Dépliages et interprétation abstraite pour réseaux de régulation biologiques paramétrés

The analysis of dynamics of biological regulatory networks, notably signalling and gene regulatory networks, faces the uncertainty of the exact computational model. Indeed, most of the knowledge available concerns the existence of (possibly indirect) interactions between biological entities (species), e.g. proteins, RNAs, genes, etc. The details on how different regulators of a same target cooperate, and even more so on consistent rates for those interactions, however, are rarely available. In this regard, qualitative modelling approaches in the form of discrete regulatory networks, such as Boolean and Thomas networks, offer an appropriate level of abstraction for the biological regulatory network dynamics. As discrete regulatory networks are based on an influence graph, they require few additional parameters compared to classical quantitative models. Nevertheless, determining the discrete parameters is a well known challenge, and a major bottleneck for providing robust predictions from computational models.The influence graph of a regulatory network establishes dependencies for the evolution of each specie, specified by the directed edges of the graph. The dependencies alone, however, do not suffice to specify the logical function governing the evolution of a specie. Instead the logical functions associated to each specie, constrained by the influence graph, are encoded within the parameters of a discrete regulatory network. The space of admissible logical functions is then represented by a parametric regulatory network. On the one hand, parametric regulatory networks can be used for identification of parameter values for which the resulting discrete regulatory network satisfies given (dynamical) properties. Parameter identification of regulatory networks can thus be seen as a particular instance of model synthesis, in the constrained setting of the underlying influence graph. On the other hand, parametric regulatory networks may be analysed as a stand-alone model, for making predictions that are robust with respect to variability in the network.The analysis of parametric regulatory network dynamics is hampered by dual combinatorial explosion, of the state space and of the parameter space. In this thesis, we develop novel methods of parametric regulatory network analysis, in the form of specialised semantics, aimed at alleviating the combinatorial explosion. First, we introduce abstract interpretation for the set of admissible parameter evaluations (parametrisations).The abstraction allows us to represent any set of parametrisations by a constant size encoding, at the cost of a conservative over-approximation. Second, we lift partial order semantics in the form of unfolding from Petri nets to parametric regulatory networks. The influence graphs of biological regulatory networks tend to be relatively sparse, allowing for a lot of concurrency. This can be harnessed by partial order reduction methods to produce concise state space representations.The two approaches are aimed at tackling both aspects of the dual combinatorial explosion and are introduced in a compatible manner, allowing one to employ them simultaneously. Such application is supported by a prototype implementation used to conduct experiments on various parametric regulatory networks. We further consider refinements of the methods, such as an on-the-run model reduction method lifted to parametric regulatory networks from automata networks.L'analyse de la dynamique des réseaux de régulation biologique, notamment des réseaux de signalisation et de régulation génique, fait face à l'incertitude du modèle de calcul exact. En effet, la plupart des connaissances disponibles concernent l'existence d'interactions (éventuellement indirectes) entre des entités biologiques (espèces), par ex. protéines, ARN, gènes, etc. Les détails sur la manière dont les différents régulateurs d'une même cible coopèrent, et plus encore sur les taux cohérents pour ces interactions, sont cependant rarement disponibles. A cet égard, des approches de modélisation qualitative sous forme de réseaux de régulation discrets, tels que les réseaux booléens et Thomas, offrir un niveau d'abstraction approprié pour la dynamique du réseau de régulation biologique. Les réseaux de régulation discrets étant basés sur un graphe d'influence, ils nécessitent peu de paramètres supplémentaires par rapport aux modèles quantitatifs classiques. Néanmoins, la détermination des paramètres discrets est un défi bien connu et un goulot d'étranglement majeur pour fournir des prédictions robustes à partir de modèles informatiques.Le graphe d'influence d'un réseau de régulation établit des dépendances pour l'évolution de chaque espèce, spécifiées par les arêtes dirigées du graphe. Les dépendances seules, cependant, ne suffisent pas pour spécifier la fonction logique régissant l'évolution d'une espèce. Au lieu de cela, les fonctions logiques associées à chaque espèce, contraintes par le graphe d'influence, sont codées dans les paramètres d'un réseau de régulation discret. L'espace des fonctions logiques admissibles est alors représenté par un réseau de régulation paramétrique. D'une part, les réseaux de régulation paramétriques peuvent être utilisés pour l'identification de valeurs de paramètres pour lesquelles le réseau de régulation discret résultant satisfait des propriétés (dynamiques) données. L'identification des paramètres des réseaux de régulation peut ainsi être vue comme un exemple particulier de synthèse de modèle, dans le cadre contraint du graphe d'influence sous-jacent. D'autre part, les réseaux de régulation paramétriques peuvent être analysés comme un modèle autonome, pour faire des prédictions robustes vis-à-vis de la variabilité du réseau.L'analyse de la dynamique du réseau de régulation paramétrique est entravée par la double explosion combinatoire, de l'espace d'états et de l'espace des paramètres. Dans cette thèse, nous développons de nouvelles méthodes d'analyse de réseau de régulation paramétrique, sous forme de sémantique spécialisée, visant à atténuer l'explosion combinatoire. Tout d'abord, nous introduisons une interprétation abstraite de l'ensemble des évaluations de paramètres admissibles (paramétrisations). L'abstraction permet de représenter n'importe quel ensemble de paramétrisations par un encodage de taille constante, au prix d'une sur-approximation conservatrice. Deuxièmement, nous élevons la sémantique d'ordre partiel sous la forme d'un déploiement des réseaux de Petri vers des réseaux de régulation paramétriques. Les graphiques d'influence des réseaux de régulation biologique ont tendance à être relativement clairsemés, ce qui permet une grande concurrence. Cela peut être exploité par des méthodes de réduction d'ordre partiel pour produire des représentations d'espace d'état concises.Les deux approches visent à aborder les deux aspects de la double explosion combinatoire et sont introduites de manière compatible, ce qui permet de les utiliser simultanément. Une telle application est soutenue par une implémentation prototype utilisée pour mener des expériences sur divers réseaux de régulation paramétriques. Nous considérons en outre des raffinements des méthodes, comme une méthode de réduction de modèle à la volée portée aux réseaux de régulation paramétriques à partir de réseaux d'automates

Therapeutic target discovery using Boolean network attractors: avoiding pathological phenotypes

Target identification, one of the steps of drug discovery, aims at identifying biomolecules whose function should be therapeutically altered in order to cure the considered pathology. This work proposes an algorithm for in silico target identification using Boolean network attractors. It assumes that attractors of dynamical systems, such as Boolean networks, correspond to phenotypes produced by the modeled biological system. Under this assumption, and given a Boolean network modeling a pathophysiology, the algorithm identifies target combinations able to remove attractors associated with pathological phenotypes. It is tested on a Boolean model of the mammalian cell cycle bearing a constitutive inactivation of the retinoblastoma protein, as seen in cancers, and its applications are illustrated on a Boolean model of Fanconi anemia. The results show that the algorithm returns target combinations able to remove attractors associated with pathological phenotypes and then succeeds in performing the proposed in silico target identification. However, as with any in silico evidence, there is a bridge to cross between theory and practice, thus requiring it to be used in combination with wet lab experiments. Nevertheless, it is expected that the algorithm is of interest for target identification, notably by exploiting the inexpensiveness and predictive power of computational approaches to optimize the efficiency of costly wet lab experiments.Comment: Since the publication of this article and among the possible improvements mentioned in the Conclusion, two improvements have been done: extending the algorithm for multivalued logic and considering the basins of attraction of the pathological attractors for selecting the therapeutic bullet

Most Permissive Semantics of Boolean Networks

As shown in (http://dx.doi.org/10.1101/2020.03.22.998377), the usual update modes of Boolean networks (BNs), including synchronous and (generalized) asynchronous, fail to capture behaviors introduced by multivalued refinements. Thus, update modes do not allow a correct abstract reasoning on dynamics of biological systems, as they may lead to reject valid BN models.This technical report lists the main definitions and properties of the most permissive semantics of BNs introduced in http://dx.doi.org/10.1101/2020.03.22.998377. This semantics meets with a correct abstraction of any multivalued refinements, with any update mode. It subsumes all the usual updating modes, while enabling new behaviors achievable by more concrete models. Moreover, it appears that classical dynamical analyzes of reachability and attractors have a simpler computational complexity:- reachability can be assessed in a polynomial number of iterations. The computation of iterations is in NP in the very general case, and is linear when local functions are monotonic, or with some usual representations of functions of BNs (binary decision diagrams, Petri nets, automata networks, etc.). Thus, reachability is in P with locally-monotonic BNs, and P$^{\text{NP}}$ otherwise (instead of being PSPACE-complete with update modes);- deciding wherever a configuration belongs to an attractor is in coNP with locally-monotonic BNs, and coNP$^{\text{coNP}}$ otherwise (instead of PSPACE-complete with update modes).Furthermore, we demonstrate that the semantics completely captures any behavior achievable with any multilevel or ODE refinement of the BN; and the semantics is minimal with respect to this model refinement criteria: to any most permissive trajectory, there exists a multilevel refinement of the BN which can reproduce it.In brief, the most permissive semantics of BNs enables a correct abstract reasoning on dynamics of BNs, with a greater tractability than previously introduced update modes

Analyzing Large Network Dynamics with Process Hitting

In this chapter, we introduce the Process Hitting framework, which provides the methodology of constructing the most permissive dynamics and then using successive refinements to fine tune the model. We present static analysis methods designed to identify fixed points or answer successive reachability questions, and introduce the stochastic semantics of Process Hitting too

Equilibria, Fixed Points, and Complexity Classes

Many models from a variety of areas involve the computation of an equilibrium or fixed point of some kind. Examples include Nash equilibria in games; market equilibria; computing optimal strategies and the values of competitive games (stochastic and other games); stable configurations of neural networks; analysing basic stochastic models for evolution like branching processes and for language like stochastic context-free grammars; and models that incorporate the basic primitives of probability and recursion like recursive Markov chains. It is not known whether these problems can be solved in polynomial time. There are certain common computational principles underlying different types of equilibria, which are captured by the complexity classes PLS, PPAD, and FIXP. Representative complete problems for these classes are respectively, pure Nash equilibria in games where they are guaranteed to exist, (mixed) Nash equilibria in 2-player normal form games, and (mixed) Nash equilibria in normal form games with 3 (or more) players. This paper reviews the underlying computational principles and the corresponding classes

A review of modelling and verification approaches for computational biology

This paper reviews most frequently used computational modelling approaches and formal verification techniques in computational biology. The paper also compares a number of model checking tools and software suits used in analysing biological systems and biochemical networks and verifiying a wide range of biological properties

Logical modeling of the mammalian cell cycle

Proper understanding of the behavior of complex biological regulatory networks requires the integration of heterogeneous data into predictive mathematical models. Logical modeling focuses on qualitative data and offers a flexible framework to delineate the main dynamical properties of such networks. However, formal analysis faces a combinatorial explosion as the number of regulatory components and interactions increases. Here, we show how model-checking techniques can be used to verify sophisticated dynamical properties resulting from model regulatory structure. We demonstrate the power of this approach through the updating of a model of the molecular network controlling mammalian cell cycle. We use model-checking to progressively refine this model in order to fit recent experimental observations. The resulting model accounts for the sequential activation of cyclins, the role of Skp2, and emphasizes a multifunctional role for the cell cycle inhibitor Rb

Component-wise incremental LTL model checking

Efficient symbolic and explicit-state model checking approaches have been developed for the verification of linear time temporal logic (LTL) properties. Several attempts have been made to combine the advantages of the various algorithms. Model checking LTL properties usually poses two challenges: one must compute the synchronous product of the state space and the automaton model of the desired property, then look for counterexamples that is reduced to finding strongly connected components (SCCs) in the state space of the product. In case of concurrent systems, where the phenomenon of state space explosion often prevents the successful verification, the so-called saturation algorithm has proved its efficiency in state space exploration. This paper proposes a new approach that leverages the saturation algorithm both as an iteration strategy constructing the product directly, as well as in a new fixed-point computation algorithm to find strongly connected components on-the-fly by incrementally processing the components of the model. Complementing the search for SCCs, explicit techniques and component-wise abstractions are used to prove the absence of counterexamples. The resulting on-the-fly, incremental LTL model checking algorithm proved to scale well with the size of models, as the evaluation on models of the Model Checking Contest suggests

Logical model specification aided by model- checking techniques: application to the mammalian cell cycle regulation

International audienc