GenePath: a System for Automated Construction of Genetic Networks from Mutant Data

Motivation: Genetic pathways are often used in the analysis of biological phenomena. In classical genetics, they are constructed manually from experimental data on mutants. The field lacks formalism to guide such analysis, and accounting for all the data becomes complicated when large amounts of data are considered. Results: We have developed GenePath, an intelligent assistant that mimics expert geneticists in the analysis of genetic data. GenePath employs expert-defined patterns to uncover gene relations from the data, and uses these relations as constraints that guide the search for a plausible genetic network. GenePath provides formalism to genetic data analysis, facilitates the consideration of all the available data in a consistent and systematic manner, and aids in the examination of the large number of possible consequences of a planned experiment. It also provides an explanation mechanism that traces back every finding to the pertinent data. GenePath was successfully tested on several genetic problems. Availability: GenePath can be accessed at http://genepath.org. Supplementary information: Supplementary material is available at http://genepath.org/bi-supp

Evolutionary Neural Gas (ENG): A Model of Self Organizing Network from Input Categorization

Despite their claimed biological plausibility, most self organizing networks have strict topological constraints and consequently they cannot take into account a wide range of external stimuli. Furthermore their evolution is conditioned by deterministic laws which often are not correlated with the structural parameters and the global status of the network, as it should happen in a real biological system. In nature the environmental inputs are noise affected and fuzzy. Which thing sets the problem to investigate the possibility of emergent behaviour in a not strictly constrained net and subjected to different inputs. It is here presented a new model of Evolutionary Neural Gas (ENG) with any topological constraints, trained by probabilistic laws depending on the local distortion errors and the network dimension. The network is considered as a population of nodes that coexist in an ecosystem sharing local and global resources. Those particular features allow the network to quickly adapt to the environment, according to its dimensions. The ENG model analysis shows that the net evolves as a scale-free graph, and justifies in a deeply physical sense- the term gas here used.Comment: 16 pages, 8 figure

Systems Biology Graphical Notation: Entity Relationship language Level 1

Standard graphical representations have played a crucial role in science and engineering throughout the last century. Without electrical symbolism, it is very likely that our industrial society would not have evolved at the same pace. Similarly, specialised notations such as the Feynmann notation or the process flow diagrams did a lot for the adoption of concepts in their own fields. With the advent of Systems Biology, and more recently of Synthetic Biology, the need for precise and unambiguous descriptions of biochemical interactions has become more pressing. While some ideas have been advanced over the last decade, with a few detailed proposals, no actual community standard has emerged. The Systems Biology Graphical Notation (SBGN) is a graphical representation crafted over several years by a community of biochemists, modellers and computer scientists. Three orthogonal and complementary languages have been created, the Process Descriptions, the Entity Relationships and the Activity Flows. Using these three idioms a scientist can represent any network of biochemical interactions, which can then be interpreted in an unambiguous way. The set of symbols used is limited, and the grammar quite simple, to allow its usage in textbooks and its teaching directly in high schools. The first level of the SBGN Entity Relationship language has been publicly released. Shared by the communities of biochemists, genomicians, theoreticians and computational biologists, SBGN languages will foster efficient storage, exchange and reuse of information on signalling pathways, metabolic networks and gene regulatory maps

GUBS, a Behavior-based Language for Open System Dedicated to Synthetic Biology

In this article, we propose a domain specific language, GUBS (Genomic Unified Behavior Specification), dedicated to the behavioral specification of synthetic biological devices, viewed as discrete open dynamical systems. GUBS is a rule-based declarative language. By contrast to a closed system, a program is always a partial description of the behavior of the system. The semantics of the language accounts the existence of some hidden non-specified actions possibly altering the behavior of the programmed device. The compilation framework follows a scheme similar to automatic theorem proving, aiming at improving synthetic biological design safety.Comment: In Proceedings MeCBIC 2012, arXiv:1211.347

Integrating Symbolic and Neural Processing in a Self-Organizing Architechture for Pattern Recognition and Prediction

British Petroleum (89A-1204); Defense Advanced Research Projects Agency (N00014-92-J-4015); National Science Foundation (IRI-90-00530); Office of Naval Research (N00014-91-J-4100); Air Force Office of Scientific Research (F49620-92-J-0225

Systems Biology Graphical Notation: Entity Relationship language Level 1 (Version 1.2)

Standard graphical representations have played a crucial role in science and engineering throughout the last century. Without electrical symbolism, it is very likely that our industrial society would not have evolved at the same pace. Similarly, specialised notations such as the Feynmann notation or the process flow diagrams did a lot for the adoption of concepts in their own fields. With the advent of Systems Biology, and more recently of Synthetic Biology, the need for precise and unambiguous descriptions of biochemical interactions has become more pressing. While some ideas have been advanced over the last decade, with a few detailed proposals, no actual community standard has emerged. The Systems Biology Graphical Notation (SBGN) is a graphical representation crafted over several years by a community of biochemists, modellers and computer scientists. Three orthogonal and complementary languages have been created, the Process Descriptions, the Entity Relationships and the Activity Flows. Using these three idioms a scientist can represent any network of biochemical interactions, which can then be interpreted in an unambiguous way. The set of symbols used is limited, and the grammar quite simple, to allow its usage in textbooks and its teaching directly in high schools. The current document presents version 1.2 of the first level of the SBGN Entity Relationship language. Shared by the communities of biochemists, genomicians, theoreticians and computational biologists, SBGN languages will foster efficient storage, exchange and reuse of information on signaling pathways, metabolic networks and gene regulatory maps

Mapping genetic interactions in cancer: a road to rational combination therapies.

The discovery of synthetic lethal interactions between poly (ADP-ribose) polymerase (PARP) inhibitors and BRCA genes, which are involved in homologous recombination, led to the approval of PARP inhibition as a monotherapy for patients with BRCA1/2-mutated breast or ovarian cancer. Studies following the initial observation of synthetic lethality demonstrated that the reach of PARP inhibitors is well beyond just BRCA1/2 mutants. Insights into the mechanisms of action of anticancer drugs are fundamental for the development of targeted monotherapies or rational combination treatments that will synergize to promote cancer cell death and overcome mechanisms of resistance. The development of targeted therapeutic agents is premised on mapping the physical and functional dependencies of mutated genes in cancer. An important part of this effort is the systematic screening of genetic interactions in a variety of cancer types. Until recently, genetic-interaction screens have relied either on the pairwise perturbations of two genes or on the perturbation of genes of interest combined with inhibition by commonly used anticancer drugs. Here, we summarize recent advances in mapping genetic interactions using targeted, genome-wide, and high-throughput genetic screens, and we discuss the therapeutic insights obtained through such screens. We further focus on factors that should be considered in order to develop a robust analysis pipeline. Finally, we discuss the integration of functional interaction data with orthogonal methods and suggest that such approaches will increase the reach of genetic-interaction screens for the development of rational combination therapies