Results 1  10
of
117
Modeling and simulation of genetic regulatory systems: A literature review
 JOURNAL OF COMPUTATIONAL BIOLOGY
, 2002
"... In order to understand the functioning of organisms on the molecular level, we need to know which genes are expressed, when and where in the organism, and to which extent. The regulation of gene expression is achieved through genetic regulatory systems structured by networks of interactions between ..."
Abstract

Cited by 738 (14 self)
 Add to MetaCart
(Show Context)
In order to understand the functioning of organisms on the molecular level, we need to know which genes are expressed, when and where in the organism, and to which extent. The regulation of gene expression is achieved through genetic regulatory systems structured by networks of interactions between DNA, RNA, proteins, and small molecules. As most genetic regulatory networks of interest involve many components connected through interlocking positive and negative feedback loops, an intuitive understanding of their dynamics is hard to obtain. As a consequence, formal methods and computer tools for the modeling and simulation of genetic regulatory networks will be indispensable. This paper reviews formalisms that have been employed in mathematical biology and bioinformatics to describe genetic regulatory systems, in particular directed graphs, Bayesian networks, Boolean networks and their generalizations, ordinary and partial differential equations, qualitative differential equations, stochastic equations, and rulebased formalisms. In addition, the paper discusses how these formalisms have been used in the simulation of the behavior of actual regulatory systems.
Genetic Network Inference: From CoExpression Clustering To Reverse Engineering
, 2000
"... motivation: Advances in molecular biological, analytical and computational technologies are enabling us to systematically investigate the complex molecular processes underlying biological systems. In particular, using highthroughput gene expression assays, we are able to measure the output of the ge ..."
Abstract

Cited by 336 (0 self)
 Add to MetaCart
motivation: Advances in molecular biological, analytical and computational technologies are enabling us to systematically investigate the complex molecular processes underlying biological systems. In particular, using highthroughput gene expression assays, we are able to measure the output of the gene regulatory network. We aim here to review datamining and modeling approaches for conceptualizing and unraveling the functional relationships implicit in these datasets. Clustering of coexpression profiles allows us to infer shared regulatory inputs and functional pathways. We discuss various aspects of clustering, ranging from distance measures to clustering algorithms and multiplecluster memberships. More advanced analysis aims to infer causal connections between genes directly, i.e. who is regulating whom and how. We discuss several approaches to the problem of reverse engineering of genetic networks, from discrete Boolean networks, to continuous linear and nonlinear models. We conclude that the combination of predictive modeling with systematic experimental verification will be required to gain a deeper insight into living organisms, therapeutic targeting and bioengineering.
IDENTIFICATION OF GENETIC NETWORKS FROM A SMALL NUMBER OF GENE EXPRESSION PATTERNS UNDER THE BOOLEAN NETWORK MODEL
 PACIFIC SYMPOSIUM ON BIOCOMPUTING 4:1728 (1999)
, 1999
"... ... for inferring genetic network architectures from state transition tables which correspond to time series of gene expression patterns, using the Boolean network model. Their results of computational experiments suggested that a small number of state transition (INPUT/OUTPUT) pairs are sufficient ..."
Abstract

Cited by 254 (17 self)
 Add to MetaCart
(Show Context)
... for inferring genetic network architectures from state transition tables which correspond to time series of gene expression patterns, using the Boolean network model. Their results of computational experiments suggested that a small number of state transition (INPUT/OUTPUT) pairs are sufficient in order to infer the original Boolean network correctly. This paper gives a mathematical proof for their observation. Precisely, this paper devises a much simpler algorithm for the same problem and proves that, if the indegree of each node (i.e., the number of input nodes to each node) is bounded by a constant, only O(log n) state transition pairs (from 2n pairs) are necessary and sufficient to identify the original Boolean network of n nodes correctly with high probability. We made computational experiments in order to expose the constant factor involved in O(log n) notation. The computational results show that the Boolean network of size 100,000 can be identified by our algorithm from about 100 INPUT/OUTPUT pairs if the maximum indegree is bounded by 2. It is also a merit of our algorithm that the algorithm is conceptually so simple that it is extensible for more realistic network models.
Metabolomics: the link between genotypes and phenotypes
 Plant Molecular Biology
"... Metabolites are the end products of cellular regulatory processes, and their levels can be regarded as the ultimate response of biological systems to genetic or environmental changes. In parallel to the terms ‘transcriptome ’ and ‘proteome’, the set of metabolites synthesized by a biological system ..."
Abstract

Cited by 236 (14 self)
 Add to MetaCart
(Show Context)
Metabolites are the end products of cellular regulatory processes, and their levels can be regarded as the ultimate response of biological systems to genetic or environmental changes. In parallel to the terms ‘transcriptome ’ and ‘proteome’, the set of metabolites synthesized by a biological system constitute its ‘metabolome’. Yet, unlike other functional genomics approaches, the unbiased simultaneous identification and quantification of plant metabolomes has been largely neglected. Until recently, most analyses were restricted to profiling selected classes of compounds, or to fingerprinting metabolic changes without sufficient analytical resolution to determine metabolite levels and identities individually. As a prerequisite for metabolomic analysis, careful consideration of the methods employed for tissue extraction, sample preparation, data acquisition, and data mining must be taken. In this review, the differences among metabolite target analysis, metabolite profiling, and metabolic fingerprinting are clarified, and terms are defined. Current approaches are examined, and potential applications are summarized with a special emphasis on data mining and mathematical modelling of metabolism.
Modelling gene expression data using dynamic bayesian networks
, 1999
"... Recently, there has been much interest in reverse engineering genetic networks from time series data. In this paper, we show that most of the proposed discrete time models — including the boolean network model [Kau93, SS96], the linear model of D’haeseleer et al. [DWFS99], and the nonlinear model of ..."
Abstract

Cited by 223 (1 self)
 Add to MetaCart
Recently, there has been much interest in reverse engineering genetic networks from time series data. In this paper, we show that most of the proposed discrete time models — including the boolean network model [Kau93, SS96], the linear model of D’haeseleer et al. [DWFS99], and the nonlinear model of Weaver et al. [WWS99] — are all special cases of a general class of models called Dynamic Bayesian Networks (DBNs). The advantages of DBNs include the ability to model stochasticity, to incorporate prior knowledge, and to handle hidden variables and missing data in a principled way. This paper provides a review of techniques for learning DBNs. Keywords: Genetic networks, boolean networks, Bayesian networks, neural networks, reverse engineering, machine learning. 1
A comparison of genetic network models
 In Pac. Symp. Biocomputing
, 2001
"... The inference of genetic interactions from measured expression data is one of the most challenging tasks of modern functional genomics. When successful, the learned network of regulatory interactions yields a wealth of useful information. An inferred genetic network contains information about the p ..."
Abstract

Cited by 97 (5 self)
 Add to MetaCart
(Show Context)
The inference of genetic interactions from measured expression data is one of the most challenging tasks of modern functional genomics. When successful, the learned network of regulatory interactions yields a wealth of useful information. An inferred genetic network contains information about the pathway to which a gene belongs and which genes it interacts with. Furthermore, it explains the gene's function in terms of how it influences other genes and indicates which genes are pathway initiators and therefore potential drug targets. Obviously, such wealth comes at a price and that of genetic network modeling is that it is an extremely complex task. Therefore, it is necessary to develop sophisticated computational tools that are able to extract relevant information from a limited set of microarray measurements and integrate this with different information sources, to come up with reliable hypotheses of a genetic regulatory network. Thus far, a multitude of modeling approaches has been proposed for discovering genetic networks. However, it is unclear what the advantages and disadvantages of each of the different approaches are and how their results can be compared. In this review, genetic network models are put in a historical perspective that explains why certain models were introduced. Various modeling assumptions and their consequences are also highlighted. In addition, an overview of the principal differences and similarities between the approaches is given by considering the qualitative properties of the chosen models and their learning strategies. In pharmacogenomics and related areas, a lot of research is directed towards discovering, understanding and/or controlling the outcome of some particular biological pathway. Numerous examples exist where the manipulation of a key enzyme in such a pathway did not lead to the desired effect We know that the structure of complex genetic and biochemical networks lies hidden in the sequence information of our DNA but it is far from trivial to predict gene expression from the sequence code alone. The current availability of microarray measurements of thousands of gene expression levels during the course of an experiment or after the knockout of a gene provides a wealth of complementary information that may be exploited to unravel the complex interplay between genes. It now becomes possible to start answering some of the truly challenging questions in systems biology. For example, is it possible to model these genetic interactions as a large network of interacting elements and can these interactions be effectively learned from measured expression data? Since Kauffman Although the behavior and properties of artificial networks match the observations made in real biological systems well, the field of genetic network modeling has yet to reach its full maturity. The automatic discovery of genetic networks from expression data alone is far from trivial because of the combinatorial nature of the problem and the poor information content of 1 For reasons of brevity, the authors consistently refer only to the first author of each reference.
Modeling transcriptional control in gene networks—Methods, recent results, and future directions
 Bull Math Biol
"... Mathematical models are useful for providing a framework for integrating data and gaining insights into the static and dynamic behavior of complex biological systems such as networks of interacting genes. We review the dynamic behaviors expected from model gene networks incorporating common bioche ..."
Abstract

Cited by 76 (0 self)
 Add to MetaCart
Mathematical models are useful for providing a framework for integrating data and gaining insights into the static and dynamic behavior of complex biological systems such as networks of interacting genes. We review the dynamic behaviors expected from model gene networks incorporating common biochemical motifs, and we compare current methods for modeling genetic networks. A common modeling technique, based on simply modeling genes as ON–OFF switches, is readily implemented and allows rapid numerical simulations. However, this method may predict dynamic solutions that do not correspond to those seen when systems are modeled with a more detailed method using ordinary differential equations. Until now, the majority of gene network modeling studies have focused on determining the types of dynamics that can be generated by common biochemical motifs such as feedback loops or protein oligomerization. For example, these elements can generate multiple stable states for gene product concentrations, statedependent responses to stimuli, circadian rhythms and other oscillations, and optimal stimulus frequencies for maximal transcription. In the future, as new experimental techniques increase the ease of characterization of genetic networks, qualitative modeling will need to be supplanted by quantitative models for specific systems. c © 2000 Society for Mathematical Biology 1.
Algorithms for Identifying Boolean Networks and Related Biological Networks Based on Matrix Multiplication and Fingerprint Function
 J. COMP. BIOL
, 2000
"... Due to the recent progress of the DNA microarray technology, a large number of gene expression profile data are being produced. How to analyze gene expression data is an important topic in computational molecular biology. Several studies have been done using the Boolean network as a model of a genet ..."
Abstract

Cited by 68 (6 self)
 Add to MetaCart
(Show Context)
Due to the recent progress of the DNA microarray technology, a large number of gene expression profile data are being produced. How to analyze gene expression data is an important topic in computational molecular biology. Several studies have been done using the Boolean network as a model of a genetic network. This paper proposes efficient algorithms for identifying Boolean networks of bounded indegree and related biological networks, where identification of a Boolean network can be formalized as a problem of identifying many Boolean functions simultaneously. For the identification of a Boolean network, an 1 time naive algorithm and a simple time algorithm are known, where denotes the number of nodes, denotes the number of examples, and denotes the maximum indegree. This paper presents an improved 2 3 time MonteCarlo type randomized algorithm, where is the exponent of matrix multiplication (currently, 2 376). The algorithm is obtained by combining fast matrix multiplication with the randomized fingerprint function for string matching. Although the algorithm and its analysis are simple, the result is nontrivial and the technique can be applied to several related problems.
Computational Methods for the Identification of Differential and Coordinated Gene Expression
 Human Molecular Genetics
, 1999
"... this article, I review the theoretical and computational approaches used to: (i) identify genes differentially expressed (across cell types, developmental stages, pathological conditions, etc.); (ii) identify genes expressed in a coordinated manner across a set of conditions; and (iii) delineate clu ..."
Abstract

Cited by 63 (0 self)
 Add to MetaCart
(Show Context)
this article, I review the theoretical and computational approaches used to: (i) identify genes differentially expressed (across cell types, developmental stages, pathological conditions, etc.); (ii) identify genes expressed in a coordinated manner across a set of conditions; and (iii) delineate clusters of genes sharing coherent expression features, eventually defining global biological pathways
Modeling Tcell activation using gene expression profiling and state space modeling
 Bioinformatics
, 2004
"... Motivation: We have used statespace models to reverse engineer transcriptional networks from highly replicated gene expression profiling time series data obtained from a wellestablished model of Tcell activation. State space models are a class of dynamic Bayesian networks that assume that the obse ..."
Abstract

Cited by 63 (3 self)
 Add to MetaCart
(Show Context)
Motivation: We have used statespace models to reverse engineer transcriptional networks from highly replicated gene expression profiling time series data obtained from a wellestablished model of Tcell activation. State space models are a class of dynamic Bayesian networks that assume that the observed measurements depend on some hidden state variables that evolve according to Markovian dynamics.These hidden variables can capture effects that cannot be measured in a gene expression profiling experiment, e.g. genes that have not been included in the microarray, levels of regulatory proteins, the effects of messenger RNA and protein degradation, etc. Results: Bootstrap confidence intervals are developed for parameters representing ‘gene–gene ’ interactions over time. Our models represent the dynamics of Tcell activation and provide a methodology for the development of rational and experimentally testable hypotheses. Availability: Supplementary data and Matlab computer source code will be made available on the web at the URL given below.