Evolutionary Dynamics in Gene Networks and Inference Algorithms

Dynamical interactions among sets of genes (and their products) regulate developmental processes and some dynamical diseases, like cancer. Gene regulatory networks (GRNs) are directed networks that define interactions (links) among different genes/proteins involved in such processes. Genetic regulation can be modified during the time course of the process, which may imply changes in the nodes activity that leads the system from a specific state to a different one at a later time (dynamics). How the GRN modifies its topology, to properly drive a developmental process, and how this regulation was acquired across evolution are questions that the evolutionary dynamics of gene networks tackles. In the present work we review important methodology in the field and highlight the combination of these methods with evolutionary algorithms. In recent years, this combination has become a powerful tool to fit models with the increasingly available experimental data.Junta de Andalucía FQM-12

Refining Ensembles of Predicted Gene Regulatory Networks Based on Characteristic Interaction Sets

Different ensemble voting approaches have been successfully applied for reverse-engineering of gene regulatory networks. They are based on the assumption that a good approximation of true network structure can be derived by considering the frequencies of individual interactions in a large number of predicted networks. Such approximations are typically superior in terms of prediction quality and robustness as compared to considering a single best scoring network only. Nevertheless, ensemble approaches only work well if the predicted gene regulatory networks are sufficiently similar to each other. If the topologies of predicted networks are considerably different, an ensemble of all networks obscures interesting individual characteristics. Instead, networks should be grouped according to local topological similarities and ensemble voting performed for each group separately. We argue that the presence of sets of co-occurring interactions is a suitable indicator for grouping predicted networks. A stepwise bottom-up procedure is proposed, where first mutual dependencies between pairs of interactions are derived from predicted networks. Pairs of co-occurring interactions are subsequently extended to derive characteristic interaction sets that distinguish groups of networks. Finally, ensemble voting is applied separately to the resulting topologically similar groups of networks to create distinct group-ensembles. Ensembles of topologically similar networks constitute distinct hypotheses about the reference network structure. Such group-ensembles are easier to interpret as their characteristic topology becomes clear and dependencies between interactions are known. The availability of distinct hypotheses facilitates the design of further experiments to distinguish between plausible network structures. The proposed procedure is a reasonable refinement step for non-deterministic reverse-engineering applications that produce a large number of candidate predictions for a gene regulatory network, e. g. due to probabilistic optimization or a cross-validation procedure

Detection of network motifs using three-way ANOVA

Motivation Gene regulatory networks (GRN) can be determined via various experimental techniques, and also by computational methods, which infer networks from gene expression data. However, these techniques treat interactions separately such that interdependencies of interactions forming meaningful subnetworks are typically not considered. Methods For the investigation of network properties and for the classification of different (sub-) networks based on gene expression data, we consider biological network motifs consisting of three genes and up to three interactions, e.g. the cascade chain (CSC), feed-forward loop (FFL), and dense-overlapping regulon (DOR). We examine several conventional methods for the inference of network motifs, which typically consider each interaction individually. In addition, we propose a new method based on three-way ANOVA (ANalysis Of VAriance) (3WA) that analyzes entire subnetworks at once. To demonstrate the advantages of such a more holistic perspective, we compare the ability of 3WA and other methods to detect and categorize network motifs on large real and artificial datasets. Results We find that conventional methods perform much better on artificial data (AUC up to 80%), than on real E. coli expression datasets (AUC 50% corresponding to random guessing). To explain this observation, we examine several important properties that differ between datasets and analyze predicted motifs in detail. We find that in case of real networks our new 3WA method outperforms (AUC 70% in E. coli) previous methods by exploiting the interdependencies in the full motif structure. Because of important differences between current artificial datasets and real measurements, the construction and testing of motif detection methods should focus on real data

Reverse engieering gene regulatory networks: Elucidation of trancriptome organization, gene function and gene regulation in mammalian systems

The main aim of this thesis was to infer mammalian gene regulatory networks from tens of thousands gene expression profiles via a new "reverse-engineering" approach. Human arid Mouse gene regulatory networks were both inferred and the results collected in a database that represents part of the non-written material that will support. the thesis (http: //rretview. tigem. it). Each gene regulatory network consists of a set of gene pairs (connections) and a score based on Mutual Information, which states their statistical dependence. The inferred connections are organized into a network that allows exploration of the global features of gene regulation in a mammalian cell. We collected a massive and heterogeneous dataset of 22,255 gene expression profiles from a variety of human samples and experimental conditions. We developed a new mutual-information (MI) reverse-engineering approach able to quantify the extent to which the mRNA levels of two genes are related to each other across such a complex dataset. The resulting network consists of 4,817,629 connections among 22,255 transcripts. The inferred connections were compared against known protein-protein and other regulatory interactions to assess their biological significance. We experimentally identified a subset of predicted protein-protein interactions not previously described in the literature. We discovered regulatory modules within the network, consisting of genes strongly connected to each other, which carry out specific biological functions. We found that these connected genes tend to be in physical proximity at the chromatin level in the nucleus. We show that the network can be used to predict the biological function and subcellular localization of a protein, and to elucidate the function of a disease-gene. Specifically we discovered that the gene granulin precursor GRN), whose mutations cause frontotemporal lobar degeneration, is involved in lysosome function. We have developed an online tool (http://netview.tigem.it) for querying and exploring the gene regulatory network

INTEGRATED GENOMIC MARKERS FOR CHEMOTHERAPEUTICS

Ph.DDOCTOR OF PHILOSOPH

Regulatory network discovery using heuristics

This thesis improves the GRN discovery process by integrating heuristic information via a co-regulation function, a post-processing procedure, and a Hub Network algorithm to build the backbone of the network.Doctor of Philosoph