Formalizing and enriching phenotype signatures using Boolean networks

Abstract

In order to predict the behavior of a biological system, one common approach is to perform a simulation on a dynamic model. Boolean networks allow to analyze the qualitative aspects of the model by identifying its steady states and attractors. Each of them, when possible, is associated with a phenotype which conveys a biological interpretation. Phenotypes are characterized by their signatures, provided by domain experts. The number of steady states tends to increase with the network size and the number of simulation conditions, which makes the biological interpretation difficult. As a first step, we explore the use of Formal Concept Analysis as a symbolic bi-clustering technics to classify and sort the steady states of a Boolean network according to biological signatures based on the hierarchy of the roles the network components play in the phenotypes. FCA generates a lattice structure describing the dependencies between proteins in the signature and steady-states of the Boolean network. We use this lattice (i) to enrich the biological signatures according to the dependencies carried by the network dynamics, (ii) to identify variants to the phenotypes and (iii) to characterize hybrid phenotypes. We applied our approach on a T helper lymphocyte (Th) differentiation network with a set of signatures corresponding to the sub-types of Th. Our method generated the same classification as a manual analysis performed by experts in the field, and was also able to work under extended simulation conditions. This led to the identification and prediction of a new hybrid sub-type later confirmed by the literature.

Keywords: Boolean networks; Dynamic models; Formal concept analysis; Phenotype signature; Steady state.