Reconstructing biological gene regulatory networks: where optimization meets big data

Many complex systems, such as communication networks, display a surprising degree of robustness: while key components regularly malfunction, local failures rarely lead to the loss of the global information-carrying ability of the network. The stability of these complex systems is often attributed to the redundant wiring of the functional web defined by the systems' components. In this paper we demonstrate that error tolerance is not shared by all redundant systems, but it is displayed only by a class of inhomogeneously wired networks, called scale-free networks. We find that scale-free networks, describing a number of systems, such as the World Wide Web, Internet, social networks or a cell, display an unexpected degree of robustness, the ability of their nodes to communicate being unaffected by even unrealistically high failure rates. However, error tolerance comes at a high price: these networks are extremely vulnerable to attacks, i.e. to the selection and removal of a few nodes that play the most important role in assuring the network's connectivity.

Little is known about the design principles of transcriptional regulation networks that control gene expression in cells. Recent advances in data collection and analysis, however, are generating unprecedented amounts of information about gene regulation networks. To understand these complex wiring diagrams, we sought to break down such networks into basic building blocks. We generalize the notion of motifs, widely used for sequence analysis, to the level of networks. We define 'network motifs' as patterns of interconnections that recur in many different parts of a network at frequencies much higher than those found in randomized networks. We applied new algorithms for systematically detecting network motifs to one of the best-characterized regulation networks, that of direct transcriptional interactions in Escherichia coli. We find that much of the network is composed of repeated appearances of three highly significant motifs. Each network motif has a specific function in determining gene expression, such as generating temporal expression programs and governing the responses to fluctuating external signals. The motif structure also allows an easily interpretable view of the entire known transcriptional network of the organism. This approach may help define the basic computational elements of other biological networks.

In order to understand the functioning of organisms on the molecular level, we need to know which genes are expressed, when and where in the organism, and to which extent. The regulation of gene expression is achieved through genetic regulatory systems structured by networks of interactions between DNA, RNA, proteins, and small molecules. As most genetic regulatory networks of interest involve many components connected through interlocking positive and negative feedback loops, an intuitive understanding of their dynamics is hard to obtain. As a consequence, formal methods and computer tools for the modeling and simulation of genetic regulatory networks will be indispensable. This paper reviews formalisms that have been employed in mathematical biology and bioinformatics to describe genetic regulatory systems, in particular directed graphs, Bayesian networks, Boolean networks and their generalizations, ordinary and partial differential equations, qualitative differential equations, stochastic equations, and rule-based formalisms. In addition, the paper discusses how these formalisms have been used in the simulation of the behavior of actual regulatory systems.