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Evolution of mosaic operons by horizontal gene transfer and gene displacement in situ -: art. no. R55

GENOME BIOLOGY 2003年第9期4卷 1-18页

作者： Omelchenko, MV Makarova, KS Wolf, YI Rogozin, IB Koonin, EV NIH Natl Ctr Biotechnol Informat Natl Lib Med Bethesda MD 20894 USA Uniformed Serv Univ Hlth Sci Dept Pathol F Edward Hebert Sch Med Bethesda MD 20814 USA

Background: Shuffling and disruption of operons and horizontal gene transfer are major contributions to the new, dynamic view of prokaryotic evolution. Under the 'selfish operon' hypothesis, operons are viewed as mobile genetic entities that are constantly disseminated via horizontal gene transfer, although their retention could be favored by the advantage of coregulation of functionally linked genes. Here we apply comparative genomics and phylogenetic analysis to examine horizontal transfer of entire operons versus displacement of individual genes within operons by horizontally acquired orthologs and independent assembly of the same or similar operons from genes with different phylogenetic affinities. Results: Since a substantial number of operons have been identified experimentally in only a few model bacteria, evolutionarily conserved gene strings were analyzed as surrogates of operons. The phylogenetic affinities within these predicted operons were assessed first by sequence similarity analysis and then by phylogenetic analysis, including statistical tests of tree topology. Numerous cases of apparent horizontal transfer of entire operons were detected. However, it was shown that apparent horizontal transfer of individual genes or arrays of genes within operons is not uncommon either and results in xenologous gene displacement in situ, that is, displacement of an ancestral gene by a horizontally transferred ortholog from a taxonomically distant organism without change of the local gene organization. On rarer occasions, operons might have evolved via independent assembly, in part from horizontally acquired genes. Conclusions: The discovery of in situ gene displacement shows that combination of rampant horizontal gene transfer with selection for preservation of operon structure provides for events in prokaryotic evolution that, a priori, seem improbable. These findings also emphasize that not all aspects of operon evolution are selfish, with operon integrity mainta

关键词： Horizontal Gene Transfer additional data file Horizontal Transfer Gene Displacement Horizontal Gene Transfer Event

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A gold standard set of mechanistically diverse enzyme superfamilies

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GENOME BIOLOGY 2006年第1期7卷 R8-R8页

作者： Brown, SD Gerlt, JA Seffernick, JL Babbitt, PC Univ Calif San Francisco Dept Biopharmaceut Sci San Francisco CA 94143 USA Univ Illinois Dept Biochem Roger Adams Lab Urbana IL 61801 USA Univ Minnesota Dept Biochem Mol Biol & Biophys Biol Proc Technol Inst St Paul MN 55108 USA Univ Minnesota Ctr Microbial & Plant Genom St Paul MN 55108 USA Univ Calif San Francisco Dept Pharmaceut Chem San Francisco CA 94143 USA

Superfamily and family analyses provide an effective tool for the functional classification of proteins, but must be automated for use on large datasets. We describe a 'gold standard' set of enzyme superfamilies, clustered according to specific sequence, structure, and functional criteria, for use in the validation of family and superfamily clustering methods. The gold standard set represents four fold classes and differing clustering difficulties, and includes five superfamilies, 91 families, 4,887 sequences and 282 structures.

关键词： additional data file Catalytic Residue Standard Family Diverse Superfamily Enolase Superfamily

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Analysis of 142 genes resolves the rapid diversification of the rice genus

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GENOME BIOLOGY 2008年第3期9卷 R49-R49页

作者： Zou, Xin-Hui Zhang, Fu-Min Zhang, Jian-Guo Zang, Li-Li Tang, Liang Wang, Jun Sang, Tao Ge, Song Chinese Acad Sci Inst Bot State Key Lab Systemat & Evolutionary Bot Beijing 100093 Peoples R China Beijing Genom Inst Beijing 101300 Peoples R China Michigan State Univ Dept Plant Biol E Lansing MI 48824 USA Chinese Acad Sci Grad Sch Beijing 100039 Peoples R China

Background: The completion of rice genome sequencing has made rice and its wild relatives an attractive system for biological studies. Despite great efforts, phylogenetic relationships among genome types and species in the rice genus have not been fully resolved. To take full advantage of rice genome resources for biological research and rice breeding, we will benefit from the availability of a robust phylogeny of the rice genus. Results: Through screening rice genome sequences, we sampled and sequenced 142 single-copy genes to clarify the relationships among all diploid genome types of the rice genus. The analysis identified two short internal branches around which most previous phylogenetic inconsistency emerged. These represent two episodes of rapid speciation that occurred approximately 5 and 10 million years ago (Mya) and gave rise to almost the entire diversity of the genus. The known chromosomal distribution of the sampled genes allowed the documentation of whole-genome sorting of ancestral alleles during the rapid speciation, which was responsible primarily for extensive incongruence between gene phylogenies and persisting phylogenetic ambiguity in the genus. Random sample analysis showed that 120 genes with an average length of 874 bp were needed to resolve both short branches with 95% confidence. Conclusion: Our phylogenomic analysis successfully resolved the phylogeny of rice genome types, which lays a solid foundation for comparative and functional genomic studies of rice and its relatives. This study also highlights that organismal genomes might be mosaics of conflicting genealogies because of rapid speciation and demonstrates the power of phylogenomics in the reconstruction of rapid diversification.

关键词： Maximum Parsimony additional data file Rice Genome Phylogenetic Network Sister Relationship

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Systematic bioinformatic analysis of expression levels of 17,330 human genes across 9,783 samples from 175 types of healthy and pathological tissues

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GENOME BIOLOGY 2008年第9期9卷 R139-R139页

作者： Kilpinen, Sami Autio, Reija Ojala, Kalle Iljin, Kristiina Bucher, Elmar Sara, Henri Pisto, Tommi Saarela, Matti Skotheim, Rolf I. Bjorkman, Mari Mpindi, John-Patrick Haapa-Paananen, Saija Vainio, Paula Edgren, Henrik Wolf, Maija Astola, Jaakko Nees, Matthias Hautaniemi, Sampsa Kallioniemi, Olli VTT Tech Res Ctr Turku Finland Univ Turku Turku Finland Univ Helsinki FIMM Helsinki Finland Tampere Univ Technol Dept Signal Proc FIN-33101 Tampere Finland Natl Hosp Norway Radiumhosp Inst Canc Res Dept Canc PreventMed Ctr NO-0310 Oslo Norway Univ Helsinki Scale Biol Res Program Inst Biomed & Genome Computat Syst Biol Lab FIN-00014 Helsinki Finland

Our knowledge on tissue- and disease-specific functions of human genes is rather limited and highly context-specific. Here, we have developed a method for the comparison of mRNA expression levels of most human genes across 9,783 Affymetrix gene expression array experiments representing 43 normal human tissue types, 68 cancer types, and 64 other diseases. This database of gene expression patterns in normal human tissues and pathological conditions covers 113 million datapoints and is available from the GeneSapiens website.

关键词： additional data file Cancer Gene Malignant Peripheral Nerve Sheath Tumor Array Generation Cyclic Redundancy Check

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Blood autoantibody and cytokine profiles predict response to anti-tumor necrosis factor therapy in rheumatoid arthritis

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ARTHRITIS RESEARCH & THERAPY 2009年第3期11卷 R76-R76页

作者： Hueber, Wolfgang Tomooka, Beren H. Batliwalla, Franak Li, Wentian Monach, Paul A. Tibshirani, Robert J. Van Vollenhoven, Ronald F. Lampa, Jon Saito, Kazuyoshi Tanaka, Yoshiya Genovese, Mark C. Klareskog, Lars Gregersen, Peter K. Robinson, William H. Stanford Univ Div Rheumatol & Immunol Dept Med Stanford CA 94305 USA VA Palo Alto Hlth Care Syst GRECC Palo Alto CA 94304 USA N Shore LIJ Hlth Syst Feinstein Inst Med Res Manhasset NY 11030 USA Joslin Diabet Ctr Boston MA 02215 USA Brigham & Womens Hosp Boston MA 02115 USA Stanford Univ Dept Stat Stanford CA 94305 USA Karolinska Inst SE-17176 Stockholm Sweden Univ Occupat & Environm Hlth Dept Internal Med 1 Kitakyushu Fukuoka 8078555 Japan

Introduction Anti-TNF therapies have revolutionized the treatment of rheumatoid arthritis ( RA), a common systemic autoimmune disease involving destruction of the synovial joints. However, in the practice of rheumatology approximately one-third of patients demonstrate no clinical improvement in response to treatment with anti-TNF therapies, while another third demonstrate a partial response, and one-third an excellent and sustained response. Since no clinical or laboratory tests are available to predict response to anti-TNF therapies, great need exists for predictive biomarkers. Methods Here we present a multi-step proteomics approach using arthritis antigen arrays, a multiplex cytokine assay, and conventional ELISA, with the objective to identify a biomarker signature in three ethnically diverse cohorts of RA patients treated with the anti-TNF therapy etanercept. Results We identified a 24-biomarker signature that enabled prediction of a positive clinical response to etanercept in all three cohorts ( positive predictive values 58 to 72%;negative predictive values 63 to 78%). Conclusions We identified a multi-parameter protein biomarker that enables pretreatment classification and prediction of etanercept responders, and tested this biomarker using three independent cohorts of RA patients. Although further validation in prospective and larger cohorts is needed, our observations demonstrate that multiplex characterization of autoantibodies and cytokines provides clinical utility for predicting response to the anti-TNF therapy etanercept in RA patients.

关键词： Rheumatoid Arthritis Rheumatoid Arthritis Patient Etanercept additional data file Cartilage Oligomeric Matrix Protein

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Computational discovery of sense-antisense transcription in the human and mouse genomes

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GENOME BIOLOGY 2002年第9期3卷 research0044.1-research0044.14页

作者： Shendure, Jay Church, George M. Harvard Univ Sch Med Dept Genet Boston MA 02115 USA

Background: Overlapping but oppositely oriented transcripts have the potential to form sense-antisense perfect double-stranded (ds) RNA duplexes. Over recent years, the number and variety of examples of mammalian gene-regulatory phenomena in which endogenous dsRNA duplexes have been proposed or demonstrated to participate has greatly increased. These include genomic imprinting, RNA interference, translational regulation, alternative splicing, X-inactivation and RNA editing. We computationally mined public mouse and human expressed sequence tag (EST) databases to search for additional examples of bidirectionally transcribed genomic regions. Results: Our bioinformatics approach identified over 217 candidate overlapping transcriptional units, almost all of which are novel. From experimental validation of a subset of our predictions by orientation-specific RT-PCR, we estimate that our methodology has a specificity of 84% or greater. In many cases, regions of sense-antisense overlap within the 5'- or 3'-untranslated regions of a given transcript correlate with genomic patterns of mouse-human conservation. Conclusions: Our results, in conjunction with the literature, bring the total number of predicted and validated examples of overlapping but oppositely oriented transcripts to over 300. Several of these cases support the hypothesis that a subset of the instances of substantial mouse-human conservation in the 5' and 3' UTRs of transcripts might be explained in part by functionality of an overlapping transcriptional unit.

关键词： additional data file Antisense Transcript UniGene Cluster Antisense Transcription Directional Cloning

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Impairment of organ-specific T cell negative selection by diabetes susceptibility genes: genomic analysis by mRNA profiling

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GENOME BIOLOGY 2007年第1期8卷 1-23页

作者： Liston, Adrian Hardy, Kristine Pittelkow, Yvonne Wilson, Susan R. Makaroff, Lydia E. Fahrer, Aude M. Goodnow, Christopher C. Australian Natl Univ John Curtin Sch Med Res Canberra ACT 2601 Australia Australian Natl Univ Inst Math Sci Canberra ACT 2601 Australia Australian Natl Univ Australian Phenom Facil Canberra ACT 2601 Australia Univ Washington Dept Immunol Seattle WA 98195 USA

Background: T cells in the thymus undergo opposing positive and negative selection processes so that the only T cells entering circulation are those bearing a T cell receptor (TCR) with a low affinity for self. The mechanism differentiating negative from positive selection is poorly understood, despite the fact that inherited defects in negative selection underlie organ-specific autoimmune disease in AIRE-deficient people and the non-obese diabetic (NOD) mouse strain. Results: Here we use homogeneous populations of T cells undergoing either positive or negative selection in vivo together with genome-wide transcription profiling on microarrays to identify the gene expression differences underlying negative selection to an Aire-dependent organ-specific antigen, including the upregulation of a genomic cluster in the cytogenetic band 2F. Analysis of defective negative selection in the autoimmune-prone NOD strain demonstrates a global impairment in the induction of the negative selection response gene set, but little difference in positive selection response genes. Combining expression differences with genetic linkage data, we identify differentially expressed candidate genes, including Bim, Bnip3, Smox, Pdrg1, Id1, Pdcd1, Ly6c, Pdia3, Trim30 and Trim12. Conclusion: The data provide a molecular map of the negative selection response in vivo and, by analysis of deviations from this pathway in the autoimmune susceptible NOD strain, suggest that susceptibility arises from small expression differences in genes acting at multiple points in the pathway between the TCR and cell death.

关键词： Negative Selection additional data file Double Positive Cell Double Positive Single Positive

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Optimization and clinical validation of a pathogen detection microarray

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GENOME BIOLOGY 2007年第5期8卷 R93-R93页

作者： Wong, Christopher W. Heng, Charlie Lee Wah Yee, Leong Wan Soh, Shirlena W. L. Kartasasmita, Cissy B. Simoes, Eric A. F. Hibberd, Martin L. Sung, Wing-Kin Miller, Lance D. Genome Inst Singapore Singapore Singapore Padjadjaran State Univ Fac Med Dept Pediat Hasan Saikin Hosp Bandung Indonesia Univ Colorado Sect Infect Dis Denver CO 80202 USA Univ Colorado Hlth Sci Ctr Denver CO 80206 USA Childrens Hosp Denver CO 80218 USA

DNA microarrays used as "genomic sensors" have great potential in clinical diagnostics. Biases inherent in random PCR-amplification, cross-hybridization effects, and inadequate microarray analysis, however, limit detection sensitivity and specificity. Here, we have studied the relationships between viral amplification efficiency, hybridization signal, and target-probe annealing specificity using a customized microarray platform. Novel features of this platform include the development of a robust algorithm that accurately predicts PCR bias during DNA amplification and can be used to improve PCR primer design, as well as a powerful statistical concept for inferring pathogen identity from probe recognition signatures. Compared to real-time PCR, the microarray platform identified pathogens with 94% accuracy (76% sensitivity and 100% specificity) in a panel of 36 patient specimens. Our findings show that microarrays can be used for the robust and accurate diagnosis of pathogens, and further substantiate the use of microarray technology in clinical diagnostics.

关键词： Respiratory Syncytial Virus additional data file Microarray Platform Pathogen Detection Lower Respiratory Tract Infection

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Fast-evolving noncoding sequences in the human genome

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GENOME BIOLOGY 2007年第6期8卷 R118-R118页

作者： Bird, Christine P. Stranger, Barbara E. Liu, Maureen Thomas, Daryl J. Ingle, Catherine E. Beazley, Claude MillerO, Webb Hurles, Matthew E. Dermitzakis, Emmanouil T. Wellcome Trust Sanger Inst Hinxton CB10 1SA England Univ Calif Santa Cruz Ctr Biomol Sci & Engn Santa Cruz CA 95064 USA Penn State Univ Dept Comp Sci & Engn University Pk PA 16802 USA

Background: Gene regulation is considered one of the driving forces of evolution. Although protein-coding DNA sequences and RNA genes have been subject to recent evolutionary events in the human lineage, it has been hypothesized that the large phenotypic divergence between humans and chimpanzees has been driven mainly by changes in gene regulation rather than altered protein-coding gene sequences. Comparative analysis of vertebrate genomes has revealed an abundance of evolutionarily conserved but noncoding sequences. These conserved noncoding (CNC) sequences may well harbor critical regulatory variants that have driven recent human evolution. Results: Here we identify 1,356 CNC sequences that appear to have undergone dramatic human-specific changes in selective pressures, at least 15% of which have substitution rates significantly above that expected under neutrality. The 1,356 'accelerated CNC' (ANC) sequences are enriched in recent segmental duplications, suggesting a recent change in selective constraint following duplication. In addition, single nucleotide polymorphisms within ANC sequences have a significant excess of high frequency derived alleles and high F(ST)values relative to controls, indicating that acceleration and positive selection are recent in human populations. Finally, a significant number of single nucleotide polymorphisms within ANC sequences are associated with changes in gene expression. The probability of variation in an ANC sequence being associated with a gene expression phenotype is fivefold higher than variation in a control CNC sequence. Conclusion: Our analysis suggests that ANC sequences have until very recently played a role in human evolution, potentially through lineage-specific changes in gene regulation.

关键词： Substitution Rate additional data file Segmental Duplication Selective Constraint Human Lineage

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The IL-10 and IFN-γ pathways are essential to the potent immunosuppressive activity of cultured CD8⁺ NKT-like cells

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GENOME BIOLOGY 2008年第7期9卷 R119-R119页

作者： Zhou, Li Wang, Hongjie Zhong, Xing Jin, Yulan Mi, Qing-Sheng Sharma, Ashok McIndoe, Richard A. Garge, Nikhil Podolsky, Robert She, Jin-Xiong Med Coll Georgia Ctr Biotechnol & Genom Med Augusta GA 30912 USA Med Coll Georgia Dept Pathol Augusta GA 30912 USA Med Coll Georgia Dept Med Augusta GA 30912 USA

Background: CD8(+) NKT-like cells are naturally occurring but rare T cells that express both T cell and natural killer cell markers. These cells may play key roles in establishing tolerance to self-antigens;however, their mechanism of action and molecular profiles are poorly characterized due to their low frequencies. We developed an efficient in vitro protocol to produce CD8(+) T cells that express natural killer cell markers (CD8(+) NKT-like cells) and extensively characterized their functional and molecular phenotypes using a variety of techniques. Results: Large numbers of CD8(+) NKT-like cells were obtained through culture of naive CD8(+) T cells using anti-CD3/anti-CD28-coated beads and high dose IL-2. These cells possess potent activity in suppressing the proliferation of naive responder T cells. Gene expression profiling suggests that the cultured CD8(+) NKT-like cells and the nave CD8(+) T cells differ by more than 2-fold for about 3,000 genes, among which 314 are upregulated by more than 5-fold and 113 are upregulated by more than 10-fold in the CD8(+) NKT-like cells. A large proportion of the highly upregulated genes are soluble factors or surface markers that have previously been implicated in immune suppression or are likely to possess immunosuppressive properties. Many of these genes are regulated by two key cytokines, IL-10 and IFN-gamma. The immunosuppressive activities of cells cultured from IL-10(-/-) and IFN-gamma(-/-) mice are reduced by about 70% and about 50%, respectively, compared to wild-type mice. Conclusion: Immunosuppressive CD8(+) NKT-like cells can be efficiently produced and their immunosuppressive activity is related to many surface and soluble molecules regulated by IL-10 and IFN-gamma.

关键词： Treg Cell additional data file Suppressive Activity Suppressive Function iNKT Cell

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