Reconstruction of Causal Networks by Set Covering

We present a method for the reconstruction of networks, based on the order of nodes visited by a stochastic branching process. Our algorithm reconstructs a network of minimal size that ensures consistency with the data. Crucially, we show that global consistency with the data can be achieved through purely local considerations, inferring the neighbourhood of each node in turn. The optimisation problem solved for each individual node can be reduced to a Set Covering Problem, which is known to be NP-hard but can be approximated well in practice. We then extend our approach to account for noisy data, based on the Minimum Description Length principle. We demonstrate our algorithms on synthetic data, generated by an SIR-like epidemiological model.Comment: Under consideration for the ECML PKDD 2010 conferenc

Adaptive evolution of transcription factor binding sites

The regulation of a gene depends on the binding of transcription factors to specific sites located in the regulatory region of the gene. The generation of these binding sites and of cooperativity between them are essential building blocks in the evolution of complex regulatory networks. We study a theoretical model for the sequence evolution of binding sites by point mutations. The approach is based on biophysical models for the binding of transcription factors to DNA. Hence we derive empirically grounded fitness landscapes, which enter a population genetics model including mutations, genetic drift, and selection. We show that the selection for factor binding generically leads to specific correlations between nucleotide frequencies at different positions of a binding site. We demonstrate the possibility of rapid adaptive evolution generating a new binding site for a given transcription factor by point mutations. The evolutionary time required is estimated in terms of the neutral (background) mutation rate, the selection coefficient, and the effective population size. The efficiency of binding site formation is seen to depend on two joint conditions: the binding site motif must be short enough and the promoter region must be long enough. These constraints on promoter architecture are indeed seen in eukaryotic systems. Furthermore, we analyse the adaptive evolution of genetic switches and of signal integration through binding cooperativity between different sites. Experimental tests of this picture involving the statistics of polymorphisms and phylogenies of sites are discussed.Comment: published versio