RMut: R package for a Boolean sensitivity analysis against various types of mutations

There have been many in silico studies based on a Boolean network model to investigate network sensitivity against gene or interaction mutations. However, there are no proper tools to examine the network sensitivity against many different types of mutations, including user-defined ones. To address this issue, we developed RMut, which is an R package to analyze the Boolean network-based sensitivity by efficiently employing not only many well-known node-based and edgetic mutations but also novel user-defined mutations. In addition, RMut can specify the mutation area and the duration time for more precise analysis. RMut can be used to analyze large-scale networks because it is implemented in a parallel algorithm using the OpenCL library. In the first case study, we observed that the real biological networks were most sensitive to overexpression/state-flip and edge-addition/-reverse mutations among node-based and edgetic mutations, respectively. In the second case study, we showed that edgetic mutations can predict drug-targets better than node-based mutations. Finally, we examined the network sensitivity to double edge-removal mutations and found an interesting synergistic effect. Taken together, these findings indicate that RMut is a flexible R package to efficiently analyze network sensitivity to various types of mutations. RMut is available at https://github.com/csclab/RMut.

[1]  Alex Madrahimov,et al.  The Cell Collective: Toward an open and collaborative approach to systems biology , 2012, BMC Systems Biology.

[2]  Jun Wang,et al.  Generalizing DTW to the multi-dimensional case requires an adaptive approach , 2016, Data Mining and Knowledge Discovery.

[3]  C. Nguyên,et al.  A small molecule inhibitor of β-catenin/cyclic AMP response element-binding protein transcription , 2004 .

[4]  J. Micol,et al.  Understanding synergy in genetic interactions. , 2009, Trends in genetics : TIG.

[5]  Colin Campbell,et al.  Stabilization of perturbed Boolean network attractors through compensatory interactions , 2014, BMC Systems Biology.

[6]  Leman Akoglu,et al.  Optimizing network robustness by edge rewiring: a general framework , 2016, Data Mining and Knowledge Discovery.

[7]  I. Arisi,et al.  Targeting the MDM2/MDM4 interaction interface as a promising approach for p53 reactivation therapy. , 2015, Cancer research.

[8]  Dajun Yang,et al.  MI-63: A novel small-molecule inhibitor targets MDM2 and induces apoptosis in embryonal and alveolar rhabdomyosarcoma cells with wild-type p53 , 2009, British Journal of Cancer.

[9]  Andrew Wuensche,et al.  A model of transcriptional regulatory networks based on biases in the observed regulation rules , 2002, Complex..

[10]  G. Prelich Gene Overexpression: Uses, Mechanisms, and Interpretation , 2012, Genetics.

[11]  Hans A. Kestler,et al.  BoolNet - an R package for generation, reconstruction and analysis of Boolean networks , 2010, Bioinform..

[12]  Guillaume Vogt,et al.  Gain-of-glycosylation mutations. , 2007, Current opinion in genetics & development.

[13]  Giancarlo Mauri,et al.  CABeRNET: a Cytoscape app for augmented Boolean models of gene regulatory NETworks , 2015, BMC Bioinformatics.

[14]  Xuequn Shang,et al.  An efficient algorithm to identify the optimal one-bit perturbation based on the basin-of-state size of Boolean networks , 2016, Scientific reports.

[15]  D. Milani,et al.  Beckwith – wiedemann and iMAGe syndromes : two very different diseases caused by mutations on the same gene , 2014 .

[16]  Kwang-Hyun Cho,et al.  Investigations into the relationship between feedback loops and functional importance of a signal transduction network based on Boolean network modeling , 2007, BMC Bioinformatics.

[17]  N. Moghrabi,et al.  The first case report of double homozygous of 2 different mutations in the CFTR gene in Saudi Arabia , 2017, International journal of pediatrics & adolescent medicine.

[18]  Judy H. Cho,et al.  [Letters to Nature] , 1975, Nature.

[19]  Eugenio Azpeitia,et al.  A Dynamic Gene Regulatory Network Model That Recovers the Cyclic Behavior of Arabidopsis thaliana Cell Cycle , 2015, PLoS Comput. Biol..

[20]  Francisco Azuaje,et al.  Identification of potential targets in biological signalling systems through network perturbation analysis , 2010, Biosyst..

[21]  Jean-Marc Schwartz,et al.  A MAPK-Driven Feedback Loop Suppresses Rac Activity to Promote RhoA-Driven Cancer Cell Invasion , 2016, PLoS Comput. Biol..

[22]  Aurélien Naldi,et al.  Diversity and Plasticity of Th Cell Types Predicted from Regulatory Network Modelling , 2010, PLoS Comput. Biol..

[23]  N. Jayaram,et al.  Evaluating tools for transcription factor binding site prediction , 2016, BMC Bioinformatics.

[24]  M. Vidal,et al.  Mutations that disrupt PHOXB interaction with the neuronal calcium sensor HPCAL1 impede cellular differentiation in neuroblastoma , 2014, Oncogene.

[25]  Thomas Madej,et al.  Modulating protein-protein interactions with small molecules: the importance of binding hotspots. , 2012, Journal of molecular biology.

[26]  Edward R. Dougherty,et al.  Optimal Experimental Design for Gene Regulatory Networks in the Presence of Uncertainty , 2015, IEEE/ACM Transactions on Computational Biology and Bioinformatics.

[27]  Emmanuel Barillot,et al.  Predicting genetic interactions from Boolean models of biological networks. , 2015, Integrative biology : quantitative biosciences from nano to macro.

[28]  Steven Henikoff,et al.  SIFT: predicting amino acid changes that affect protein function , 2003, Nucleic Acids Res..

[29]  M. Sternberg,et al.  The effects of non-synonymous single nucleotide polymorphisms (nsSNPs) on protein-protein interactions. , 2013, Journal of molecular biology.

[30]  Kwang-Hyun Cho,et al.  Coherent coupling of feedback loops: a design principle of cell signaling networks , 2008, Bioinform..

[31]  G. Barsh,et al.  Dominant Red Coat Color in Holstein Cattle Is Associated with a Missense Mutation in the Coatomer Protein Complex, Subunit Alpha (COPA) Gene , 2015, PloS one.

[32]  Denis Thieffry,et al.  Genetic control of flower morphogenesis in Arabidopsis thaliana: a logical analysis , 1999, Bioinform..

[33]  Andrea Crisanti,et al.  A CRISPR-Cas9 Gene Drive System Targeting Female Reproduction in the Malaria Mosquito vector Anopheles gambiae , 2015, Nature Biotechnology.

[34]  Stefan Bornholdt,et al.  Boolean Network Model Predicts Knockout Mutant Phenotypes of Fission Yeast , 2013, PloS one.

[35]  G. Church,et al.  Modular epistasis in yeast metabolism , 2005, Nature Genetics.

[36]  J. Wells,et al.  Small-molecule inhibitors of protein-protein interactions: progressing toward the reality. , 2014, Chemistry & biology.

[37]  R. Laubenbacher,et al.  Regulatory patterns in molecular interaction networks. , 2011, Journal of theoretical biology.

[38]  S. Pongor,et al.  Multiple weak hits confuse complex systems: a transcriptional regulatory network as an example. , 2004, Physical review. E, Statistical, nonlinear, and soft matter physics.

[39]  Edward R. Dougherty,et al.  Effect of Function Perturbation on the Steady-State Distribution of Genetic Regulatory Networks: Optimal Structural Intervention , 2008, IEEE Transactions on Signal Processing.

[40]  Ruth Nussinov,et al.  Druggable orthosteric and allosteric hot spots to target protein-protein interactions. , 2014, Current pharmaceutical design.

[41]  Hong Ma,et al.  A small molecule inhibitor of beta-catenin/CREB-binding protein transcription [corrected]. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[42]  Kwang-Hyun Cho,et al.  Dynamical Robustness against Multiple Mutations in Signaling Networks , 2016, IEEE/ACM Transactions on Computational Biology and Bioinformatics.

[43]  Edwin Wang,et al.  Protein evolution on a human signaling network , 2009, BMC Systems Biology.

[44]  Albert,et al.  Emergence of scaling in random networks , 1999, Science.

[45]  P. Leighton,et al.  Germline Gene Editing in Chickens by Efficient CRISPR-Mediated Homologous Recombination in Primordial Germ Cells , 2016, PloS one.

[46]  L. Donehower,et al.  Effects of genetic background on tumorigenesis in p53‐deficient mice , 1995, Molecular carcinogenesis.

[47]  Carsten Peterson,et al.  Random Boolean network models and the yeast transcriptional network , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[48]  E. Dougherty,et al.  Gene perturbation and intervention in probabilistic Boolean networks. , 2002, Bioinformatics.

[49]  Péter Csermely,et al.  The efficiency of multi-target drugs: the network approach might help drug design. , 2004, Trends in pharmacological sciences.

[50]  M. Vidal,et al.  Edgetic perturbation models of human inherited disorders , 2009, Molecular systems biology.

[51]  S. Kauffman,et al.  Genetic networks with canalyzing Boolean rules are always stable. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[52]  M. Aldana,et al.  Floral Morphogenesis: Stochastic Explorations of a Gene Network Epigenetic Landscape , 2008, PloS one.

[53]  M. Vidal,et al.  Edgotype: a fundamental link between genotype and phenotype. , 2013, Current opinion in genetics & development.

[54]  Edda Klipp,et al.  BooleSim: an interactive Boolean network simulator , 2014, Bioinform..

[55]  K. B. Ward,et al.  Crystal structure of sickle-cell deoxyhemoglobin at 5 A resolution. , 1975, Journal of molecular biology.

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

[57]  J. Parry The use of yeast cultures for the detection of environmental mutagens using a fluctuation test. , 1977, Mutation research.

[58]  Daniel F. Voytas,et al.  Efficient TALEN-mediated gene knockout in livestock , 2012, Proceedings of the National Academy of Sciences.

[59]  B. Shastry Overexpression of genes in health and sickness. A bird's eye view. , 1995, Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology.

[60]  István A. Kovács,et al.  Widespread Macromolecular Interaction Perturbations in Human Genetic Disorders , 2015, Cell.

[61]  D. Thieffry,et al.  Dynamical Analysis of the Regulatory Network Defining the Dorsal–Ventral Boundary of the Drosophila Wing Imaginal Disc , 2006, Genetics.

[62]  R. Schwarz,et al.  The metabolic background is a global player in Saccharomyces gene expression epistasis , 2016, Nature Microbiology.

[63]  V. Ingram,et al.  A Specific Chemical Difference Between the Globins of Normal Human and Sickle-Cell Anæmia Hæmoglobin , 1956, Nature.

[64]  Madhav V. Marathe,et al.  GDSCalc: A Web-Based Application for Evaluating Discrete Graph Dynamical Systems , 2015, PloS one.

[65]  Haiyuan Yu,et al.  Three-dimensional reconstruction of protein networks provides insight into human genetic disease , 2012, Nature Biotechnology.

[66]  Duc-Hau Le,et al.  NetDS: a Cytoscape plugin to analyze the robustness of dynamics and feedforward/feedback loop structures of biological networks , 2011, Bioinform..

[67]  Duc-Hau Le,et al.  PANET: A GPU-Based Tool for Fast Parallel Analysis of Robustness Dynamics and Feed-Forward/Feedback Loop Structures in Large-Scale Biological Networks , 2014, PloS one.

[68]  Daniel Segrè,et al.  Epistatic Interaction Maps Relative to Multiple Metabolic Phenotypes , 2011, PLoS genetics.

[69]  D. Spring,et al.  Overcoming Chemical, Biological, and Computational Challenges in the Development of Inhibitors Targeting Protein-Protein Interactions , 2015, Chemistry & biology.

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

[71]  K. Bhat,et al.  An ARF-independent c-MYC-activated tumor suppression pathway mediated by ribosomal protein-Mdm2 Interaction. , 2010, Cancer cell.

[72]  Holger Gohlke,et al.  Targeting protein-protein interactions with small molecules: challenges and perspectives for computational binding epitope detection and ligand finding. , 2006, Current medicinal chemistry.

[73]  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.

[74]  Edward R. Dougherty,et al.  The impact of function perturbations in Boolean networks , 2007, Bioinform..

[75]  Adam Godzik,et al.  Analysis of Individual Protein Regions Provides Novel Insights on Cancer Pharmacogenomics , 2015, PLoS Comput. Biol..

[76]  N. Wu,et al.  Production of p53 gene knockout rats by homologous recombination in embryonic stem cells , 2010, Nature.

[77]  E. Rebar,et al.  Genome editing with engineered zinc finger nucleases , 2010, Nature Reviews Genetics.

[78]  Antoine H. C. van Kampen,et al.  Use of prior knowledge for the analysis of high-throughput transcriptomics and metabolomics data , 2014, BMC Systems Biology.

[79]  P. Slootweg,et al.  Gain-of-function mutations in the tumor suppressor gene p53. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[80]  R. Reski,et al.  Plant nuclear gene knockout reveals a role in plastid division for the homolog of the bacterial cell division protein FtsZ, an ancestral tubulin. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[81]  Jun Qiao,et al.  Efficient Gene Knockout in Goats Using CRISPR/Cas9 System , 2014, PloS one.

[82]  Paul Shannon,et al.  Derivation of genetic interaction networks from quantitative phenotype data , 2005, Genome Biology.

[83]  Ozlem Keskin,et al.  Hot spots in protein-protein interfaces: towards drug discovery. , 2014, Progress in biophysics and molecular biology.

[84]  Aurélien Naldi,et al.  Logical modelling of gene regulatory networks with GINsim. , 2012, Methods in molecular biology.

[85]  David S. Wishart,et al.  DrugBank 4.0: shedding new light on drug metabolism , 2013, Nucleic Acids Res..

[86]  Chang S. Chan,et al.  The evolution of thymic lymphomas in p53 knockout mice , 2014, Genes & development.

[87]  E. Lander,et al.  Comprehensive assessment of cancer missense mutation clustering in protein structures , 2015, Proceedings of the National Academy of Sciences.

[88]  Nobuhiro Suzuki,et al.  ABA Is Required for Plant Acclimation to a Combination of Salt and Heat Stress , 2016, PloS one.

[89]  R. Albert,et al.  Predicting Essential Components of Signal Transduction Networks: A Dynamic Model of Guard Cell Abscisic Acid Signaling , 2006, PLoS biology.

[90]  Peter Grindrod,et al.  A dynamical systems view of network centrality , 2014, Proceedings of the Royal Society A: Mathematical, Physical and Engineering Sciences.

[91]  Ulrich M. Tillich,et al.  The Optimal Mutagen Dosage to Induce Point-Mutations in Synechocystis sp. PCC6803 and Its Application to Promote Temperature Tolerance , 2012, PloS one.

[92]  M. Groenen,et al.  Early and late feathering in turkey and chicken: same gene but different mutations , 2018, Genetics Selection Evolution.

[93]  C. Tse,et al.  ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. , 2008, Cancer research.

[94]  Daniel F. Gudbjartsson,et al.  Nonsense mutation in the LGR4 gene is associated with several human diseases and other traits , 2013, Nature.

[95]  K. Lindblad-Toh,et al.  A Frameshift Mutation in Golden Retriever Dogs with Progressive Retinal Atrophy Endorses SLC4A3 as a Candidate Gene for Human Retinal Degenerations , 2011, PloS one.

[96]  Hung-Cuong Trinh,et al.  Effective Boolean dynamics analysis to identify functionally important genes in large-scale signaling networks , 2015, Biosyst..

[97]  L. Ellis,et al.  Targeting RING domains of Mdm2–MdmX E3 complex activates apoptotic arm of the p53 pathway in leukemia/lymphoma cells , 2015, Cell Death and Disease.