How to understand the cell by breaking it: network analysis of gene perturbation screens

Modern high-throughput gene perturbation screens are key technologies at the forefront of genetic research. Combined with rich phenotypic descriptors they enable researchers to observe detailed cellular reactions to experimental perturbations on a genome-wide scale. This review surveys the current state-of-the-art in analyzing perturbation screens from a network point of view. We describe approaches to make the step from the parts list to the wiring diagram by using phenotypes for network inference and integrating them with complementary data sources. The first part of the review describes methods to analyze one- or low-dimensional phenotypes like viability or reporter activity; the second part concentrates on high-dimensional phenotypes showing global changes in cell morphology, transcriptome or proteome.Comment: Review based on ISMB 2009 tutorial; after two rounds of revisio

InnateDB: systems biology of innate immunity and beyond—recent updates and continuing curation

peer-reviewedInnateDB (http://www.innatedb.com) is an integrated analysis platform that has been specifically designed to facilitate systems-level analyses of mammalian innate immunity networks, pathways and genes. In this article, we provide details of recent updates and improvements to the database. InnateDB now contains >196 000 human, mouse and bovine experimentally validated molecular interactions and 3000 pathway annotations of relevance to all mammalian cellular systems (i.e. not just immune relevant pathways and interactions). In addition, the InnateDB team has, to date, manually curated in excess of 18 000 molecular interactions of relevance to innate immunity, providing unprecedented insight into innate immunity networks, pathways and their component molecules. More recently, InnateDB has also initiated the curation of allergy- and asthma-related interactions. Furthermore, we report a range of improvements to our integrated bioinformatics solutions including web service access to InnateDB interaction data using Proteomics Standards Initiative Common Query Interface, enhanced Gene Ontology analysis for innate immunity, and the availability of new network visualizations tools. Finally, the recent integration of bovine data makes InnateDB the first integrated network analysis platform for this agriculturally important model organism.This work was supported by Genome BC through the Pathogenomics of Innate Immunity (PI2) project and by the Foundation for the National Institutes of Health and the Canadian Institutes of Health Research under the Grand Challenges in Global Health Research Initiative [Grand Challenges ID: 419]. Further funding was also provided by AllerGen grants 12ASI1 and 12B&B2. D.J.L. was funded in part during this project by a postdoctoral trainee award from the Michael Smith Foundation for Health Research (MSFHR). F.S.L.B. is a MSFHR Senior Scholar and R.E.W.H. holds a Canada Research Chair (CRC). Funding to enable bovine systems biology in InnateDB is provided by Teagasc [RMIS6018] and the Teagasc Walsh Fellowship scheme. IMEx is funded by the European Commission under the PSIMEx project [contract number FP7-HEALTH-2007-223411]. Funding for open access charge: Teagasc [RMIS6018]

Genes2Networks: Connecting Lists of Proteins by Using Background Literature-based Mammalian Networks

In recent years, in-silico literature-based mammalian protein-protein interaction network datasets have been developed. These datasets contain binary interactions extracted manually from legacy experimental biomedical research literature. Placing lists of genes or proteins identified as significantly changing in multivariate experiments, in the context of background knowledge about binary interactions, can be used to place these genes or proteins in the context of pathways and protein complexes.
Genes2Networks is a software system that integrates the content of ten mammalian literature-based interaction network datasets. Filtering to prune low-confidence interactions was implemented. Genes2Networks is delivered as a web-based service using AJAX. The system can be used to extract relevant subnetworks created from “seed” lists of human Entrez gene names. The output includes a dynamic linkable three color web-based network map, with a statistical analysis report that identifies significant intermediate nodes used to connect the seed list. Genes2Networks is available at http://actin.pharm.mssm.edu/genes2networks.
Genes2Network is a powerful web-based software application tool that can help experimental biologists to interpret high-throughput experimental results used in genomics and proteomics studies where the output of these experiments is a list of significantly changing genes or proteins. The system can be used to find relationships between nodes from the seed list, and predict novel nodes that play a key role in a common function

BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models

Background: Quantitative models of biochemical and cellular systems are used to answer a variety of questions in the biological sciences. The number of published quantitative models is growing steadily thanks to increasing interest in the use of models as well as the development of improved software systems and the availability of better, cheaper computer hardware. To maximise the benefits of this growing body of models, the field needs centralised model repositories that will encourage, facilitate and promote model dissemination and reuse. Ideally, the models stored in these repositories should be extensively tested and encoded in community-supported and standardised formats. In addition, the models and their components should be cross-referenced with other resources in order to allow their unambiguous identification. Description: BioModels Database http://www.ebi.ac.uk/biomodels/ is aimed at addressing exactly these needs. It is a freely-accessible online resource for storing, viewing, retrieving, and analysing published, peer-reviewed quantitative models of biochemical and cellular systems. The structure and behaviour of each simulation model distributed by BioModels Database are thoroughly checked; in addition, model elements are annotated with terms from controlled vocabularies as well as linked to relevant data resources. Models can be examined online or downloaded in various formats. Reaction network diagrams generated from the models are also available in several formats. BioModels Database also provides features such as online simulation and the extraction of components from large scale models into smaller submodels. Finally, the system provides a range of web services that external software systems can use to access up-to-date data from the database. Conclusions: BioModels Database has become a recognised reference resource for systems biology. It is being used by the community in a variety of ways; for example, it is used to benchmark different simulation systems, and to study the clustering of models based upon their annotations. Model deposition to the database today is advised by several publishers of scientific journals. The models in BioModels Database are freely distributed and reusable; the underlying software infrastructure is also available from SourceForge https://sourceforge.net/projects/biomodels/ under the GNU General Public License

Genes2Networks: Connecting Lists of Proteins by Using Background Literature-based Mammalian Networks

In recent years, in-silico literature-based mammalian protein-protein interaction network datasets have been developed. These datasets contain binary interactions extracted manually from legacy experimental biomedical research literature. Placing lists of genes or proteins identified as significantly changing in multivariate experiments, in the context of background knowledge about binary interactions, can be used to place these genes or proteins in the context of pathways and protein complexes.
Genes2Networks is a software system that integrates the content of ten mammalian literature-based interaction network datasets. Filtering to prune low-confidence interactions was implemented. Genes2Networks is delivered as a web-based service using AJAX. The system can be used to extract relevant subnetworks created from “seed” lists of human Entrez gene names. The output includes a dynamic linkable three color web-based network map, with a statistical analysis report that identifies significant intermediate nodes used to connect the seed list. Genes2Networks is available at http://actin.pharm.mssm.edu/genes2networks.
Genes2Network is a powerful web-based software application tool that can help experimental biologists to interpret high-throughput experimental results used in genomics and proteomics studies where the output of these experiments is a list of significantly changing genes or proteins. The system can be used to find relationships between nodes from the seed list, and predict novel nodes that play a key role in a common function

AGMIAL: implementing an annotation strategy for prokaryote genomes as a distributed system

We have implemented a genome annotation system for prokaryotes called AGMIAL. Our approach embodies a number of key principles. First, expert manual annotators are seen as a critical component of the overall system; user interfaces were cyclically refined to satisfy their needs. Second, the overall process should be orchestrated in terms of a global annotation strategy; this facilitates coordination between a team of annotators and automatic data analysis. Third, the annotation strategy should allow progressive and incremental annotation from a time when only a few draft contigs are available, to when a final finished assembly is produced. The overall architecture employed is modular and extensible, being based on the W3 standard Web services framework. Specialized modules interact with two independent core modules that are used to annotate, respectively, genomic and protein sequences. AGMIAL is currently being used by several INRA laboratories to analyze genomes of bacteria relevant to the food-processing industry, and is distributed under an open source license

Aging cellular networks: chaperones as major participants

We increasingly rely on the network approach to understand the complexity of cellular functions. Chaperones (heat shock proteins) are key "networkers", which have among their functions to sequester and repair damaged protein. In order to link the network approach and chaperones with the aging process, we first summarize the properties of aging networks suggesting a "weak link theory of aging". This theory suggests that age-related random damage primarily affects the overwhelming majority of the low affinity, transient interactions (weak links) in cellular networks leading to increased noise, destabilization and diversity. These processes may be further amplified by age-specific network remodelling and by the sequestration of weakly linked cellular proteins to protein aggregates of aging cells. Chaperones are weakly linked hubs [i.e., network elements with a large number of connections] and inter-modular bridge elements of protein-protein interaction, signalling and mitochondrial networks. As aging proceeds, the increased overload of damaged proteins is an especially important element contributing to cellular disintegration and destabilization. Additionally, chaperone overload may contribute to the increase of "noise" in aging cells, which leads to an increased stochastic resonance resulting in a deficient discrimination between signals and noise. Chaperone- and other multi-target therapies, which restore the missing weak links in aging cellular networks, may emerge as important anti-aging interventions.Comment: 7 pages, 4 figure