20,620 research outputs found
Inferring Regulatory Networks by Combining Perturbation Screens and Steady State Gene Expression Profiles
Reconstructing transcriptional regulatory networks is an important task in
functional genomics. Data obtained from experiments that perturb genes by
knockouts or RNA interference contain useful information for addressing this
reconstruction problem. However, such data can be limited in size and/or are
expensive to acquire. On the other hand, observational data of the organism in
steady state (e.g. wild-type) are more readily available, but their
informational content is inadequate for the task at hand. We develop a
computational approach to appropriately utilize both data sources for
estimating a regulatory network. The proposed approach is based on a three-step
algorithm to estimate the underlying directed but cyclic network, that uses as
input both perturbation screens and steady state gene expression data. In the
first step, the algorithm determines causal orderings of the genes that are
consistent with the perturbation data, by combining an exhaustive search method
with a fast heuristic that in turn couples a Monte Carlo technique with a fast
search algorithm. In the second step, for each obtained causal ordering, a
regulatory network is estimated using a penalized likelihood based method,
while in the third step a consensus network is constructed from the highest
scored ones. Extensive computational experiments show that the algorithm
performs well in reconstructing the underlying network and clearly outperforms
competing approaches that rely only on a single data source. Further, it is
established that the algorithm produces a consistent estimate of the regulatory
network.Comment: 24 pages, 4 figures, 6 table
Buffered Qualitative Stability explains the robustness and evolvability of transcriptional networks
The gene regulatory network (GRN) is the central decision‐making module of the cell. We have developed a theory called Buffered Qualitative Stability (BQS) based on the hypothesis that GRNs are organised so that they remain robust in the face of unpredictable environmental and evolutionary changes. BQS makes strong and diverse predictions about the network features that allow stable responses under arbitrary perturbations, including the random addition of new connections. We show that the GRNs of E. coli, M. tuberculosis, P. aeruginosa, yeast, mouse, and human all verify the predictions of BQS. BQS explains many of the small- and large‐scale properties of GRNs, provides conditions for evolvable robustness, and highlights general features of transcriptional response. BQS is severely compromised in a human cancer cell line, suggesting that loss of BQS might underlie the phenotypic plasticity of cancer cells, and highlighting a possible sequence of GRN alterations concomitant with cancer initiation. DOI: http://dx.doi.org/10.7554/eLife.02863.00
Sparse regulatory networks
In many organisms the expression levels of each gene are controlled by the
activation levels of known "Transcription Factors" (TF). A problem of
considerable interest is that of estimating the "Transcription Regulation
Networks" (TRN) relating the TFs and genes. While the expression levels of
genes can be observed, the activation levels of the corresponding TFs are
usually unknown, greatly increasing the difficulty of the problem. Based on
previous experimental work, it is often the case that partial information about
the TRN is available. For example, certain TFs may be known to regulate a given
gene or in other cases a connection may be predicted with a certain
probability. In general, the biology of the problem indicates there will be
very few connections between TFs and genes. Several methods have been proposed
for estimating TRNs. However, they all suffer from problems such as unrealistic
assumptions about prior knowledge of the network structure or computational
limitations. We propose a new approach that can directly utilize prior
information about the network structure in conjunction with observed gene
expression data to estimate the TRN. Our approach uses penalties on the
network to ensure a sparse structure. This has the advantage of being
computationally efficient as well as making many fewer assumptions about the
network structure. We use our methodology to construct the TRN for E. coli and
show that the estimate is biologically sensible and compares favorably with
previous estimates.Comment: Published in at http://dx.doi.org/10.1214/10-AOAS350 the Annals of
Applied Statistics (http://www.imstat.org/aoas/) by the Institute of
Mathematical Statistics (http://www.imstat.org
Inference of the genetic network regulating lateral root initiation in Arabidopsis thaliana
Regulation of gene expression is crucial for organism growth, and it is one of the challenges in Systems Biology to reconstruct the underlying regulatory biological networks from transcriptomic data. The formation of lateral roots in Arabidopsis thaliana is stimulated by a cascade of regulators of which only the interactions of its initial elements have been identified. Using simulated gene expression data with known network topology, we compare the performance of inference algorithms, based on different approaches, for which ready-to-use software is available. We show that their performance improves with the network size and the inclusion of mutants. We then analyse two sets of genes, whose activity is likely to be relevant to lateral root initiation in Arabidopsis, by integrating sequence analysis with the intersection of the results of the best performing methods on time series and mutants to infer their regulatory network. The methods applied capture known interactions between genes that are candidate regulators at early stages of development. The network inferred from genes significantly expressed during lateral root formation exhibits distinct scale-free, small world and hierarchical properties and the nodes with a high out-degree may warrant further investigation
Mathematical modelling plant signalling networks
During the last two decades, molecular genetic studies and the completion of the sequencing of the Arabidopsis thaliana genome have increased knowledge of hormonal regulation in plants. These signal transduction pathways act in concert through gene regulatory and signalling networks whose main components have begun to be elucidated. Our understanding of the resulting cellular processes is hindered by the complex, and sometimes counter-intuitive, dynamics of the networks, which may be interconnected through feedback controls and cross-regulation. Mathematical modelling provides a valuable tool to investigate such dynamics and to perform in silico experiments that may not be easily carried out in a laboratory. In this article, we firstly review general methods for modelling gene and signalling networks and their application in plants. We then describe specific models of hormonal perception and cross-talk in plants. This sub-cellular analysis paves the way for more comprehensive mathematical studies of hormonal transport and signalling in a multi-scale setting
Penalized Likelihood Methods for Estimation of Sparse High Dimensional Directed Acyclic Graphs
Directed acyclic graphs (DAGs) are commonly used to represent causal
relationships among random variables in graphical models. Applications of these
models arise in the study of physical, as well as biological systems, where
directed edges between nodes represent the influence of components of the
system on each other. The general problem of estimating DAGs from observed data
is computationally NP-hard, Moreover two directed graphs may be observationally
equivalent. When the nodes exhibit a natural ordering, the problem of
estimating directed graphs reduces to the problem of estimating the structure
of the network. In this paper, we propose a penalized likelihood approach that
directly estimates the adjacency matrix of DAGs. Both lasso and adaptive lasso
penalties are considered and an efficient algorithm is proposed for estimation
of high dimensional DAGs. We study variable selection consistency of the two
penalties when the number of variables grows to infinity with the sample size.
We show that although lasso can only consistently estimate the true network
under stringent assumptions, adaptive lasso achieves this task under mild
regularity conditions. The performance of the proposed methods is compared to
alternative methods in simulated, as well as real, data examples.Comment: 19 pages, 8 figure
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