A proposal for using the ensemble approach to understand genetic regulatory networks.

Understanding the genetic regulatory network comprising genes, RNA, proteins and the network connections and dynamical control rules among them, is a major task of contemporary systems biology. I focus here on the use of the ensemble approach to find one or more well-defined ensembles of model networks whose statistical features match those of real cells and organisms. Such ensembles should help explain and predict features of real cells and organisms. More precisely, an ensemble of model networks is defined by constraints on the "wiring diagram" of regulatory interactions, and the "rules" governing the dynamical behavior of regulated components of the network. The ensemble consists of all networks consistent with those constraints. Here I discuss ensembles of random Boolean networks, scale free Boolean networks, "medusa" Boolean networks, continuous variable networks, and others. For each ensemble, M statistical features, such as the size distribution of avalanches in gene activity changes unleashed by transiently altering the activity of a single gene, the distribution in distances between gene activities on different cell types, and others, are measured. This creates an M-dimensional space, where each ensemble corresponds to a cluster of points or distributions. Using current and future experimental techniques, such as gene arrays, these M properties are to be measured for real cells and organisms, again yielding a cluster of points or distributions in the M-dimensional space. The procedure then finds ensembles close to those of real cells and organisms, and hill climbs to attempt to match the observed M features. Thus obtains one or more ensembles that should predict and explain many features of the regulatory networks in cells and organisms.