EURASIP journal on bioinformatics & systems biology最新文献

In recent work, attempts have been made to link the structure of biochemical networks to their complex dynamics. It was shown that structurally stable network motifs are enriched in such networks. In this work, we investigate to what extent these findings apply to metabolic networks. To this end, we extend a previously proposed method by changing the null model for determining motif enrichment, by using interaction types directly obtained from structural interaction matrices, by generating a distribution of partial derivatives of reaction rates and by simulating enzymatic regulation on metabolic networks. Our findings suggest that the conclusions drawn in previous work cannot be extended to metabolic networks, that is, structurally stable network motifs are not enriched in metabolic networks.

Computational gene regulation models provide a means for scientists to draw biological inferences from time-course gene expression data. Based on the state-space approach, we developed a new modeling tool for inferring gene regulatory networks, called time-delayed Gene Regulatory Networks (tdGRNs). tdGRN takes time-delayed regulatory relationships into consideration when developing the model. In addition, a priori biological knowledge from genome-wide location analysis is incorporated into the structure of the gene regulatory network. tdGRN is evaluated on both an artificial dataset and a published gene expression data set. It not only determines regulatory relationships that are known to exist but also uncovers potential new ones. The results indicate that the proposed tool is effective in inferring gene regulatory relationships with time delay. tdGRN is complementary to existing methods for inferring gene regulatory networks. The novel part of the proposed tool is that it is able to infer time-delayed regulatory relationships.

To accomplish adaptability, all living organisms are constructed of regulatory networks on different levels which are capable to differentially respond to a variety of environmental inputs. Structure of regulatory networks determines their phenotypical plasticity, that is, the degree of detail and appropriateness of regulatory replies to environmental or developmental challenges. This regulatory network structure is encoded within the genotype. Our conceptual simulation study investigates how network structure constrains the evolution of networks and their adaptive abilities. The focus is on the structural parameter network size. We show that small regulatory networks adapt fast, but not as good as larger networks in the longer perspective. Selection leads to an optimal network size dependent on heterogeneity of the environment and time pressure of adaptation. Optimal mutation rates are higher for smaller networks. We put special emphasis on discussing our simulation results on the background of functional observations from experimental and evolutionary biology.

The reverse engineering of transcription regulatory networks from expression data is gaining large interest in the bioinformatics community. An important family of inference techniques is represented by algorithms based on information theoretic measures which rely on the computation of pairwise mutual information. This paper aims to study the impact of the entropy estimator on the quality of the inferred networks. This is done by means of a comprehensive study which takes into consideration three state-of-the-art mutual information algorithms: ARACNE, CLR, and MRNET. Two different setups are considered in this work. The first one considers a set of 12 synthetically generated datasets to compare 8 different entropy estimators and three network inference algorithms. The two methods emerging as the most accurate ones from the first set of experiments are the MRNET method combined with the newly applied Spearman correlation and the CLR method combined with the Pearson correlation. The validation of these two techniques is then carried out on a set of 10 public domain microarray datasets measuring the transcriptional regulatory activity in the yeast organism.

Compressive sensing microarrays (CSMs) are DNA-based sensors that operate using group testing and compressive sensing (CS) principles. In contrast to conventional DNA microarrays, in which each genetic sensor is designed to respond to a single target, in a CSM, each sensor responds to a set of targets. We study the problem of designing CSMs that simultaneously account for both the constraints from CS theory and the biochemistry of probe-target DNA hybridization. An appropriate cross-hybridization model is proposed for CSMs, and several methods are developed for probe design and CS signal recovery based on the new model. Lab experiments suggest that in order to achieve accurate hybridization profiling, consensus probe sequences are required to have sequence homology of at least 80% with all targets to be detected. Furthermore, out-of-equilibrium datasets are usually as accurate as those obtained from equilibrium conditions. Consequently, one can use CSMs in applications in which only short hybridization times are allowed.

We propose a network structure-based model for heterosis, and investigate it relying on metabolite profiles from Arabidopsis. A simple feed-forward two-layer network model (the Steinbuch matrix) is used in our conceptual approach. It allows for directly relating structural network properties with biological function. Interpreting heterosis as increased adaptability, our model predicts that the biological networks involved show increasing connectivity of regulatory interactions. A detailed analysis of metabolite profile data reveals that the increasing-connectivity prediction is true for graphical Gaussian models in our data from early development. This mirrors properties of observed heterotic Arabidopsis phenotypes. Furthermore, the model predicts a limit for increasing hybrid vigor with increasing heterozygosity--a known phenomenon in the literature.

Understanding the mechanisms of gene transcriptional regulation through analysis of high-throughput postgenomic data is one of the central problems of computational systems biology. Various approaches have been proposed, but most of them fail to address at least one of the following objectives: (1) allow for the fact that transcription factors are potentially subject to posttranscriptional regulation; (2) allow for the fact that transcription factors cooperate as a functional complex in regulating gene expression, and (3) provide a model and a learning algorithm with manageable computational complexity. The objective of the present study is to propose and test a method that addresses these three issues. The model we employ is a mixture of factor analyzers, in which the latent variables correspond to different transcription factors, grouped into complexes or modules. We pursue inference in a Bayesian framework, using the Variational Bayesian Expectation Maximization (VBEM) algorithm for approximate inference of the posterior distributions of the model parameters, and estimation of a lower bound on the marginal likelihood for model selection. We have evaluated the performance of the proposed method on three criteria: activity profile reconstruction, gene clustering, and network inference.

There has been considerable interest recently in the application of bagging in the classification of both gene-expression data and protein-abundance mass spectrometry data. The approach is often justified by the improvement it produces on the performance of unstable, overfitting classification rules under small-sample situations. However, the question of real practical interest is whether the ensemble scheme will improve performance of those classifiers sufficiently to beat the performance of single stable, nonoverfitting classifiers, in the case of small-sample genomic and proteomic data sets. To investigate that question, we conducted a detailed empirical study, using publicly-available data sets from published genomic and proteomic studies. We observed that, under t-test and RELIEF filter-based feature selection, bagging generally does a good job of improving the performance of unstable, overfitting classifiers, such as CART decision trees and neural networks, but that improvement was not sufficient to beat the performance of single stable, nonoverfitting classifiers, such as diagonal and plain linear discriminant analysis, or 3-nearest neighbors. Furthermore, as expected, the ensemble method did not improve the performance of these classifiers significantly. Representative experimental results are presented and discussed in this work.

Gene-Gene dependency plays a very important role in system biology as it pertains to the crucial understanding of different biological mechanisms. Time-course microarray data provides a new platform useful to reveal the dynamic mechanism of gene-gene dependencies. Existing interaction measures are mostly based on association measures, such as Pearson or Spearman correlations. However, it is well known that such interaction measures can only capture linear or monotonic dependency relationships but not for nonlinear combinatorial dependency relationships. With the invocation of hidden Markov models, we propose a new measure of pairwise dependency based on transition probabilities. The new dynamic interaction measure checks whether or not the joint transition kernel of the bivariate state variables is the product of two marginal transition kernels. This new measure enables us not only to evaluate the strength, but also to infer the details of gene dependencies. It reveals nonlinear combinatorial dependency structure in two aspects: between two genes and across adjacent time points. We conduct a bootstrap-based chi(2) test for presence/absence of the dependency between every pair of genes. Simulation studies and real biological data analysis demonstrate the application of the proposed method. The software package is available under request.

An approximate representation for the state space of a context-sensitive probabilistic Boolean network has previously been proposed and utilized to devise therapeutic intervention strategies. Whereas the full state of a context-sensitive probabilistic Boolean network is specified by an ordered pair composed of a network context and a gene-activity profile, this approximate representation collapses the state space onto the gene-activity profiles alone. This reduction yields an approximate transition probability matrix, absent of context, for the Markov chain associated with the context-sensitive probabilistic Boolean network. As with many approximation methods, a price must be paid for using a reduced model representation, namely, some loss of optimality relative to using the full state space. This paper examines the effects on intervention performance caused by the reduction with respect to various values of the model parameters. This task is performed using a new derivation for the transition probability matrix of the context-sensitive probabilistic Boolean network. This expression of transition probability distributions is in concert with the original definition of context-sensitive probabilistic Boolean network. The performance of optimal and approximate therapeutic strategies is compared for both synthetic networks and a real case study. It is observed that the approximate representation describes the dynamics of the context-sensitive probabilistic Boolean network through the instantaneously random probabilistic Boolean network with similar parameters.