Cancer disease occurs because of a disorder in the cellular regulatory mechanism, Which causes cellular malformation. The genes that start the malformation are called Cancer driver genes (CDGs) . Numerous computational methods have been introduced to identify cancer driver genes that use the concept of mutation.Regarding abnormalities spread in human cell and tumor development, CDGs are likely to be the potential types of gene with high influence in the network. This increases the importance of influence diffusion concept for the identification of CDGs.recently developed a method based on influence maximization for identifying cancer driver genes. One of the challenges in these types of networks is to find the power of regulatory interaction between edges.The current study developed a technique to identify cancer driver gene and predict the impact of regulatory interactions in a transcriptional regulatory network. This technique utilizes the concept of influence diffusion and optimizes the Hyperlink-Induced Topic Search algorithm based on the influence diffusion. The results suggest the better performance of our proposed technique than the other computational and network-based approaches.
The diverse, specialized genes in today's lifeforms evolved from a common core of ancient, elementary genes. However, these genes did not evolve individually: gene expression is controlled by a complex network of interactions, and alterations in one gene may drive reciprocal changes in its proteins' binding partners. We show that the topology of a leukemia gene regulatory network is strongly coupled with evolutionary properties. Slowly-evolving ("cold"), old genes tend to interact with each other, as do rapidly-evolving ("hot"), young genes, causing genes to evolve in clusters. We argue that g…
Identification of genes that initiate cell anomalies and cause cancer in humans is among the important fields in the oncology researches. The mutation and development of anomalies in these genes are then transferred to other genes in the cell and therefore disrupt the normal functionality of the cell. These genes are known as cancer driver genes (CDGs). Various methods have been proposed for predicting CDGs, most of which based on genomic data and based on computational methods. Therefore, some researchers have developed novel bioinformatics approaches. In this study, we propose an algorithm, …
HyperNetWalk: A Unified Framework for Personalized and Cohort-Level Cancer Driver Gene Identification via Reverse Inference on Layered Signaling-Regulatory Network
State Key Laboratory of Mathematical Sciences, Academy of Mathematics and Systems Science, Chinese Academy of Sciences（中国科学院数学与系统科学研究院数学科学学院）；School of Mathematical Sciences, University of Chinese Academy of Sciences（中国科学院大学数学科学学院）；School of Mathematics, Shandong University（山东大学数学学院）
Gene Regulatory Networks (GRNs) consisting of combinations of transcription factors (TFs) and their cis promoters are assumed to be sufficient to direct the development of organisms. Mutations in GRNs are assumed to be the primary drivers for the evolution of multicellular life. Here it is proven that neither of these assumptions is correct. They are inconsistent with fundamental principles of combinatorics of bounded encoded networks. It is shown there are inherent complexity and control capacity limits for any gene regulatory network that is based solely on protein coding genes such as trans…
Deciphering the control principles of metabolism and its interaction with other cellular functions is central to biomedicine and biotechnology. Yet, understanding the efficient control of metabolic fluxes remains elusive for large-scale metabolic networks. Existing methods either require specifying a cellular objective or are limited to small networks due to computational complexity. Here we develop an efficient computational framework for flux control by introducing a complete set of flux coupling relations. We analyze 23 metabolic networks from all kingdoms of life, and identify the driver r…
Biological Regulatory Network Inference through Circular Causal Structure Learning
Data Science & Artificial Intelligence Research Institute, China Unicom（中国联通数据科学与人工智能研究院）；School of Artificial Intelligence, Jilin University（吉林大学人工智能学院）；International Center of Future Science, Jilin University（吉林大学未来科学国际中心）；Engineering Research Center of Knowledge-Driven Human-Machine Intelligence, MOE（教育部知识驱动人机智能工程研究中心）
Regulatory interactions between genes show a large amount of cross-species variability, even when the underlying functions are conserved: There are many ways to achieve the same function. Here we investigate the ability of regulatory networks to reproduce given expression levels within a simple model of gene regulation. We find an exponentially large space of regulatory networks compatible with a given set of expression levels, giving rise to an extensive entropy of networks. Typical realisations of regulatory networks are found to share a bias towards symmetric interactions, in line with empi…
The biological processes of cellular decision making and differentiation involve a plethora of signalling pathways and gene regulatory circuits. These networks, in their turn, exhibit a multitude of motifs playing crucial parts in regulating network activity. Here, we compare the topological placement of motifs in gene regulatory and signalling networks and find that it suggests different evolutionary strategies in motif distribution for distinct cellular subnetworks.
Inference of gene regulatory networks has been an active area of research for around 20 years, leading to the development of sophisticated inference algorithms based on a variety of assumptions and approaches. With the always increasing demand for more accurate and powerful models, the inference problem remains of broad scientific interest. The abstract representation of biological systems through gene regulatory networks represents a powerful method to study such systems, encoding different amounts and types of information. In this review, we summarize the different types of inference algorit…
We study the oscillatory behaviour of a gene regulatory network with interlinked positive and negative feedback loop. Frequency and amplitude are two important properties of oscillation. Studied network produces two different modes of oscillation. In one mode (mode 1) frequency remains constant over a wide range amplitude and in other mode (mode 2) the amplitude of oscillation remains constant over a wide range of frequency. Our study reproduces both features of oscillations in a single gene regulatory network and show that the negative plus positive feedback loops in gene regulatory network o…
Genes are frequently regulated in complex manners, necessitating modelling approaches which go beyond simple (linear) gene-to-gene interactions and address the modularity of cis-regulatory regions and alternate transcription initiation sites. In particular, sharp expression patterns (peaks or stripes) indicate that gene regulation involves nonlinear transcription factor kinetics (beyond first-order). We propose a methodology for approaching this problem, using the example of the multiple cis-regulatory modules (CRMs) and two transcripts (P1 and P2) found in the Drosophila hunchback (hb) and (C…
Cardiac development is complex, multiscale process encompassing cell fate adoption, differentiation and morphogenesis. To elucidate pathways underlying this process, a recently developed algorithm to reverse engineer gene regulatory networks was applied to time-course microarray data obtained from the developing mouse heart. The algorithm generates many different putative network topologies that are capable of explaining the experimental data via model simulation. To cull specious network interactions, thousands of topologies are merged and filtered to generate a scale-free, hierarchical netwo…
We propose a new multi-network-based strategy to integrate different layers of genomic information and use them in a coordinate way to identify driving cancer genes. The multi-networks that we consider combine transcription factor co-targeting, microRNA co-targeting, protein-protein interaction and gene co-expression networks. The rationale behind this choice is that gene co-expression and protein-protein interactions require a tight coregulation of the partners and that such a fine tuned regulation can be obtained only combining both the transcriptional and post-transcriptional layers of regu…
From the response to external stimuli to cell division and death, the dynamics of living cells is based on the expression of specific genes at specific times. The decision when to express a gene is implemented by the binding and unbinding of transcription factor molecules to regulatory DNA. Here, we construct stochastic models of gene expression dynamics and test them on experimental time-series data of messenger-RNA concentrations. The models are used to infer biophysical parameters of gene transcription, including the statistics of transcription factor-DNA binding and the target genes contro…
Integrating expression data with gene interactions in a network is essential for understanding the functional organization of the cells. Consequently, knowledge of interaction types in biological networks is important for data interpretation. Signing of Regulatory Networks (SIREN) plugin for Cytoscape is an open-source Java tool for discrimination of interaction type (activatory or inhibitory) in gene regulatory networks. Utilizing an information theory based concept, SIREN seeks to identify the interaction type of pairs of genes by examining their corresponding gene expression profiles. We in…
Regulatory networks describe the interactions between molecular or cellular regulators, like transcription factors and genes in gene regulatory networks, kinases and their receptors in signalling networks, or neurons in neural networks. A long-standing aim of quantitative biology is to reconstruct such networks on the basis of large-scale data. Our aim is to leverage fluctuations around the non-equilibrium steady state for network inference. To this end, we use a stochastic model of gene regulation or neural dynamics and solve it approximately within a Gaussian mean-field theory. We develop a …
Modeling Dynamics, Cell Type Specificity, and Perturbations in Gene Regulatory Networks
Wisconsin Institute for Discovery, University of Wisconsin-Madison（威斯康星发现研究所，威斯康星大学麦迪逊分校）；Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison（威斯康星大学麦迪逊分校生物统计与医学信息学系）
In this paper, we conduct theoretical analyses on inferring the structure of gene regulatory networks. Depending on the experimental method and data type, the inference problem is classified into 20 different scenarios. For each scenario, we discuss the problem that with enough data, under what assumptions, what can be inferred about the structure. For scenarios that have been covered in the literature, we provide a brief review. For scenarios that have not been covered in literature, if the structure can be inferred, we propose new mathematical inference methods and evaluate them on simulated…
Interactions between genes and gene products give rise to complex circuits that enable cells to process information and respond to external signals. Theoretical studies often describe these interactions using continuous, stochastic, or logical approaches. We propose a new modeling framework for gene regulatory networks, that combines the intuitive appeal of a qualitative description of gene states with a high flexibility in incorporating stochasticity in the duration of cellular processes. We apply our methods to the regulatory network of the segment polarity genes, thus gaining novel insights…
Modeling stochasticity in gene regulatory networks is an important and complex problem in molecular systems biology. To elucidate intrinsic noise, several modeling strategies such as the Gillespie algorithm have been used successfully. This paper contributes an approach as an alternative to these classical settings. Within the discrete paradigm, where genes, proteins, and other molecular components of gene regulatory networks are modeled as discrete variables and are assigned as logical rules describing their regulation through interactions with other components. Stochasticity is modeled at th…
The problem of reliability of the dynamics in biological regulatory networks is studied in the framework of a generalized Boolean network model with continuous timing and noise. Using well-known artificial genetic networks such as the repressilator, we discuss concepts of reliability of rhythmic attractors. In a simple evolution process we investigate how overall network structure affects the reliability of the dynamics. In the course of the evolution, networks are selected for reliable dynamics. We find that most networks can be easily evolved towards reliable functioning while preserving the…
A widely used approach to describe the dynamics of gene regulatory networks is based on the chemical master equation, which considers probability distributions over all possible combinations of molecular counts. The analysis of such models is extremely challenging due to their large discrete state space. We therefore propose a hybrid approximation approach based on a system of partial differential equations, where we assume a continuous-deterministic evolution for the protein counts. We discuss efficient analysis methods for both modeling approaches and compare their performance. We show that …
The set of regulatory interactions between genes, mediated by transcription factors, forms a species' transcriptional regulatory network (TRN). By comparing this network with measured gene expression data one can identify functional properties of the TRN and gain general insight into transcriptional control. We define the subnet of a node as the subgraph consisting of all nodes topologically downstream of the node, including itself. Using a large set of microarray expression data of the bacterium Escherichia coli, we find that the gene expression in different subnets exhibits a structured patt…
In synthetic biology, gene regulatory circuits are often constructed by combining smaller circuit components. Connections between components are achieved by transcription factors acting on promoters. If the individual components behave as true modules and certain module interface conditions are satisfied, the function of the composite circuits can in principle be predicted. In this paper, we investigate one of the interface conditions: fan-out. We quantify the fan-out, a concept widely used in electric engineering, to indicate the maximum number of the downstream inputs that an upstream output…
Understanding design principles of molecular interaction networks is an important goal of molecular systems biology. Some insights have been gained into features of their network topology through the discovery of graph theoretic patterns that constrain network dynamics. This paper contributes to the identification of patterns in the mechanisms that govern network dynamics. The control of nodes in gene regulatory, signaling, and metabolic networks is governed by a variety of biochemical mechanisms, with inputs from other network nodes that act additively or synergistically. This paper focuses o…
The complex dynamics of gene expression in living cells can be well-approximated using Boolean networks. The average sensitivity is a natural measure of stability in these systems: values below one indicate typically stable dynamics associated with an ordered phase, whereas values above one indicate chaotic dynamics. This yields a theoretically motivated adaptive advantage to being near the critical value of one, at the boundary between order and chaos. Here, we measure average sensitivity for 66 publicly available Boolean network models describing the function of gene regulatory circuits acro…
Ring oscillators are biochemical circuits consisting of a ring of interactions capable of sustained oscillations. The non-linear interactions between genes hinder the analytical insight into their function, usually requiring computational exploration. Here we show that, despite the apparent complexity, the stability of the unique steady state in an incoherent feedback ring depends only on the degradation rates and a single parameter summarizing the feedback of the circuit. Concretely, we show that the range of regulatory parameters that yield oscillatory behaviour, is maximized when the degrad…
Numerous real-world systems can be naturally modeled as multilayer networks, enabling an efficient way to characterize those complex systems. Much evidence in the context of system biology indicated that the collections between different molecular networks can dramatically impact the global network functions. Here, we focus on the molecular multiplex networks coupled by the transcriptional regulatory network (TRN) and protein-protein interaction (PPI) network, exploring the controllability and energy requiring in these types of molecular multiplex networks. We find that the driver nodes tend t…
GeneNetMiner is standalone software which parses the sentences of iHOP and captures regulatory relations. The regulatory relations are either gene gene regulations or gene biological processes relations. Capturing of gene biological process relations is a unique feature for the tools of this kind. These relations can be used to build up gene regulatory networks for specific biological processes, diseases, or phenotypes. Users are able to search genes and biological processes to find the regulatory relationships between them. Each regulatory relationship has been assigned a confidence score, wh…
Developing and maintaining life requires a lot of computation. This is done by gene regulatory networks. But we have little understanding of how this computation is organized. I show that there is a direct correspondence between the structural and functional building blocks of regulatory networks, which I call regulatory motifs. I derive a simple bound on the range of function that these motifs can perform, in terms of the local network structure. I prove that this range is a small fraction of all possible functions, which severely constrains global network behavior. Part of this restriction i…
Increased biological complexity is generally associated with the addition of new genetic information, which must be integrated into the existing regulatory network that operates within the cell. General arguments on network control, as well as several recent genomic observations, indicate that regulatory gene number grows disproportionally fast with increasing genome size. We present two models for the growth of regulatory networks. Both predict that the number of transcriptional regulators will scale quadratically with total gene number. This appears to be in good quantitative agreement with …
Genetic regulatory networks enable cells to respond to the changes in internal and external conditions by dynamically coordinating their gene expression profiles. Our ability to make quantitative measurements in these biochemical circuits has deepened our understanding of what kinds of computations genetic regulatory networks can perform and with what reliability. These advances have motivated researchers to look for connections between the architecture and function of genetic regulatory networks. Transmitting information between network's inputs and its outputs has been proposed as one such p…
In this review we discuss different mathematical models of gene regulatory networks as relevant to the onset and development of cancer. After discussion of alternative modelling approaches, we use a paradigmatic two-gene network to focus on the role played by time delays in the dynamics of gene regulatory networks. We contrast the dynamics of the reduced model arising in the limit of fast mRNA dynamics with that of the full model. The review concludes with the discussion of some open problems.
The study of fluctuations in gene regulatory networks is extended to the case of Gaussian colored noise. Firstly, the solution of the corresponding Langevin equation with colored noise is expressed in terms of an Ito integral. Then, two important lemmas concerning the variance of an Ito integral and the covariance of two Ito integrals are shown. Based on the lemmas, we give the general formulae for the variances and covariance of molecular concentrations for a regulatory network near a stable equilibrium explicitly. Two examples, the gene auto-regulatory network and the toggle switch, are pres…
Background:Gene regulations often change over time rather than being constant. But many of gene regulatory networks extracted from databases are static. The tumor suppressor gene $P53$ is involved in the pathogenesis of many tumors, and its inhibition effects occur after a certain period. Therefore, it is of great significance to elucidate the regulation mechanism over time points. Result:A qualitative method for representing dynamic gene regulatory network is developed, called CdtGRN. It adopts the combination of convolutional neural networks(CNN) and fully connected networks(DNN) as the core…
New approach to design a dynamic model of genes with multiple autonomous regulatory modules by evolution in silico is proposed. The approach is based on Genetic Algorithms, enforced by new crossover operators, especially worked out for these purposes. The approach exploits the subbasin-portal architecture of the fitness functions suitable for this kind of evolutionary modeling. The effectiveness of the approach is demonstrated on a series of benchmark tests.
Biological systems and processes are networks of complex nonlinear regulatory interactions between nucleic acids, proteins, and metabolites. A natural way in which to represent these interaction networks is through the use of a graph. In this formulation, each node represents a nucleic acid, protein, or metabolite and edges represent intermolecular interactions (inhibition, regulation, promotion, coexpression, etc.). In this work, a novel algorithm for the discovery of latent graph structures given experimental data is presented.
Gene regulatory networks arise in all living cells, allowing the control of gene expression patterns. The study of their topology has revealed that certain subgraphs of interactions or "motifs" appear at anomalously high frequencies. We ask here whether this phenomenon may emerge because of the functions carried out by these networks. Given a framework for describing regulatory interactions and dynamics, we consider in the space of all regulatory networks those that have a prescribed function. Monte Carlo sampling is then used to determine how these functional networks lead to specific motif s…
A description for regulatory genetic network based on generalized potential energy is constructed. The potential energy is derived from the steady state solution of linearized Fokker-Plank equation, and the result is shown to be equivalent to the system of coupled oscillators. The correspondence between the quantities from the mechanical picture and the steady-state fluctuations is established. Explicit calculation is given for auto-regulatory networks in which, the force constant associated with the degree of protein is very weak. Negative feedback not only suppresses the fluctuations but als…
University of Cambridge（剑桥大学）；Computer Laboratory（计算机实验室）
Delays in protein synthesis cause a confounding effect when constructing Gene Regulatory Networks (GRNs) from RNA-sequencing time-series data. Accurate GRNs can be very insightful when modelling development, disease pathways, and drug side-effects. We present a model which incorporates translation delays by combining mechanistic equations and Bayesian approaches to fit to experimental data. This enables greater biological interpretability, and the use of Gaussian processes enables non-linear expressivity through kernels as well as naturally accounting for biological variation.
The structure of a stochastic nonlinear gene regulatory network is uncovered by studying its response to input signal generators. Four applications are studied in detail: a nonlinear connection of two linear systems, the design of a logic pulse, a molecular amplifier and the interference of three signal generators in E2F1 regulatory element. The gene interactions are presented using molecular diagrams that have a precise mathematical structure and retain the biological meaning of the processes.
Genetic Regulatory Networks (GRNs) plays a vital role in the understanding of complex biological processes. Modeling GRNs is significantly important in order to reveal fundamental cellular processes, examine gene functions and understanding their complex relationships. Understanding the interactions between genes gives rise to develop better method for drug discovery and diagnosis of the disease since many diseases are characterized by abnormal behaviour of the genes. In this paper we have reviewed various evolutionary algorithms-based approach for modeling GRNs and discussed various opportuni…
The influence of decay in dynamic models of gene regulatory networks
Kyiv-Mohyla Academy（基辅莫希拉学院）；Institute of Mathematics, NAS of Ukraine（乌克兰国家科学院数学研究所）；Institute of Mathematics and Computer Science, University of Latvia（拉脱维亚大学数学与计算机科学研究所）；Daugavpils University（道加夫皮尔斯大学）
Genetic regulatory networks with adaptive responses are widely studied in biology. Usually, models consisting only of a few nodes have been considered. They present one input receptor for activation and one output node where the adaptive response is computed. In this work, we design genetic regulatory networks with many receptors and many output nodes able to produce delayed adaptive responses. This design is performed by using an evolutionary algorithm of mutations and selections that minimizes an error function defined by the adaptive response in signal shapes. We present several examples of…
The effect of signal integration through cis-regulatory modules (CRMs) on synchronization and clustering of populations of two-component genetic oscillators coupled by quorum sensing is in detail investigated. We find that the CRMs play an important role in achieving synchronization and clustering. For this, we investigate 6 possible cis-regulatory input functions (CRIFs) with AND, OR, ANDN, ORN, XOR, and EQU types of responses in two possible kinds of cell-to-cell communications: activator-regulated communication (i.e., the autoinducer regulates the activator) and repressor-regulated communic…
We investigate a quantitative network of gene expression dynamics describing the competence development in Bacillus subtilis. First, we introduce an Onsager-Machlup approach to quantify the most probable transition pathway for both excitable and bistable dynamics. Then, we apply a machine learning method to calculate the most probable transition pathway via the Euler-Lagrangian equation. Finally, we analyze how the noise intensity affects the transition phenomena.
Random Boolean networks have been used widely to explore aspects of gene regulatory networks. A modified form of the model through which to systematically explore the effects of increasing the number of gene states has previously been introduced. In this paper, these discrete dynamical networks are coevolved within coupled, rugged fitness landscapes to explore their behaviour. Results suggest the general properties of the Boolean model remain with higher valued logic regardless of the update scheme or fitness sampling method. Introducing topological asymmetry in the coevolving networks is seen…
The time taken for gene expression varies not least because proteins vary in length considerably. This paper uses an abstract, tuneable Boolean regulatory network model to explore gene expression time variation. In particular, it is shown how non-uniform expression times can emerge under certain conditions through simulated evolution. That is, gene expression time variance appears beneficial in the shaping of the dynamical behaviour of the regulatory network without explicit consideration of protein function.
Network of packages with regulatory interactions (dependences and conflicts) from Debian GNU/Linux operating system is compiled and used as analogy of a gene regulatory network. Using a trace-back algorithm we assembly networks from the potential pool of packages for both scale-free and exponential topology from real and a null model data, respectively. We calculate the maximum number of packages that can be functionally installed in the system (i.e., the active network size). We show that scale-free regulatory networks allow a larger active network size than random ones. Small genomes with sc…
Gene regulatory networks are collections of genes that interact with one other and with other substances in the cell. By measuring gene expression over time using high-throughput technologies, it may be possible to reverse engineer, or infer, the structure of the gene network involved in a particular cellular process. These gene expression data typically have a high dimensionality and a limited number of biological replicates and time points. Due to these issues and the complexity of biological systems, the problem of reverse engineering networks from gene expression data demands a specialized…
The cell cycle is a tightly controlled process, yet its underlying genetic network shows marked differences across species. Which of the associated structural features follow solely from the ability to impose the appropriate gene expression patterns? We tackle this question in silico by examining the ensemble of all regulatory networks which satisfy the constraint of producing a given sequence of gene expressions. We focus on three cell cycle profiles coming from baker's yeast, fission yeast and mammals. First, we show that the networks in each of the ensembles use just a few interactions that…
