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1.  A Quick Guide for Building a Successful Bioinformatics Community 
PLoS Computational Biology  2015;11(2):e1003972.
“Scientific community” refers to a group of people collaborating together on scientific-research-related activities who also share common goals, interests, and values. Such communities play a key role in many bioinformatics activities. Communities may be linked to a specific location or institute, or involve people working at many different institutions and locations. Education and training is typically an important component of these communities, providing a valuable context in which to develop skills and expertise, while also strengthening links and relationships within the community. Scientific communities facilitate: (i) the exchange and development of ideas and expertise; (ii) career development; (iii) coordinated funding activities; (iv) interactions and engagement with professionals from other fields; and (v) other activities beneficial to individual participants, communities, and the scientific field as a whole. It is thus beneficial at many different levels to understand the general features of successful, high-impact bioinformatics communities; how individual participants can contribute to the success of these communities; and the role of education and training within these communities. We present here a quick guide to building and maintaining a successful, high-impact bioinformatics community, along with an overview of the general benefits of participating in such communities. This article grew out of contributions made by organizers, presenters, panelists, and other participants of the ISMB/ECCB 2013 workshop “The ‘How To Guide’ for Establishing a Successful Bioinformatics Network” at the 21st Annual International Conference on Intelligent Systems for Molecular Biology (ISMB) and the 12th European Conference on Computational Biology (ECCB).
doi:10.1371/journal.pcbi.1003972
PMCID: PMC4318577  PMID: 25654371
2.  Information Content-Based Gene Ontology Functional Similarity Measures: Which One to Use for a Given Biological Data Type? 
PLoS ONE  2014;9(12):e113859.
The current increase in Gene Ontology (GO) annotations of proteins in the existing genome databases and their use in different analyses have fostered the improvement of several biomedical and biological applications. To integrate this functional data into different analyses, several protein functional similarity measures based on GO term information content (IC) have been proposed and evaluated, especially in the context of annotation-based measures. In the case of topology-based measures, each approach was set with a specific functional similarity measure depending on its conception and applications for which it was designed. However, it is not clear whether a specific functional similarity measure associated with a given approach is the most appropriate, given a biological data set or an application, i.e., achieving the best performance compared to other functional similarity measures for the biological application under consideration. We show that, in general, a specific functional similarity measure often used with a given term IC or term semantic similarity approach is not always the best for different biological data and applications. We have conducted a performance evaluation of a number of different functional similarity measures using different types of biological data in order to infer the best functional similarity measure for each different term IC and semantic similarity approach. The comparisons of different protein functional similarity measures should help researchers choose the most appropriate measure for the biological application under consideration.
doi:10.1371/journal.pone.0113859
PMCID: PMC4256219  PMID: 25474538
3.  Using biological networks to improve our understanding of infectious diseases 
Infectious diseases are the leading cause of death, particularly in developing countries. Although many drugs are available for treating the most common infectious diseases, in many cases the mechanism of action of these drugs or even their targets in the pathogen remain unknown. In addition, the key factors or processes in pathogens that facilitate infection and disease progression are often not well understood. Since proteins do not work in isolation, understanding biological systems requires a better understanding of the interconnectivity between proteins in different pathways and processes, which includes both physical and other functional interactions. Such biological networks can be generated within organisms or between organisms sharing a common environment using experimental data and computational predictions. Though different data sources provide different levels of accuracy, confidence in interactions can be measured using interaction scores. Connections between interacting proteins in biological networks can be represented as graphs and edges, and thus studied using existing algorithms and tools from graph theory. There are many different applications of biological networks, and here we discuss three such applications, specifically applied to the infectious disease tuberculosis, with its causative agent Mycobacterium tuberculosis and host, Homo sapiens. The applications include the use of the networks for function prediction, comparison of networks for evolutionary studies, and the generation and use of host–pathogen interaction networks.
doi:10.1016/j.csbj.2014.08.006
PMCID: PMC4212278  PMID: 25379138
Biological networks; Tuberculosis; Pathogen; Evolution; Protein–protein interaction
4.  The use of semantic similarity measures for optimally integrating heterogeneous Gene Ontology data from large scale annotation pipelines 
Frontiers in Genetics  2014;5:264.
With the advancement of new high throughput sequencing technologies, there has been an increase in the number of genome sequencing projects worldwide, which has yielded complete genome sequences of human, animals and plants. Subsequently, several labs have focused on genome annotation, consisting of assigning functions to gene products, mostly using Gene Ontology (GO) terms. As a consequence, there is an increased heterogeneity in annotations across genomes due to different approaches used by different pipelines to infer these annotations and also due to the nature of the GO structure itself. This makes a curator's task difficult, even if they adhere to the established guidelines for assessing these protein annotations. Here we develop a genome-scale approach for integrating GO annotations from different pipelines using semantic similarity measures. We used this approach to identify inconsistencies and similarities in functional annotations between orthologs of human and Drosophila melanogaster, to assess the quality of GO annotations derived from InterPro2GO mappings compared to manually annotated GO annotations for the Drosophila melanogaster proteome from a FlyBase dataset and human, and to filter GO annotation data for these proteomes. Results obtained indicate that an efficient integration of GO annotations eliminates redundancy up to 27.08 and 22.32% in the Drosophila melanogaster and human GO annotation datasets, respectively. Furthermore, we identified lack of and missing annotations for some orthologs, and annotation mismatches between InterPro2GO and manual pipelines in these two proteomes, thus requiring further curation. This simplifies and facilitates tasks of curators in assessing protein annotations, reduces redundancy and eliminates inconsistencies in large annotation datasets for ease of comparative functional genomics.
doi:10.3389/fgene.2014.00264
PMCID: PMC4123725  PMID: 25147557
functional annotation; Gene Ontology annotation; annotation pipeline; manual annotation; electronic annotation
5.  Population-specific common SNPs reflect demographic histories and highlight regions of genomic plasticity with functional relevance 
BMC Genomics  2014;15(1):437.
Background
Population differentiation is the result of demographic and evolutionary forces. Whole genome datasets from the 1000 Genomes Project (October 2012) provide an unbiased view of genetic variation across populations from Europe, Asia, Africa and the Americas. Common population-specific SNPs (MAF > 0.05) reflect a deep history and may have important consequences for health and wellbeing. Their interpretation is contextualised by currently available genome data.
Results
The identification of common population-specific (CPS) variants (SNPs and SSV) is influenced by admixture and the sample size under investigation. Nine of the populations in the 1000 Genomes Project (2 African, 2 Asian (including a merged Chinese group) and 5 European) revealed that the African populations (LWK and YRI), followed by the Japanese (JPT) have the highest number of CPS SNPs, in concordance with their histories and given the populations studied. Using two methods, sliding 50-SNP and 5-kb windows, the CPS SNPs showed distinct clustering across large genome segments and little overlap of clusters between populations. iHS enrichment score and the population branch statistic (PBS) analyses suggest that selective sweeps are unlikely to account for the clustering and population specificity. Of interest is the association of clusters close to recombination hotspots. Functional analysis of genes associated with the CPS SNPs revealed over-representation of genes in pathways associated with neuronal development, including axonal guidance signalling and CREB signalling in neurones.
Conclusions
Common population-specific SNPs are non-randomly distributed throughout the genome and are significantly associated with recombination hotspots. Since the variant alleles of most CPS SNPs are the derived allele, they likely arose in the specific population after a split from a common ancestor. Their proximity to genes involved in specific pathways, including neuronal development, suggests evolutionary plasticity of selected genomic regions. Contrary to expectation, selective sweeps did not play a large role in the persistence of population-specific variation. This suggests a stochastic process towards population-specific variation which reflects demographic histories and may have some interesting implications for health and susceptibility to disease.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-437) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2164-15-437
PMCID: PMC4092225  PMID: 24906912
6.  A web-based protein interaction network visualizer 
BMC Bioinformatics  2014;15:129.
Background
Interaction between proteins is one of the most important mechanisms in the execution of cellular functions. The study of these interactions has provided insight into the functioning of an organism’s processes. As of October 2013, Homo sapiens had over 170000 Protein-Protein interactions (PPI) registered in the Interologous Interaction Database, which is only one of the many public resources where protein interactions can be accessed. These numbers exemplify the volume of data that research on the topic has generated. Visualization of large data sets is a well known strategy to make sense of information, and protein interaction data is no exception. There are several tools that allow the exploration of this data, providing different methods to visualize protein network interactions. However, there is still no native web tool that allows this data to be explored interactively online.
Results
Given the advances that web technologies have made recently it is time to bring these interactive views to the web to provide an easily accessible forum to visualize PPI. We have created a Web-based Protein Interaction Network Visualizer: PINV, an open source, native web application that facilitates the visualization of protein interactions (http://biosual.cbio.uct.ac.za/pinv.html). We developed PINV as a set of components that follow the protocol defined in BioJS and use the D3 library to create the graphic layouts. We demonstrate the use of PINV with multi-organism interaction networks for a predicted target from Mycobacterium tuberculosis, its interacting partners and its orthologs.
Conclusions
The resultant tool provides an attractive view of complex, fully interactive networks with components that allow the querying, filtering and manipulation of the visible subset. Moreover, as a web resource, PINV simplifies sharing and publishing, activities which are vital in today’s research collaborative environments. The source code is freely available for download at https://github.com/4ndr01d3/biosual.
doi:10.1186/1471-2105-15-129
PMCID: PMC4029974  PMID: 24885165
Visualization; Protein-Protein Interactions; PPI; Web development
7.  PPI layouts: BioJS components for the display of Protein-Protein Interactions 
F1000Research  2014;3:50.
Summary: We present two web-based components for the display of Protein-Protein Interaction networks using different self-organizing layout methods: force-directed and circular. These components conform to the BioJS standard and can be rendered in an HTML5-compliant browser without the need for third-party plugins. We provide examples of interaction networks and how the components can be used to visualize them, and refer to a more complex tool that uses these components.
Availability: http://github.com/biojs/biojs; http://dx.doi.org/10.5281/zenodo.7753
doi:10.12688/f1000research.3-50.v1
PMCID: PMC4103490  PMID: 25075288
8.  DaGO-Fun: tool for Gene Ontology-based functional analysis using term information content measures 
BMC Bioinformatics  2013;14:284.
Background
The use of Gene Ontology (GO) data in protein analyses have largely contributed to the improved outcomes of these analyses. Several GO semantic similarity measures have been proposed in recent years and provide tools that allow the integration of biological knowledge embedded in the GO structure into different biological analyses. There is a need for a unified tool that provides the scientific community with the opportunity to explore these different GO similarity measure approaches and their biological applications.
Results
We have developed DaGO-Fun, an online tool available at http://web.cbio.uct.ac.za/ITGOM, which incorporates many different GO similarity measures for exploring, analyzing and comparing GO terms and proteins within the context of GO. It uses GO data and UniProt proteins with their GO annotations as provided by the Gene Ontology Annotation (GOA) project to precompute GO term information content (IC), enabling rapid response to user queries.
Conclusions
The DaGO-Fun online tool presents the advantage of integrating all the relevant IC-based GO similarity measures, including topology- and annotation-based approaches to facilitate effective exploration of these measures, thus enabling users to choose the most relevant approach for their application. Furthermore, this tool includes several biological applications related to GO semantic similarity scores, including the retrieval of genes based on their GO annotations, the clustering of functionally related genes within a set, and term enrichment analysis.
doi:10.1186/1471-2105-14-284
PMCID: PMC3849277  PMID: 24067102
9.  Determining Ancestry Proportions in Complex Admixture Scenarios in South Africa Using a Novel Proxy Ancestry Selection Method 
PLoS ONE  2013;8(9):e73971.
Admixed populations can make an important contribution to the discovery of disease susceptibility genes if the parental populations exhibit substantial variation in susceptibility. Admixture mapping has been used successfully, but is not designed to cope with populations that have more than two or three ancestral populations. The inference of admixture proportions and local ancestry and the imputation of missing genotypes in admixed populations are crucial in both understanding variation in disease and identifying novel disease loci. These inferences make use of reference populations, and accuracy depends on the choice of ancestral populations. Using an insufficient or inaccurate ancestral panel can result in erroneously inferred ancestry and affect the detection power of GWAS and meta-analysis when using imputation. Current algorithms are inadequate for multi-way admixed populations. To address these challenges we developed PROXYANC, an approach to select the best proxy ancestral populations. From the simulation of a multi-way admixed population we demonstrate the capability and accuracy of PROXYANC and illustrate the importance of the choice of ancestry in both estimating admixture proportions and imputing missing genotypes. We applied this approach to a complex, uniquely admixed South African population. Using genome-wide SNP data from over 764 individuals, we accurately estimate the genetic contributions from the best ancestral populations: isiXhosa , ‡Khomani SAN , European , Indian , and Chinese . We also demonstrate that the ancestral allele frequency differences correlate with increased linkage disequilibrium in the South African population, which originates from admixture events rather than population bottlenecks.
Nomenclature
The collective term for people of mixed ancestry in southern Africa is “Coloured,” and this is officially recognized in South Africa as a census term, and for self-classification. Whilst we acknowledge that some cultures may use this term in a derogatory manner, these connotations are not present in South Africa, and are certainly not intended here.
doi:10.1371/journal.pone.0073971
PMCID: PMC3774743  PMID: 24066090
10.  Information Content-Based Gene Ontology Semantic Similarity Approaches: Toward a Unified Framework Theory 
BioMed Research International  2013;2013:292063.
Several approaches have been proposed for computing term information content (IC) and semantic similarity scores within the gene ontology (GO) directed acyclic graph (DAG). These approaches contributed to improving protein analyses at the functional level. Considering the recent proliferation of these approaches, a unified theory in a well-defined mathematical framework is necessary in order to provide a theoretical basis for validating these approaches. We review the existing IC-based ontological similarity approaches developed in the context of biomedical and bioinformatics fields to propose a general framework and unified description of all these measures. We have conducted an experimental evaluation to assess the impact of IC approaches, different normalization models, and correction factors on the performance of a functional similarity metric. Results reveal that considering only parents or only children of terms when assessing information content or semantic similarity scores negatively impacts the approach under consideration. This study produces a unified framework for current and future GO semantic similarity measures and provides theoretical basics for comparing different approaches. The experimental evaluation of different approaches based on different term information content models paves the way towards a solution to the issue of scoring a term's specificity in the GO DAG.
doi:10.1155/2013/292063
PMCID: PMC3775452  PMID: 24078912
11.  Predicting and Analyzing Interactions between Mycobacterium tuberculosis and Its Human Host 
PLoS ONE  2013;8(7):e67472.
The outcome of infection by Mycobacterium tuberculosis (Mtb) depends greatly on how the host responds to the bacteria and how the bacteria manipulates the host, which is facilitated by protein–protein interactions. Thus, to understand this process, there is a need for elucidating protein interactions between human and Mtb, which may enable us to characterize specific molecular mechanisms allowing the bacteria to persist and survive under different environmental conditions. In this work, we used the interologs method based on experimentally verified intra-species and inter-species interactions to predict human-Mtb functional interactions. These interactions were further filtered using known human-Mtb interactions and genes that are differentially expressed during infection, producing 190 interactions. Further analysis of the subcellular location of proteins involved in these human-Mtb interactions confirms feasibility of these interactions. We also conducted functional analysis of human and Mtb proteins involved in these interactions, checking whether these proteins play a role in infection and/or disease, and enriching Mtb proteins in a previously predicted list of drug targets. We found that the biological processes of the human interacting proteins suggested their involvement in apoptosis and production of nitric oxide, whereas those of the Mtb interacting proteins were relevant to the intracellular environment of Mtb in the host. Mapping these proteins onto KEGG pathways highlighted proteins belonging to the tuberculosis pathway and also suggested that Mtb proteins might use the host to acquire nutrients, which is in agreement with the intracellular lifestyle of Mtb. This indicates that these interactions can shed light on the interplay between Mtb and its human host and thus, contribute to the process of designing novel drugs with new biological mechanisms of action.
doi:10.1371/journal.pone.0067472
PMCID: PMC3699628  PMID: 23844013
12.  Best practices in bioinformatics training for life scientists 
Briefings in Bioinformatics  2013;14(5):528-537.
The mountains of data thrusting from the new landscape of modern high-throughput biology are irrevocably changing biomedical research and creating a near-insatiable demand for training in data management and manipulation and data mining and analysis. Among life scientists, from clinicians to environmental researchers, a common theme is the need not just to use, and gain familiarity with, bioinformatics tools and resources but also to understand their underlying fundamental theoretical and practical concepts. Providing bioinformatics training to empower life scientists to handle and analyse their data efficiently, and progress their research, is a challenge across the globe. Delivering good training goes beyond traditional lectures and resource-centric demos, using interactivity, problem-solving exercises and cooperative learning to substantially enhance training quality and learning outcomes. In this context, this article discusses various pragmatic criteria for identifying training needs and learning objectives, for selecting suitable trainees and trainers, for developing and maintaining training skills and evaluating training quality. Adherence to these criteria may help not only to guide course organizers and trainers on the path towards bioinformatics training excellence but, importantly, also to improve the training experience for life scientists.
doi:10.1093/bib/bbt043
PMCID: PMC3771230  PMID: 23803301
bioinformatics; training; bioinformatics courses; training life scientists; train the trainers
13.  iAnn: an event sharing platform for the life sciences 
Bioinformatics  2013;29(15):1919-1921.
Summary: We present iAnn, an open source community-driven platform for dissemination of life science events, such as courses, conferences and workshops. iAnn allows automatic visualisation and integration of customised event reports. A central repository lies at the core of the platform: curators add submitted events, and these are subsequently accessed via web services. Thus, once an iAnn widget is incorporated into a website, it permanently shows timely relevant information as if it were native to the remote site. At the same time, announcements submitted to the repository are automatically disseminated to all portals that query the system. To facilitate the visualization of announcements, iAnn provides powerful filtering options and views, integrated in Google Maps and Google Calendar. All iAnn widgets are freely available.
Availability: http://iann.pro/iannviewer
Contact: manuel.corpas@tgac.ac.uk
doi:10.1093/bioinformatics/btt306
PMCID: PMC3712218  PMID: 23742982
14.  Accumulation of Splice Variants and Transcripts in Response to PI3K Inhibition in T Cells 
PLoS ONE  2013;8(2):e50695.
Background
Measles virus (MV) causes T cell suppression by interference with phosphatidylinositol-3-kinase (PI3K) activation. We previously found that this interference affected the activity of splice regulatory proteins and a T cell inhibitory protein isoform was produced from an alternatively spliced pre-mRNA.
Hypothesis
Differentially regulated and alternatively splice variant transcripts accumulating in response to PI3K abrogation in T cells potentially encode proteins involved in T cell silencing.
Methods
To test this hypothesis at the cellular level, we performed a Human Exon 1.0 ST Array on RNAs isolated from T cells stimulated only or stimulated after PI3K inhibition. We developed a simple algorithm based on a splicing index to detect genes that undergo alternative splicing (AS) or are differentially regulated (RG) upon T cell suppression.
Results
Applying our algorithm to the data, 9% of the genes were assigned as AS, while only 3% were attributed to RG. Though there are overlaps, AS and RG genes differed with regard to functional regulation, and were found to be enriched in different functional groups. AS genes targeted extracellular matrix (ECM)-receptor interaction and focal adhesion pathways, while RG genes were mainly enriched in cytokine-receptor interaction and Jak-STAT. When combined, AS/RG dependent alterations targeted pathways essential for T cell receptor signaling, cytoskeletal dynamics and cell cycle entry.
Conclusions
PI3K abrogation interferes with key T cell activation processes through both differential expression and alternative splicing, which together actively contribute to T cell suppression.
doi:10.1371/journal.pone.0050695
PMCID: PMC3562341  PMID: 23383294
15.  Latent Tuberculosis: Models, Computational Efforts and the Pathogen’s Regulatory Mechanisms during Dormancy 
Latent tuberculosis is a clinical syndrome that occurs after an individual has been exposed to the Mycobacterium tuberculosis (Mtb) Bacillus, the infection has been established and an immune response has been generated to control the pathogen and force it into a quiescent state. Mtb can exit this quiescent state where it is unresponsive to treatment and elusive to the immune response, and enter a rapid replicating state, hence causing infection reactivation. It remains a gray area to understand how the pathogen causes a persistent infection and it is unclear whether the organism will be in a slow replicating state or a dormant non-replicating state. The ability of the pathogen to adapt to changing host immune response mechanisms, in which it is exposed to hypoxia, low pH, nitric oxide (NO), nutrient starvation, and several other anti-microbial effectors, is associated with a high metabolic plasticity that enables it to metabolize under these different conditions. Adaptive gene regulatory mechanisms are thought to coordinate how the pathogen changes their metabolic pathways through mechanisms that sense changes in oxygen tension and other stress factors, hence stimulating the pathogen to make necessary adjustments to ensure survival. Here, we review studies that give insights into latency/dormancy regulatory mechanisms that enable infection persistence and pathogen adaptation to different stress conditions. We highlight what mathematical and computational models can do and what they should do to enhance our current understanding of TB latency.
doi:10.3389/fbioe.2013.00004
PMCID: PMC4090907  PMID: 25023946
Mycobacterium tuberculosis; latency and dormancy regulation; latency models; mathematical and computational modeling
16.  MyDas, an Extensible Java DAS Server 
PLoS ONE  2012;7(9):e44180.
A large number of diverse, complex, and distributed data resources are currently available in the Bioinformatics domain. The pace of discovery and the diversity of information means that centralised reference databases like UniProt and Ensembl cannot integrate all potentially relevant information sources. From a user perspective however, centralised access to all relevant information concerning a specific query is essential. The Distributed Annotation System (DAS) defines a communication protocol to exchange annotations on genomic and protein sequences; this standardisation enables clients to retrieve data from a myriad of sources, thus offering centralised access to end-users.
We introduce MyDas, a web server that facilitates the publishing of biological annotations according to the DAS specification. It deals with the common functionality requirements of making data available, while also providing an extension mechanism in order to implement the specifics of data store interaction. MyDas allows the user to define where the required information is located along with its structure, and is then responsible for the communication protocol details.
doi:10.1371/journal.pone.0044180
PMCID: PMC3441562  PMID: 23028496
18.  A Topology-Based Metric for Measuring Term Similarity in the Gene Ontology 
Advances in Bioinformatics  2012;2012:975783.
The wide coverage and biological relevance of the Gene Ontology (GO), confirmed through its successful use in protein function prediction, have led to the growth in its popularity. In order to exploit the extent of biological knowledge that GO offers in describing genes or groups of genes, there is a need for an efficient, scalable similarity measure for GO terms and GO-annotated proteins. While several GO similarity measures exist, none adequately addresses all issues surrounding the design and usage of the ontology. We introduce a new metric for measuring the distance between two GO terms using the intrinsic topology of the GO-DAG, thus enabling the measurement of functional similarities between proteins based on their GO annotations. We assess the performance of this metric using a ROC analysis on human protein-protein interaction datasets and correlation coefficient analysis on the selected set of protein pairs from the CESSM online tool. This metric achieves good performance compared to the existing annotation-based GO measures. We used this new metric to assess functional similarity between orthologues, and show that it is effective at determining whether orthologues are annotated with similar functions and identifying cases where annotation is inconsistent between orthologues.
doi:10.1155/2012/975783
PMCID: PMC3361142  PMID: 22666244
19.  Manual GO annotation of predictive protein signatures: the InterPro approach to GO curation 
InterPro amalgamates predictive protein signatures from a number of well-known partner databases into a single resource. To aid with interpretation of results, InterPro entries are manually annotated with terms from the Gene Ontology (GO). The InterPro2GO mappings are comprised of the cross-references between these two resources and are the largest source of GO annotation predictions for proteins. Here, we describe the protocol by which InterPro curators integrate GO terms into the InterPro database. We discuss the unique challenges involved in integrating specific GO terms with entries that may describe a diverse set of proteins, and we illustrate, with examples, how InterPro hierarchies reflect GO terms of increasing specificity. We describe a revised protocol for GO mapping that enables us to assign GO terms to domains based on the function of the individual domain, rather than the function of the families in which the domain is found. We also discuss how taxonomic constraints are dealt with and those cases where we are unable to add any appropriate GO terms. Expert manual annotation of InterPro entries with GO terms enables users to infer function, process or subcellular information for uncharacterized sequences based on sequence matches to predictive models.
Database URL: http://www.ebi.ac.uk/interpro. The complete InterPro2GO mappings are available at: ftp://ftp.ebi.ac.uk/pub/databases/GO/goa/external2go/interpro2go
doi:10.1093/database/bar068
PMCID: PMC3270475  PMID: 22301074
20.  Generation and Analysis of Large-Scale Data-Driven Mycobacterium tuberculosis Functional Networks for Drug Target Identification 
Advances in Bioinformatics  2011;2011:801478.
Technological developments in large-scale biological experiments, coupled with bioinformatics tools, have opened the doors to computational approaches for the global analysis of whole genomes. This has provided the opportunity to look at genes within their context in the cell. The integration of vast amounts of data generated by these technologies provides a strategy for identifying potential drug targets within microbial pathogens, the causative agents of infectious diseases. As proteins are druggable targets, functional interaction networks between proteins are used to identify proteins essential to the survival, growth, and virulence of these microbial pathogens. Here we have integrated functional genomics data to generate functional interaction networks between Mycobacterium tuberculosis proteins and carried out computational analyses to dissect the functional interaction network produced for identifying drug targets using network topological properties. This study has provided the opportunity to expand the range of potential drug targets and to move towards optimal target-based strategies.
doi:10.1155/2011/801478
PMCID: PMC3235424  PMID: 22190924
21.  InterPro in 2011: new developments in the family and domain prediction database 
Nucleic Acids Research  2011;40(Database issue):D306-D312.
InterPro (http://www.ebi.ac.uk/interpro/) is a database that integrates diverse information about protein families, domains and functional sites, and makes it freely available to the public via Web-based interfaces and services. Central to the database are diagnostic models, known as signatures, against which protein sequences can be searched to determine their potential function. InterPro has utility in the large-scale analysis of whole genomes and meta-genomes, as well as in characterizing individual protein sequences. Herein we give an overview of new developments in the database and its associated software since 2009, including updates to database content, curation processes and Web and programmatic interfaces.
doi:10.1093/nar/gkr948
PMCID: PMC3245097  PMID: 22096229
22.  myKaryoView: A Light-Weight Client for Visualization of Genomic Data 
PLoS ONE  2011;6(10):e26345.
The Distributed Annotation System (DAS) is a protocol for easy sharing and integration of biological annotations. In order to visualize feature annotations in a genomic context a client is required. Here we present myKaryoView, a simple light-weight DAS tool for visualization of genomic annotation. myKaryoView has been specifically configured to help analyse data derived from personal genomics, although it can also be used as a generic genome browser visualization. Several well-known data sources are provided to facilitate comparison of known genes and normal variation regions. The navigation experience is enhanced by simultaneous rendering of different levels of detail across chromosomes. A simple interface is provided to allow searches for any SNP, gene or chromosomal region. User-defined DAS data sources may also be added when querying the system. We demonstrate myKaryoView capabilities for adding user-defined sources with a set of genetic profiles of family-related individuals downloaded directly from 23andMe. myKaryoView is a web tool for visualization of genomic data specifically designed for direct-to-consumer genomic data that uses publicly available data distributed throughout the Internet. It does not require data to be held locally and it is capable of rendering any feature as long as it conforms to DAS specifications. Configuration and addition of sources to myKaryoView can be done through the interface. Here we show a proof of principle of myKaryoView's ability to display personal genomics data with 23andMe genome data sources. The tool is available at: http://mykaryoview.com.
doi:10.1371/journal.pone.0026345
PMCID: PMC3202530  PMID: 22046276
23.  Dasty3, a WEB framework for DAS 
Bioinformatics  2011;27(18):2616-2617.
Motivation: Dasty3 is a highly interactive and extensible Web-based framework. It provides a rich Application Programming Interface upon which it is possible to develop specialized clients capable of retrieving information from DAS sources as well as from data providers not using the DAS protocol. Dasty3 provides significant improvements on previous Web-based frameworks and is implemented using the 1.6 DAS specification.
Availability: Dasty3 is an open-source tool freely available at http://www.ebi.ac.uk/dasty/ under the terms of the GNU General public license. Source and documentation can be found at http://code.google.com/p/dasty/.
Contact: hhe@ebi.ac.uk
doi:10.1093/bioinformatics/btr433
PMCID: PMC3167052  PMID: 21798964
24.  From sets to graphs: towards a realistic enrichment analysis of transcriptomic systems 
Bioinformatics  2011;27(13):i366-i373.
Motivation: Current gene set enrichment approaches do not take interactions and associations between set members into account. Mutual activation and inhibition causing positive and negative correlation among set members are thus neglected. As a consequence, inconsistent regulations and contextless expression changes are reported and, thus, the biological interpretation of the result is impeded.
Results: We analyzed established gene set enrichment methods and their result sets in a large-scale investigation of 1000 expression datasets. The reported statistically significant gene sets exhibit only average consistency between the observed patterns of differential expression and known regulatory interactions. We present Gene Graph Enrichment Analysis (GGEA) to detect consistently and coherently enriched gene sets, based on prior knowledge derived from directed gene regulatory networks. Firstly, GGEA improves the concordance of pairwise regulation with individual expression changes in respective pairs of regulating and regulated genes, compared with set enrichment methods. Secondly, GGEA yields result sets where a large fraction of relevant expression changes can be explained by nearby regulators, such as transcription factors, again improving on set-based methods. Thirdly, we demonstrate in additional case studies that GGEA can be applied to human regulatory pathways, where it sensitively detects very specific regulation processes, which are altered in tumors of the central nervous system. GGEA significantly increases the detection of gene sets where measured positively or negatively correlated expression patterns coincide with directed inducing or repressing relationships, thus facilitating further interpretation of gene expression data.
Availability: The method and accompanying visualization capabilities have been bundled into an R package and tied to a grahical user interface, the Galaxy workflow environment, that is running as a web server.
Contact: Ludwig.Geistlinger@bio.ifi.lmu.de; Ralf.Zimmer@bio.ifi.lmu.de
doi:10.1093/bioinformatics/btr228
PMCID: PMC3117393  PMID: 21685094
25.  DAS Writeback: A Collaborative Annotation System 
BMC Bioinformatics  2011;12:143.
Background
Centralised resources such as GenBank and UniProt are perfect examples of the major international efforts that have been made to integrate and share biological information. However, additional data that adds value to these resources needs a simple and rapid route to public access. The Distributed Annotation System (DAS) provides an adequate environment to integrate genomic and proteomic information from multiple sources, making this information accessible to the community. DAS offers a way to distribute and access information but it does not provide domain experts with the mechanisms to participate in the curation process of the available biological entities and their annotations.
Results
We designed and developed a Collaborative Annotation System for proteins called DAS Writeback. DAS writeback is a protocol extension of DAS to provide the functionalities of adding, editing and deleting annotations. We implemented this new specification as extensions of both a DAS server and a DAS client. The architecture was designed with the involvement of the DAS community and it was improved after performing usability experiments emulating a real annotation task.
Conclusions
We demonstrate that DAS Writeback is effective, usable and will provide the appropriate environment for the creation and evolution of community protein annotation.
doi:10.1186/1471-2105-12-143
PMCID: PMC3115852  PMID: 21569281

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