30,702 research outputs found
A fast and efficient gene-network reconstruction method from multiple over-expression experiments
<p>Abstract</p> <p>Background</p> <p>Reverse engineering of gene regulatory networks presents one of the big challenges in systems biology. Gene regulatory networks are usually inferred from a set of single-gene over-expressions and/or knockout experiments. Functional relationships between genes are retrieved either from the steady state gene expressions or from respective time series.</p> <p>Results</p> <p>We present a novel algorithm for gene network reconstruction on the basis of steady-state gene-chip data from over-expression experiments. The algorithm is based on a straight forward solution of a linear gene-dynamics equation, where experimental data is fed in as a first predictor for the solution. We compare the algorithm's performance with the NIR algorithm, both on the well known <it>E. coli </it>experimental data and on in-silico experiments.</p> <p>Conclusion</p> <p>We show superiority of the proposed algorithm in the number of correctly reconstructed links and discuss computational time and robustness. The proposed algorithm is not limited by combinatorial explosion problems and can be used in principle for large networks.</p
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
Two-photon imaging and analysis of neural network dynamics
The glow of a starry night sky, the smell of a freshly brewed cup of coffee
or the sound of ocean waves breaking on the beach are representations of the
physical world that have been created by the dynamic interactions of thousands
of neurons in our brains. How the brain mediates perceptions, creates thoughts,
stores memories and initiates actions remains one of the most profound puzzles
in biology, if not all of science. A key to a mechanistic understanding of how
the nervous system works is the ability to analyze the dynamics of neuronal
networks in the living organism in the context of sensory stimulation and
behaviour. Dynamic brain properties have been fairly well characterized on the
microscopic level of individual neurons and on the macroscopic level of whole
brain areas largely with the help of various electrophysiological techniques.
However, our understanding of the mesoscopic level comprising local populations
of hundreds to thousands of neurons (so called 'microcircuits') remains
comparably poor. In large parts, this has been due to the technical
difficulties involved in recording from large networks of neurons with
single-cell spatial resolution and near- millisecond temporal resolution in the
brain of living animals. In recent years, two-photon microscopy has emerged as
a technique which meets many of these requirements and thus has become the
method of choice for the interrogation of local neural circuits. Here, we
review the state-of-research in the field of two-photon imaging of neuronal
populations, covering the topics of microscope technology, suitable fluorescent
indicator dyes, staining techniques, and in particular analysis techniques for
extracting relevant information from the fluorescence data. We expect that
functional analysis of neural networks using two-photon imaging will help to
decipher fundamental operational principles of neural microcircuits.Comment: 36 pages, 4 figures, accepted for publication in Reports on Progress
in Physic
How to understand the cell by breaking it: network analysis of gene perturbation screens
Modern high-throughput gene perturbation screens are key technologies at the
forefront of genetic research. Combined with rich phenotypic descriptors they
enable researchers to observe detailed cellular reactions to experimental
perturbations on a genome-wide scale. This review surveys the current
state-of-the-art in analyzing perturbation screens from a network point of
view. We describe approaches to make the step from the parts list to the wiring
diagram by using phenotypes for network inference and integrating them with
complementary data sources. The first part of the review describes methods to
analyze one- or low-dimensional phenotypes like viability or reporter activity;
the second part concentrates on high-dimensional phenotypes showing global
changes in cell morphology, transcriptome or proteome.Comment: Review based on ISMB 2009 tutorial; after two rounds of revisio
A sparse regulatory network of copy-number driven expression reveals putative breast cancer oncogenes
The influence of DNA cis-regulatory elements on a gene's expression has been
intensively studied. However, little is known about expressions driven by
trans-acting DNA hotspots. DNA hotspots harboring copy number aberrations are
recognized to be important in cancer as they influence multiple genes on a
global scale. The challenge in detecting trans-effects is mainly due to the
computational difficulty in detecting weak and sparse trans-acting signals
amidst co-occuring passenger events. We propose an integrative approach to
learn a sparse interaction network of DNA copy-number regions with their
downstream targets in a breast cancer dataset. Information from this network
helps distinguish copy-number driven from copy-number independent expression
changes on a global scale. Our result further delineates cis- and trans-effects
in a breast cancer dataset, for which important oncogenes such as ESR1 and
ERBB2 appear to be highly copy-number dependent. Further, our model is shown to
be efficient and in terms of goodness of fit no worse than other state-of the
art predictors and network reconstruction models using both simulated and real
data.Comment: Accepted at IEEE International Conference on Bioinformatics &
Biomedicine (BIBM 2010
Detection of regulator genes and eQTLs in gene networks
Genetic differences between individuals associated to quantitative phenotypic
traits, including disease states, are usually found in non-coding genomic
regions. These genetic variants are often also associated to differences in
expression levels of nearby genes (they are "expression quantitative trait
loci" or eQTLs for short) and presumably play a gene regulatory role, affecting
the status of molecular networks of interacting genes, proteins and
metabolites. Computational systems biology approaches to reconstruct causal
gene networks from large-scale omics data have therefore become essential to
understand the structure of networks controlled by eQTLs together with other
regulatory genes, and to generate detailed hypotheses about the molecular
mechanisms that lead from genotype to phenotype. Here we review the main
analytical methods and softwares to identify eQTLs and their associated genes,
to reconstruct co-expression networks and modules, to reconstruct causal
Bayesian gene and module networks, and to validate predicted networks in
silico.Comment: minor revision with typos corrected; review article; 24 pages, 2
figure
Inferring causal relations from multivariate time series : a fast method for large-scale gene expression data
Various multivariate time series analysis techniques have been developed with the aim of inferring causal relations between time series. Previously, these techniques have proved their effectiveness on economic and neurophysiological data, which normally consist of hundreds of samples. However, in their applications to gene regulatory inference, the small sample size of gene expression time series poses an obstacle. In this paper, we describe some of the most commonly used multivariate inference techniques and show the potential challenge related to gene expression analysis. In response, we propose a directed partial correlation (DPC) algorithm as an efficient and effective solution to causal/regulatory relations inference on small sample gene expression data. Comparative evaluations on the existing techniques and the proposed method are presented. To draw reliable conclusions, a comprehensive benchmarking on data sets of various setups is essential. Three experiments are designed to assess these methods in a coherent manner. Detailed analysis of experimental results not only reveals good accuracy of the proposed DPC method in large-scale prediction, but also gives much insight into all methods under evaluation
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