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Deep short-read sequencing of chromosome 17 from the mouse strains A/J and CAST/Ei identifies significant germline variation and candidate genes that regulate liver triglyceride levels

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GENOME BIOLOGY 2009年第10期10卷 R112-R112页

作者： Sudbery, Ian Stalker, Jim Simpson, Jared T. Keane, Thomas Rust, Alistair G. Hurles, Matthew E. Walter, Klaudia Lynch, Dee Teboul, Lydia Brown, Steve D. Li, Heng Ning, Zemin Nadeau, Joseph H. Croniger, Colleen M. Durbin, Richard Adams, David J. Wellcome Trust Sanger Inst Hinxton CB10 1HH England MRC Harwell Mammalian Genet Unit Didcot OX11 ORD Oxon England Case Western Reserve Univ Dept Genet Cleveland OH 44106 USA

Genome sequences are essential tools for comparative and mutational analyses. Here we present the short read sequence of mouse chromosome 17 from the Mus musculus domesticus derived strain A/J, and the Mus musculus castaneus derived strain CAST/Ei. We describe approaches for the accurate identification of nucleotide and structural variation in the genomes of vertebrate experimental organisms, and show how these techniques can be applied to help prioritize candidate genes within quantitative trait loci.

关键词： Hide Markov Model Copy Number Variation additional data file Mapping Depth Mouse Chromosome

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Genomic features of Bordetella parapertussis clades with distinct host species specificity

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GENOME BIOLOGY 2006年第9期7卷 R81-R81页

作者： Brinig, Mary M. Register, Karen B. Ackermann, Mark R. Relman, David A. Stanford Univ Sch Med Dept Microbiol & Immunol Stanford CA 94305 USA VA Palo Alto Hlth Care Syst Palo Alto CA 94304 USA USDA ARS Natl Anim Dis Ctr Resp Div Livestock Res Unit Ames IA 50010 USA Iowa State Univ Dept Vet Pathol Ames IA 50011 USA Stanford Univ Sch Med Dept Med Stanford CA 94305 USA

Background: The respiratory pathogen Bordetella parapertussis is a valuable model in which to study the complex phenotype of host specificity because of its unique two-species host range. One subset of strains, including the sequenced representative, causes whooping cough in humans, while other strains infect only sheep. The disease process in sheep is not well understood, nor are the genetic and transcriptional differences that might provide the basis for host specificity among ovine and human strains. Results: We found 40 previously unknown genomic regions in an ovine strain of B. parapertussis using subtractive hybridization, including unique lipopolysaccharide genes. A microarray survey of the gene contents of 71 human and ovine strains revealed further differences, with 47 regions of difference distinguishing the host-restricted subgroups. In addition, sheep and human strains displayed distinct whole-genome transcript abundance profiles. We developed an animal model in which sheep were inoculated with a sheep strain, human strain, or mixture of the two. We found that the ovine strain persisted in the nasal cavity for 12 to 14 days, while the human strain colonized at lower levels and was no longer detected by 7 days post-inoculation. The ovine strain induced less granulocyte infiltration of the nasal mucosa. Conclusion: Several factors may play a role in determining host range of B. parapertussis. Human- and ovine-associated strains have differences in content and sequence of genes encoding proteins that mediate host-pathogen contact, such as lipopolysaccharide and fimbriae, as well as variation in regulation of toxins, type III secretion genes, and other virulence-associated genes.

关键词： Pertussis Comparative Genomic Hybridization additional data file Suppression Subtractive Hybridization Array Element

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A functional difficulty and functional pain instrument for hip and knee osteoarthritis

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ARTHRITIS RESEARCH & THERAPY 2009年第4期11卷 R107-R107页

作者： Jette, Alan M. McDonough, Christine M. Ni, Pengsheng Haley, Stephen M. Hambleton, Ronald K. Olarsch, Sippy Hunter, David J. Kim, Young-jo Felson, David T. Boston Univ Sch Publ Hlth Hlth & Disabil Res Inst Boston MA 02118 USA Dartmouth Coll Dartmouth Inst Hlth Policy & Clin Practice Lebanon NH 03766 USA Univ Massachusetts Sch Educ Dept Educ Policy Res & Adm Ctr Educ Assessment Amherst MA 01003 USA New England Baptist Hosp Div Res Boston MA 02120 USA Harvard Univ Harvard Med Sch Boston MA 02115 USA Childrens Hosp Dept Orthoped Surg Boston MA 02115 USA Boston Univ Sch Med Boston MA 02118 USA

Introduction The objectives of this study were to develop a functional outcome instrument for hip and knee osteoarthritis research (OA-FUNCTION-CAT) using item response theory (IRT) and computer adaptive test (CAT) methods and to assess its psychometric performance compared to the current standard in the field. Methods We conducted an extensive literature review, focus groups, and cognitive testing to guide the construction of an item bank consisting of 125 functional activities commonly affected by hip and knee osteoarthritis. We recruited a convenience sample of 328 adults with confirmed hip and/or knee osteoarthritis. Subjects reported their degree of functional difficulty and functional pain in performing each activity in the item bank and completed the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Confirmatory factor analyses were conducted to assess scale uni-dimensionality, and IRT methods were used to calibrate the items and examine the fit of the data. We assessed the performance of OA-FUNCTION-CATs of different lengths relative to the full item bank and WOMAC using CAT simulation analyses. Results Confirmatory factor analyses revealed distinct functional difficulty and functional pain domains. Descriptive statistics for scores from 5-, 10-, and 15-item CATs were similar to those for the full item bank. The 10- item OA-FUNCTION-CAT scales demonstrated a high degree of accuracy compared with the item bank (r = 0.96 and 0.89, respectively). Compared to the WOMAC, both scales covered a broader score range and demonstrated a higher degree of precision at the ceiling and reliability across the range of scores. Conclusions The OA-FUNCTION-CAT provided superior reliability throughout the score range and improved breadth and precision at the ceiling compared with the WOMAC. Further research is needed to assess whether these improvements carry over into superior ability to measure change.

关键词： Differential Item Functioning Item Response Theory additional data file Item Bank Item Response Theory Model

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Investigations into the relationship between feedback loops and functional importance of a signal transduction network based on Boolean network modeling

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BMC BIOINFORMATICS 2007年第1期8卷 1-9页

作者： Kwon, Yung-Keun Choi, Sun Shim Cho, Kwang-Hyun Korea Adv Inst Sci & Technol Dept Bio & Brain Engn Taejon 305701 South Korea Korea Adv Inst Sci & Technol KI BioCentury Taejon 305701 South Korea Kangwon Natl Univ Coll Biosci & Biotechnol Chunchon 200701 Gangwon Do South Korea Kangwon Natl Univ Inst Biosci & Biotechnol Chunchon 200701 Gangwon Do South Korea

Background: A number of studies on biological networks have been carried out to unravel the topological characteristics that can explain the functional importance of network nodes. For instance, connectivity, clustering coefficient, and shortest path length were previously proposed for this purpose. However, there is still a pressing need to investigate another topological measure that can better describe the functional importance of network nodes. In this respect, we considered a feedback loop which is ubiquitously found in various biological networks. Results: We discovered that the number of feedback loops (NuFBL) is a crucial measure for evaluating the importance of a network node and verified this through a signal transduction network in the hippocampal CAI neuron of mice as well as through generalized biological network models represented by Boolean networks. In particular, we observed that the proteins with a larger NuFBL are more likely to be essential and to evolve slowly in the hippocampal CAI neuronal signal transduction network. Then, from extensive simulations based on the Boolean network models, we proved that a network node with the larger NuFBL is likely to be more important as the mutations of the initial state or the update rule of such a node made the network converge to a different attractor. These results led us to infer that such a strong positive correlation between the NuFBL and the importance of a network node might be an intrinsic principle of biological networks in view of network dynamics. Conclusion: The presented analysis on topological characteristics of biological networks showed that the number of feedback loops is positively correlated with the functional importance of network nodes. This result also suggests the existence of unknown feedback loops around functionally important nodes in biological networks.

关键词： Feedback Loop additional data file Network Node Cluster Coefficient Biological Network

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Analysis of feedback loops and robustness in network evolution based on Boolean models

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BMC BIOINFORMATICS 2007年第1期8卷 1-9页

作者： Kwon, Yung-Keun Cho, Kwang-Hyun Korea Adv Inst Sci & Technol Dept Bio & Brain Engn Taejon 305701 South Korea Korea Adv Inst Sci & Technol KI BioCentury Taejon 305701 South Korea

Background: Many biological networks such as protein-protein interaction networks, signaling networks, and metabolic networks have topological characteristics of a scale-free degree distribution. Preferential attachment has been considered as the most plausible evolutionary growth model to explain this topological property. Although various studies have been undertaken to investigate the structural characteristics of a network obtained using this growth model, its dynamical characteristics have received relatively less attention. Results: In this paper, we focus on the robustness of a network that is acquired during its evolutionary process. Through simulations using Boolean network models, we found that preferential attachment increases the number of coupled feedback loops in the course of network evolution. Whereas, if networks evolve to have more coupled feedback loops rather than following preferential attachment, the resulting networks are more robust than those obtained through preferential attachment, although both of them have similar degree distributions. Conclusion: The presented analysis demonstrates that coupled feedback loops may play an important role in network evolution to acquire robustness. The result also provides a hint as to why various biological networks have evolved to contain a number of coupled feedback loops.

关键词： Feedback Loop additional data file Degree Distribution Biological Network Preferential Attachment

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Orthogonal projections to latent structures as a strategy for microarray data normalization

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BMC BIOINFORMATICS 2007年第1期8卷 1-10页

作者： Bylesjo, Max Eriksson, Daniel Sjodin, Andreas Jansson, Stefan Moritz, Thomas Trygg, Johan Umea Univ Dept Chem Res Grp Chemometr S-90187 Umea Sweden Swedish Univ Agr Sci Umea Plant Sci Ctr Dept Forest Genet & Plant Physiol S-90183 Umea Sweden Umea Univ Umea Plant Sci Ctr Dept Plant Physiol S-90187 Umea Sweden

Background: During generation of microarray data, various forms of systematic biases are frequently introduced which limits accuracy and precision of the results. In order to properly estimate biological effects, these biases must be identified and discarded. Results: We introduce a normalization strategy for multi-channel microarray data based on orthogonal projections to latent structures (OPLS);a multivariate regression method. The effect of applying the normalization methodology on single-channel Affymetrix data as well as dual-channel cDNA data is illustrated. We provide a parallel comparison to a wide range of commonly employed normalization methods with diverse properties and strengths based on sensitivity and specificity from external (spike-in) controls. On the illustrated data sets, the OPLS normalization strategy exhibits leading average true negative and true positive rates in comparison to other evaluated methods. Conclusion: The OPLS methodology identifies joint variation within biological samples to enable the removal of sources of variation that are non-correlated (orthogonal) to the within-sample variation. This ensures that structured variation related to the underlying biological samples is separated from the remaining, bias-related sources of systematic variation. As a consequence, the methodology does not require any explicit knowledge regarding the presence or characteristics of certain biases. Furthermore, there is no underlying assumption that the majority of elements should be non-differentially expressed, making it applicable to specialized boutique arrays.

关键词： Partial Little Square Normalization Method additional data file True Negative Rate Orthogonal Signal Correction

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Host origin of plastid solute transporters in the first photosynthetic eukaryotes

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GENOME BIOLOGY 2007年第10期8卷 R212-R212页

作者： Tyra, Heather M. Linka, Marc weber, Andreas P. M. Bhattacharya, Debashish Univ Iowa Dept Biol Sci Iowa City IA 52242 USA Univ Iowa Roy J Carver Ctr Comparat Genom Iowa City IA 52242 USA Michigan State Univ Dept Plant Biol E Lansing MI 48824 USA

Background: It is generally accepted that a single primary endosymbiosis in the Plantae (red, green (including land plants), and glaucophyte algae) common ancestor gave rise to the ancestral photosynthetic organelle (plastid). Plastid establishment necessitated many steps, including the transfer and activation of endosymbiont genes that were relocated to the nuclear genome of the 'host' followed by import of the encoded proteins into the organelle. These innovations are, however, highly complex and could not have driven the initial formation of the endosymbiosis. We postulate that the re- targeting of existing host solute transporters to the plastid fore- runner was critical for the early success of the primary endosymbiosis, allowing the host to harvest endosymbiont primary production. Results: We tested this model of transporter evolution by conducting a comprehensive analysis of the plastid permeome in Arabidopsis thaliana. Of 137 well-annotated transporter proteins that were initially considered, 83 that are broadly distributed in Plantae were submitted to phylogenetic analysis. Consistent with our hypothesis, we find that 58% of Arabidopsis transporters, including all carbohydrate transporters, are of host origin, whereas only 12% arose from the cyanobacterial endosymbiont. Four transporter genes are derived from a Chlamydia- like source, suggesting that establishment of the primary plastid likely involved contributions from at least two prokaryotic sources. Conclusion: Our results indicate that the existing plastid solute transport system shared by Plantae is derived primarily from host genes. Important contributions also came from the cyanobacterial endosymbiont and Chlamydia-like bacteria likely co-resident in the first algae.

关键词： Horizontal Gene Transfer additional data file Cyanidioschyzon Merolae Primary Plastid Primary Endosymbiosis

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A steganalysis-based approach to comprehensive identification and characterization of functional regulatory elements

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GENOME BIOLOGY 2006年第6期7卷 R49-R49页

作者： Wang, Guandong Zhang, Weixiong Washington Univ Dept Comp Sci & Engn St Louis MO 63130 USA Washington Univ Dept Genet St Louis MO 63130 USA

The comprehensive identification of cis-regulatory elements on a genome scale is a challenging problem. We develop a novel, steganalysis-based approach for genome-wide motif finding, called WordSpy, by viewing regulatory regions as a stegoscript with cis-elements embedded in 'background' sequences. We apply WordSpy to the promoters of cell-cycle-related genes of Saccharomyces cerevisiae and Arabidopsis thaliana, identifying all known cell-cycle motifs with high ranking. WordSpy can discover a complete set of cis-elements and facilitate the systematic study of regulatory networks.

关键词： additional data file Secret Message Profile Motif Putative Motif Word Sampling

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Systems analysis of circadian time-dependent neuronal epidermal growth factor receptor signaling

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GENOME BIOLOGY 2006年第6期7卷 R48-R48页

作者： Zak, Daniel E. Hao, Haiping Vadigepalli, Rajanikanth Miller, Gregory M. Ogunnaike, Babatunde A. Schwaber, James S. Thomas Jefferson Univ Dept Pathol Daniel Baugh Inst Funct Genom & Computat Biol Philadelphia PA 19107 USA Univ Delaware Dept Chem Engn Newark DE 19716 USA

Background: Identifying the gene regulatory networks governing physiological signal integration remains an important challenge in circadian biology. Epidermal growth factor receptor (EGFR) has been implicated in circadian function and is expressed in the suprachiasmatic nuclei (SCN), the core circadian pacemaker. The transcription networks downstream of EGFR in the SCN are unknown but, by analogy to other SCN inputs, we expect the response to EGFR activation to depend on circadian timing. Results: We have undertaken a systems-level analysis of EGFR circadian time-dependent signaling in the SCN. We collected gene-expression profiles to study how the SCN response to EGFR activation depends on circadian timing. Mixed-model analysis of variance (ANOVA) was employed to identify genes with circadian time-dependent EGFR regulation. The expression data were integrated with transcription-factor binding predictions through gene group enrichment analyses to generate robust hypotheses about transcription-factors responsible for the circadian phase-dependent EGFR responses. Conclusion: The analysis results suggest that the transcriptional response to EGFR signaling in the SCN may be partly mediated by established transcription-factors regulated via EGFR transription-factors (AP1, Ets1, C/EBP), transcription- factors involved in circadian clock entrainment (CREB), and by core clock transcription- factors (Ror alpha). Quantitative real-time PCR measurements of several transcription- factor expression levels support a model in which circadian time-dependent EGFR responses are partly achieved by circadian regulation of upstream signaling components. Our study suggests an important role for EGFR signaling in SCN function and provides an example for gaining physiological insights through systems-level analysis.

关键词： Epidermal Growth Factor Receptor Circadian Clock additional data file Epidermal Growth Factor Receptor Signaling Epidermal Growth Factor Receptor Activation

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Exploring systemic RNA interference in insects:: a genome-wide survey for RNAi genes in Tribolium

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GENOME BIOLOGY 2008年第1期9卷 R10-R10页

作者： Tomoyasu, Yoshinori Miller, Sherry C. Tomita, Shuichiro Schoppmeier, Michael Grossmann, Daniela Bucher, Gregor Kansas State Univ Div Biol Manhattan KS 66506 USA Kansas State Univ K State Arthropod Genom Ctr Manhattan KS 66506 USA Nat Inst Agrobiol Sci Insect Genom Res Unit Tsuchiura Ibaraki 3058634 Japan Univ Erlangen Nurnberg Inst Biol Abt Entwicklungsbiol D-91058 Erlangen Germany Univ Gottingen Johann Friedrich Bluembach Inst Zool & Anthropol Abt Entwicklungsbiol D-37077 Gottingen Germany

Background: RNA interference (RNAi) is a highly conserved cellular mechanism. In some organisms, such as Caenorhabditis elegans, the RNAi response can be transmitted systemically. Some insects also exhibit a systemic RNAi response. However, Drosophila, the leading insect model organism, does not show a robust systemic RNAi response, necessitating another model system to study the molecular mechanism of systemic RNAi in insects. Results: We used Tribolium, which exhibits robust systemic RNAi, as an alternative model system. We have identified the core RNAi genes, as well as genes potentially involved in systemic RNAi, from the Tribolium genome. Both phylogenetic and functional analyses suggest that Tribolium has a somewhat larger inventory of core component genes than Drosophila, perhaps allowing a more sensitive response to double-stranded RNA (dsRNA). We also identified three Tribolium homologs of C. elegans sid-1, which encodes a possible dsRNA channel. However, detailed sequence analysis has revealed that these Tribolium homologs share more identity with another C. elegans gene, tag-130. We analyzed tag-130 mutants, and found that this gene does not have a function in systemic RNAi in C. elegans. Likewise, the Tribolium sid-like genes do not seem to be required for systemic RNAi. These results suggest that insect sid-1-like genes have a different function than dsRNA uptake. Moreover, Tribolium lacks homologs of several genes important for RNAi in C. elegans. Conclusion: Although both Tribolium and C. elegans show a robust systemic RNAi response, our genome-wide survey reveals significant differences between the RNAi mechanisms of these organisms. Thus, insects may use an alternative mechanism for the systemic RNAi response. Understanding this process would assist with rendering other insects amenable to systemic RNAi, and may influence pest control approaches.

关键词： Enhance Green Fluorescence Protein additional data file RNAi Pathway Enhance Green Fluorescence Protein Expression Argonaute Protein

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