiling Array Express (At-TAX), which is based on whole-genome tiling arrays. We demonstrate that tiling arrays are accurate tools for gene expression analysis and identified more than 1,000 unannotated transcribed regions. Visualizations of gene expression estimates, transcribed regions, and tiling probe measurements are accessible online at the At-TAX homepage.

关键词： additional data file Annotate Gene Locked Nucleic Acid Tiling Array Gene Expression Estimate

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Strong-association-rule mining for large-scale gene-expression data analysis: a case study on human SAGE data

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GENOME BIOLOGY 2002年第12期3卷 research0067.1-research0067.16页

作者： Becquet, Celine Blachon, Sylvain Jeudy, Baptiste Boulicaut, Jean-Francois Gandrillon, Olivier Univ Lyon 1 Equipe Signalisat & Identites Cellulaires Ctr Genet Mol & Cellulaire CNRSUMR 5534 F-69622 Villeurbanne France Inst Natl Sci Appl Lab Ingn Syst Informat F-69621 Villeurbanne France

Background: The association-rules discovery (ARD) technique has yet to be applied to gene-expression data analysis. Even in the absence of previous biological knowledge, it should identify sets of genes whose expression is correlated. The first association-rule miners appeared six years ago and proved efficient at dealing with sparse and weakly correlated data. A huge international research effort has led to new algorithms for tackling difficult contexts and these are particularly suited to analysis of large gene-expression matrices. To validate the ARD technique we have applied it to freely available human serial analysis of gene expression (SAGE) data. Results: The approach described here enables us to designate sets of strong association rules. We normalized the SAGE data before applying our association rule miner. Depending on the discretization algorithm used, different properties of the data were highlighted. Both common and specific interpretations could be made from the extracted rules. In each and every case the extracted collections of rules indicated that a very strong co-regulation of mRNA encoding ribosomal proteins occurs in the dataset. Several rules associating proteins involved in signal transduction were obtained and analyzed, some pointing to yet-unexplored directions. Furthermore, by examining a subset of these rules, we were able both to reassign a wrongly labeled tag, and to propose a function for an expressed sequence tag encoding a protein of unknown function. Conclusions: We show that ARD is a promising technique that turns out to be complementary to existing gene-expression clustering techniques.

关键词： Association Rule additional data file Frequent Itemsets Association Rule Miner Frequency Threshold

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An integrated gene annotation and transcriptional profiling approach towards the full gene content of the Drosophila genome -: art. no. R3

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GENOME BIOLOGY 2004年第1期5卷 1-17页

作者： Hild, M Beckmann, B Haas, SA Koch, B Solovyev, V Busold, C Fellenberg, K Boutros, M Vingron, M Sauer, F Hoheisel, JD Paro, R Max Planck Inst Mol Genet D-14195 Berlin Germany Heidelberg Univ ZMBH D-69120 Heidelberg Germany Deutsch Krebsforschungszentrum Div Funct Genome Anal D-69120 Heidelberg Germany Softberry Inc Mt Kisko NY 10549 USA Univ Calif Riverside Dept Biochem Riverside CA 92521 USA

Background: While the genome sequences for a variety of organisms are now available, the precise number of the genes encoded is still a matter of debate. For the human genome several stringent annotation approaches have resulted in the same number of potential genes, but a careful comparison revealed only limited overlap. This indicates that only the combination of different computational prediction methods and experimental evaluation of such in silico data will provide more complete genome annotations. In order to get a more complete gene content of the Drosophila melanogaster genome, we based our new D. melanogaster whole-transcriptome microarray, the Heidelberg FlyArray, on the combination of the Berkeley Drosophila Genome Project (BDGP) annotation and a novel ab initio gene prediction of lower stringency using the Fgenesh software. Results: Here we provide evidence for the transcription of approximately 2,600 additional genes predicted by Fgenesh. Validation of the developmental profiling data by RT-PCR and in situ hybridization indicates a lower limit of 2,000 novel annotations, thus substantially raising the number of genes that make a fly. Conclusions: The successful design and application of this novel Drosophila microarray on the basis of our integrated in silico/wet biology approach confirms our expectation that in silico approaches alone will always tend to be incomplete. The identification of at least 2,000 novel genes highlights the importance of gathering experimental evidence to discover all genes within a genome. Moreover, as such an approach is independent of homology criteria, it will allow the discovery of novel genes unrelated to known protein families or those that have not been strictly conserved between species.

关键词： additional data file Gene Prediction Embryonic Stage additional Exon Berkeley Drosophila Genome Project

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Normalization of two-channel microarrays accounting for experimental design and intensity-dependent relationships

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GENOME BIOLOGY 2007年第3期8卷 R44-R44页

作者： Dabney, Alan R. Storey, John D. Univ Washington Dept Biostat Seattle WA 98195 USA Univ Washington Dept Genome Sci Seattle WA 98195 USA Texas A&M Univ Dept Stat College Stn TX 77843 USA

In normalizing two-channel expression arrays, the ANOVA approach explicity incorporates the experimental design in its model, and the MA-plot based approach accounts for intensivity-dependent biases. However, both approaches can lead to inacurate normalization in fairly common scenarios. We propose a method called eCADS for normalizing two-channel microarrays that accounts for both experimental design and intensity-dependent biases. Under reasonable experimental designs, eCADS preserves differential expression relationships and requires only a single array per sample pair.

关键词： additional data file Array Function Microarray Quality Control Array Effect Direct Comparison Experiment

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