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- Alexeyenko, Andrey, et al.
(författare)
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Comparative interactomics with Funcoup 2.0
- 2012
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 40:D1, s. D821-D828
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Tidskriftsartikel (refereegranskat)abstract
- FunCoup (http://FunCoup.sbc.su.se) is a database that maintains and visualizes global gene/protein networks of functional coupling that have been constructed by Bayesian integration of diverse high-throughput data. FunCoup achieves high coverage by orthology-based integration of data sources from different model organisms and from different platforms. We here present release 2.0 in which the data sources have been updated and the methodology has been refined. It contains a new data type Genetic Interaction, and three new species: chicken, dog and zebra fish. As FunCoup extensively transfers functional coupling information between species, the new input datasets have considerably improved both coverage and quality of the networks. The number of high-confidence network links has increased dramatically. For instance, the human network has more than eight times as many links above confidence 0.5 as the previous release. FunCoup provides facilities for analysing the conservation of subnetworks in multiple species. We here explain how to do comparative interactomics on the FunCoup website.
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- Alexeyenko, Andrey, et al.
(författare)
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Dynamic Zebrafish Interactome Reveals Transcriptional Mechanisms of Dioxin Toxicity
- 2010
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 5:5, s. e10465-
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Tidskriftsartikel (refereegranskat)abstract
- Background: In order to generate hypotheses regarding the mechanisms by which 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) causes toxicity, we analyzed global gene expression changes in developing zebrafish embryos exposed to this potent toxicant in the context of a dynamic gene network. For this purpose, we also computationally inferred a zebrafish (Danio rerio) interactome based on orthologs and interaction data from other eukaryotes. Methodology/Principal Findings: Using novel computational tools to analyze this interactome, we distinguished between dioxin-dependent and dioxin-independent interactions between proteins, and tracked the temporal propagation of dioxin-dependent transcriptional changes from a few genes that were altered initially, to large groups of biologically coherent genes at later times. The most notable processes altered at later developmental stages were calcium and iron metabolism, embryonic morphogenesis including neuronal and retinal development, a variety of mitochondria-related functions, and generalized stress response (not including induction of antioxidant genes). Within the interactome, many of these responses were connected to cytochrome P4501A (cyp1a) as well as other genes that were dioxin-regulated one day after exposure. This suggests that cyp1a may play a key role initiating the toxic dysregulation of those processes, rather than serving simply as a passive marker of dioxin exposure, as suggested by earlier research. Conclusions/Significance: Thus, a powerful microarray experiment coupled with a flexible interactome and multi-pronged interactome tools (which are now made publicly available for microarray analysis and related work) suggest the hypothesis that dioxin, best known in fish as a potent cardioteratogen, has many other targets. Many of these types of toxicity have been observed in mammalian species and are potentially caused by alterations to cyp1a.
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- Alexeyenko, Andrey, et al.
(författare)
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Global networks of functional coupling in eukaryotes from comprehensive data integration
- 2009
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 19:6, s. 1107-16
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Tidskriftsartikel (refereegranskat)abstract
- No single experimental method can discover all connections in the interactome. A computational approach can help by integrating data from multiple, often unrelated, proteomics and genomics pipelines. Reconstructing global networks of functional coupling (FC) faces the challenges of scale and heterogeneity--how to efficiently integrate huge amounts of diverse data from multiple organisms, yet ensuring high accuracy. We developed FunCoup, an optimized Bayesian framework, to resolve these issues. Because interactomes comprise functional coupling of many types, FunCoup annotates network edges with confidence scores in support of different kinds of interactions: physical interaction, protein complex member, metabolic, or signaling link. This capability boosted overall accuracy. On the whole, the constructed framework was comprehensively tested to optimize the overall confidence and ensure seamless, automated incorporation of new data sets of heterogeneous types. Using over 50 data sets in seven organisms and extensively transferring information between orthologs, FunCoup predicted global networks in eight eukaryotes. For the Ciona intestinalis network, only orthologous information was used, and it recovered a significant number of experimental facts. FunCoup predictions were validated on independent cancer mutation data. We show how FunCoup can be used for discovering candidate members of the Parkinson and Alzheimer pathways. Cross-species pathway conservation analysis provided further support to these observations.
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- Frings, Oliver, 1982-, et al.
(författare)
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MGclus : Network clustering employing shared neighbors
- 2013
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Ingår i: Molecular BioSystems. - : Royal Society of Chemistry (RSC). - 1742-206X .- 1742-2051. ; 9:7, s. 1670-1675
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Tidskriftsartikel (refereegranskat)abstract
- Network analysis is an important tool for functional annotation of genes and proteins. A common approach to discern structure in a global network is to infer network clusters, or modules, and assume a functional coherence within each module, which may represent a complex or a pathway. It is however not trivial to define optimal modules. Although many methods have been proposed, it is unclear which methods perform best in general. It seems that most methods produce far from optimal results but in different ways. MGclus is a new algorithm designed to detect modules with a strongly interconnected neighborhood in large scale biological interaction networks. In our benchmarks we found MGclus to outperform other methods when applied to random graphs with varying degree of noise, and to perform equally or better when applied to biological protein interaction networks. MGclus is implemented in Java and utilizes the JGraphT graph library. It has an easy to use command-line interface and is available for download from http://sonnhammer.sbc.su.se/download/software/ MGclus/.
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- Frings, Oliver, et al.
(författare)
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Network Analysis of Functional Genomics Data : Application to Avian Sex-Biased Gene Expression
- 2012
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Ingår i: Scientific World Journal. - : Hindawi Limited. - 1537-744X. ; , s. 130491-
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Tidskriftsartikel (refereegranskat)abstract
- Gene expression analysis is often used to investigate the molecular and functional underpinnings of a phenotype. However, differential expression of individual genes is limited in that it does not consider how the genes interact with each other in networks. To address this shortcoming we propose a number of network-based analyses that give additional functional insights into the studied process. These were applied to a dataset of sex-specific gene expression in the chicken gonad and brain at different developmental stages. We first constructed a global chicken interaction network. Combining the network with the expression data showed that most sex-biased genes tend to have lower network connectivity, that is, act within local network environments, although some interesting exceptions were found. Genes of the same sex bias were generally more strongly connected with each other than expected. We further studied the fates of duplicated sex-biased genes and found that there is a significant trend to keep the same pattern of sex bias after duplication. We also identified sex-biased modules in the network, which reveal pathways or complexes involved in sex-specific processes. Altogether, this work integrates evolutionary genomics with systems biology in a novel way, offering new insights into the modular nature of sex-biased genes.
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- McCormack, T., et al.
(författare)
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Statistical Assessment of Crosstalk Enrichment between Gene Groups in Biological Networks
- 2013
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:1, s. e54945-
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Tidskriftsartikel (refereegranskat)abstract
- Motivation: Analyzing groups of functionally coupled genes or proteins in the context of global interaction networks has become an important aspect of bioinformatic investigations. Assessing the statistical significance of crosstalk enrichment between or within groups of genes can be a valuable tool for functional annotation of experimental gene sets. Results: Here we present CrossTalkZ, a statistical method and software to assess the significance of crosstalk enrichment between pairs of gene or protein groups in large biological networks. We demonstrate that the standard z-score is generally an appropriate and unbiased statistic. We further evaluate the ability of four different methods to reliably recover crosstalk within known biological pathways. We conclude that the methods preserving the second-order topological network properties perform best. Finally, we show how CrossTalkZ can be used to annotate experimental gene sets using known pathway annotations and that its performance at this task is superior to gene enrichment analysis (GEA). Availability and Implementation: CrossTalkZ (available at http://sonnhammer.sbc.su.se/download/software/CrossTalkZ/) is implemented in C++, easy to use, fast, accepts various input file formats, and produces a number of statistics. These include z-score, p-value, false discovery rate, and a test of normality for the null distributions.
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