A Parallel Attractor Finding Algorithm Based on Boolean Satisfiability for Genetic Regulatory Networks

In biological systems, the dynamic analysis method has gained increasing attention in the past decade. The Boolean network is the most common model of a genetic regulatory network. The interactions of activation and inhibition in the genetic regulatory network are modeled as a set of functions of the Boolean network, while the state transitions in the Boolean network reflect the dynamic property of a genetic regulatory network. A difficult problem for state transition analysis is the finding of attractors. In this paper, we modeled the genetic regulatory network as a Boolean network and proposed a solving algorithm to tackle the attractor finding problem. In the proposed algorithm, we partitioned the Boolean network into several blocks consisting of the strongly connected components according to their gradients, and defined the connection between blocks as decision node. Based on the solutions calculated on the decision nodes and using a satisfiability solving algorithm, we identified the attractors in the state transition graph of each block. The proposed algorithm is benchmarked on a variety of genetic regulatory networks. Compared with existing algorithms, it achieved similar performance on small test cases, and outperformed it on larger and more complex ones, which happens to be the trend of the modern genetic regulatory network. Furthermore, while the existing satisfiability-based algorithms cannot be parallelized due to their inherent algorithm design, the proposed algorithm exhibits a good scalability on parallel computing architectures.

[1]  Giovanni De Micheli,et al.  An Efficient Method for Dynamic Analysis of Gene Regulatory Networks and in silico Gene Perturbation Experiments , 2007, RECOMB.

[2]  Harold N. Gabow,et al.  Path-based depth-first search for strong and biconnected components , 2000, Inf. Process. Lett..

[3]  Donald B. Johnson,et al.  Finding All the Elementary Circuits of a Directed Graph , 1975, SIAM J. Comput..

[4]  M. Aldana Boolean dynamics of networks with scale-free topology , 2003 .

[5]  Armin Biere,et al.  Bounded Model Checking Using Satisfiability Solving , 2001, Formal Methods Syst. Des..

[6]  M. Aldana,et al.  From Genes to Flower Patterns and Evolution: Dynamic Models of Gene Regulatory Networks , 2006, Journal of Plant Growth Regulation.

[7]  Steffen Klamt,et al.  A methodology for the structural and functional analysis of signaling and regulatory networks , 2006, BMC Bioinformatics.

[8]  D. Cheng,et al.  Analysis and control of Boolean networks: A semi-tensor product approach , 2010, 2009 7th Asian Control Conference.

[9]  S. Kauffman Metabolic stability and epigenesis in randomly constructed genetic nets. , 1969, Journal of theoretical biology.

[10]  E. Chautard,et al.  Interaction networks: from protein functions to drug discovery. A review. , 2009, Pathologie-biologie.

[11]  Randal E. Bryant,et al.  Graph-Based Algorithms for Boolean Function Manipulation , 1986, IEEE Transactions on Computers.

[12]  E A Leicht,et al.  Community structure in directed networks. , 2007, Physical review letters.

[13]  H. Othmer,et al.  The topology of the regulatory interactions predicts the expression pattern of the segment polarity genes in Drosophila melanogaster. , 2003, Journal of theoretical biology.

[14]  Tatsuya Akutsu,et al.  Finding a Periodic Attractor of a Boolean Network , 2012, IEEE/ACM Transactions on Computational Biology and Bioinformatics.

[15]  Francesco Masulli,et al.  A survey of kernel and spectral methods for clustering , 2008, Pattern Recognit..

[16]  Narsingh Deo,et al.  On Algorithms for Enumerating All Circuits of a Graph , 1976, SIAM J. Comput..

[17]  Hidde de Jong,et al.  Genetic Network Analyzer: qualitative simulation of genetic regulatory networks , 2003, Bioinform..

[18]  Qianchuan Zhao,et al.  A remark on "Scalar equations for synchronous Boolean networks with biological Applications" by C. Farrow, J. Heidel, J. Maloney, and J. Rogers , 2005, IEEE Transactions on Neural Networks.

[19]  John Maloney,et al.  Scalar equations for synchronous Boolean networks with biological applications , 2004, IEEE Transactions on Neural Networks.

[20]  T Michael,et al.  Maloney, and J. , 1992 .

[21]  Guowu Yang,et al.  An Efficient Algorithm for Computing Attractors of Synchronous And Asynchronous Boolean Networks , 2013, PloS one.

[22]  Ioannis Xenarios,et al.  A method for the generation of standardized qualitative dynamical systems of regulatory networks , 2005, Theoretical Biology and Medical Modelling.

[23]  Jongrae Kim,et al.  Aggregation Algorithm Towards Large-Scale Boolean Network Analysis , 2013, IEEE Transactions on Automatic Control.

[24]  Aurélien Naldi,et al.  Dynamical analysis of a generic Boolean model for the control of the mammalian cell cycle , 2006, ISMB.

[25]  Niklas Sörensson,et al.  An Extensible SAT-solver , 2003, SAT.

[26]  Giovanni De Micheli,et al.  Dynamic simulation of regulatory networks using SQUAD , 2007, BMC Bioinformatics.

[27]  Hidde de Jong,et al.  Modeling and Simulation of Genetic Regulatory Systems: A Literature Review , 2002, J. Comput. Biol..

[28]  Teresa M. Przytycka,et al.  Chapter 5: Network Biology Approach to Complex Diseases , 2012, PLoS Comput. Biol..

[29]  Steffen Klamt,et al.  Structural and functional analysis of cellular networks with CellNetAnalyzer , 2007, BMC Systems Biology.

[30]  S. Bornholdt,et al.  Boolean Network Model Predicts Cell Cycle Sequence of Fission Yeast , 2007, PloS one.

[31]  Thomas Dandekar,et al.  Jimena: efficient computing and system state identification for genetic regulatory networks , 2013, BMC Bioinformatics.

[32]  Maxim Teslenko,et al.  A SAT-Based Algorithm for Finding Attractors in Synchronous Boolean Networks , 2011, IEEE/ACM Transactions on Computational Biology and Bioinformatics.

[33]  Fabian J. Theis,et al.  Odefy -- From discrete to continuous models , 2010, BMC Bioinformatics.

[34]  Maxim Teslenko,et al.  Kauffman networks: analysis and applications , 2005, ICCAD-2005. IEEE/ACM International Conference on Computer-Aided Design, 2005..

[35]  Q. Ouyang,et al.  The yeast cell-cycle network is robustly designed. , 2003, Proceedings of the National Academy of Sciences of the United States of America.