Network Analysis and Modeling in Systems Biology

Abstract

This thesis is dedicated to the study and comprehension of biological networks at the molecular level. The objectives were to analyse their topology, integrate it in a genotype-phenotype analysis, develop richer mathematical descriptions for them, study their community structure and compare different methodologies for estimating their internal fluxes. The work presented in this document moves around three main axes. The first one is the biological. Which organisms were studied in this thesis? They range from the simplest biological agents, the viruses, in this case the Potyvirus genus to prokariotes such as Escherichia coli and complex eukariotes (Arabidopsis thaliana, Nicotiana benthamiana). The second axis refers to which biological networks were studied. Those are protein-protein interaction (PPIN) and metabolic networks (MN). The final axis relates to the mathematical and modelling tools used to generate knowledge from those networks. These tools can be classify in three main branches: graph theory, constraint-based modelling and multivariate statistics. The document is structured in six parts. The first part states the justification for the thesis, exposes a general thesis roadmap and enumerates its main contributions. In the second part important literature is reviewed, summarized and integrated. From the birth and development of Systems Biology to one of its most popular branches: biological network analysis. Particular focus is put on PPIN and MN and their structure, representations and features. Finally a general overview of the mathematical tools used is presented. The third, fourth and fifth parts represent the central work of this thesis. They deal respectively with genotypephenotype interaction and classical network analysis, constraint-based modelling methods comparison and modelling metabolic networks and community structure. Finally, in the sixth part the main conclusions of the thesis are summarized and enumerated. This thesis highlights the vital importance of studying biological entities as systems and how powerful and promising this integrated analysis is. Particularly, network analysis becomes a fundamental avenue of research to gain insight into those biological systems and to extract, integrate and display this new information. It generates knowledge from just data.; Esta tesis esta dedicada al estudio y comprension de redes biologicas a nivel molecular. Los objetivos fueron analizar su topologia, integrar esta en un analisis de genotipo-fenotipo, desarrollar descripciones matematicas mas completas para ellas, estudiar su estructura de comunidades y comparar diferentes metodologias para estimar sus flujos internos. El trabajo presentado en este documento gira entorno a tres ejes principales. El primero es el biologico. ?Que organismos han sido estudiados en esta tesis? Estos van desde los agentes biologicos mas simples, los virus, en este caso el genero Potyvirus, hasta procariotas como Escherichia coli y eucariotas complejos (Arabidopsis thaliana, Nicotiana benthamiana). El segundo eje…