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At least 163 records · Page 9Linked to original sources

Inferring genetic networks: An information theoretic approach

In the postgenome era many efforts have been dedicated to systematically elucidate the complex web of interacting genes and proteins. These efforts include experimental and computational methods. Microarray technology offers an opportunity for monitoring gene expression level at the genome scale. By recourse to information theory, this study proposes a mathematical approach to reconstruct gene regulatory networks at coarse-grain level from high throughput gene expression data. The method provides the {\it a posteriori} probability that a given gene regulates positively, negatively or does not regulate each one of the network genes. This approach also allows the introduction of prior knowledge and the quantification of the information gain from experimental data used in the inference procedure. This information gain can be used to chose genes to be perturbed in subsequent experiments in order to refine the knowledge about the architecture of an underlying gene regulatory network. The performance of the proposed approach has been studied by {\it in numero} experiments. Our results suggest that the approach is suitable for focusing on size-limited problems, such as, recovering a small subnetwork of interest by performing perturbation over selected genes.

q-bio.MN↗

Emergent Network Structure, evolvable Robustness and non-linear Effects of Point Mutations in an Artificial Genome Model

Genetic regulation is a key component in development, but a clear understanding of the structure and dynamics of genetic networks is not yet at hand. In this paper we investigate these properties within an artificial genome model originally introduced by Reil (1999). We analyze statistical properties of randomly generated genomes both on the sequence- and network level, and show that this model correctly predicts the frequency of genes in genomes as found in experimental data. Using an evolutionary algorithm based on stabilizing selection for a phenotype, we show that dynamical robustness against single base mutations, as well as against random changes in initial states of regulatory dynamics that mimic stochastic fluctuations in environmental conditions, can emerge in parallel. Point mutations at the sequence level have strongly non-linear effects on network wiring, including as well structurally neutral mutations and simultaneous rewiring of multiple connections, which occasionally lead to strong reorganization of the attractor landscape and metastability of evolutionary dynamics. Evolved genomes exhibit characteristic patterns on both sequence and network level.

q-bio.MN↗

Modeling of the genetic switch of bacteriophage TP901-1: A heteromer of CI and MOR ensures robust bistability

The lytic-lysogenic switch of the temperate lactococcal phage TP901-1 is fundamentally different from that of phage lambda. In phage TP901-1, the lytic promoter PL is repressed by CI whereas repression of the lysogenic promoter PR requires the presence of both of the antagonistic regulator proteins, MOR and CI. We model the central part of the switch and compare the two cases for PR repression: the one where the two regulators interact only on the DNA, and the other where the two regulators form a heteromer complex in the cytoplasm prior to DNA binding. The models are analyzed for bistability, and the predicted promoter repression folds are compared to experimental data. We conclude that the experimental data are best reproduced the latter case, where a heteromer complex forms in solution. We further find that CI sequestration by the formation of MOR:CI complexes in cytoplasm makes the genetic switch robust.

q-bio.MN↗

Proteins with greater influence on network dynamics evolve more slowly but are not more essential

A fundamental question for evolutionary biology is why rates of evolution vary dramatically between proteins. Perhaps surprisingly, it is controversial how much a protein's functional importance affects its rate of evolution. In most studies, functional importance has been measured on the coarse scale of protein knock-outs, while evolutionary rate has been measured on the fine scale of amino acid substitutions. Here we introduce dynamical influence, a finer measure of protein functional importance. To measure dynamical influence, we first use detailed biochemical models of particular reaction networks to measure the influence of each reaction rate constant on network dynamics. We then define the dynamical influence of a protein to be the average influence of the rate constants for all reactions it is involved in. Using models of a dozen biochemical systems and sequence data from vertebrates, we show that dynamical influence and evolutionary rate are negatively correlated; proteins with greater dynamical influence evolve more slowly. We also show that proteins with greater dynamical influence are not more likely to be essential. This suggests that there are many cellular reactions whose presence is essential for life, but whose quantitative rate is relatively unimportant to fitness. We also provide evidence that the effect of dynamical influence on evolutionary rate is independent of protein expression level, expression specificity, gene compactness, and reaction degree. Dynamical influence offers a finer view of functional importance, and our results suggest that focusing on essentiality may have previously led to an underestimation of the role function plays in protein evolution.

q-bio.PE↗

mRNA diffusion explains protein gradients in \textit{Drosophila} early development

We propose a new model describing the production and the establishment of the stable gradient of the Bicoid protein along the antero-posterior axis of the embryo of \textit{Drosophila}. In this model, we consider that \textit{bicoid} mRNA diffuses along the antero-posterior axis of the embryo and the protein is produced in the ribosomes localized near the syncytial nuclei. Bicoid protein stays localized near the syncytial nuclei as observed in experiments. We calibrate the parameters of the mathematical model with experimental data taken during the cleavage stages 11 to 14 of the developing embryo of \textit{Drosophila}. We obtain good agreement between the experimental and the model gradients, with relative errors in the range 5-8%. The inferred diffusion coefficient of \textit{bicoid} mRNA is in the range 4.6\times 10^{-12}-1.5\times 10^{-11}m^2s^{-1}, in agreement with the theoretical predictions and experimental measurements for the diffusion of macromolecules in the cytoplasm. We show that the model based on the mRNA diffusion hypothesis is consistent with the known observational data, supporting the recent experimental findings of the gradient of \textit{bicoid} mRNA in \textit{Drosophila} [Spirov et al. (2009) Development 136:605-614].

q-bio.QM↗

Emergent thresholds in genetic regulatory networks: Protein patterning in Drosophila morphogenesis

We present a general methodology in order to build mathematical models of genetic regulatory networks. This approach is based on the mass action law and on the Jacob and Monod operon model. The mathematical models are built symbolically by the \emph{Mathematica} software package \emph{GeneticNetworks}. This package accepts as input the interaction graphs of the transcriptional activators and repressors and, as output, gives the mathematical model in the form of a system of ordinary differential equations. All the relevant biological parameters are chosen automatically by the software. Within this framework, we show that threshold effects in biology emerge from the catalytic properties of genes and its associated conservation laws. We apply this methodology to the segment patterning in \emph{Drosophila} early development and we calibrate and validate the genetic transcriptional network responsible for the patterning of the gap proteins Hunchback and Knirps, along the antero-posterior axis of the \emph{Drosophila} embryo. This shows that patterning at the gap genes stage is a consequence of the relations between the transcriptional regulators and their initial conditions along the embryo.

q-bio.QM↗

The Stability of Boolean Networks with Generalized Canalizing Rules

Boolean networks are discrete dynamical systems in which the state (zero or one) of each node is updated at each time t to a state determined by the states at time t-1 of those nodes that have links to it. When these systems are used to model genetic control, the case of 'canalizing' update rules is of particular interest. A canalizing rule is one for which a node state at time $t$ is determined by the state at time t-1 of a single one of its inputs when that inputting node is in its canalizing state. Previous work on the order/disorder transition in Boolean networks considered complex, non-random network topology. In the current paper we extend this previous work to account for canalizing behavior.

q-bio.MN↗

Sparse essential interactions in model networks of gene regulation

Gene regulatory networks typically have low in-degrees, whereby any given gene is regulated by few of the genes in the network. What mechanisms might be responsible for these low in-degrees? Starting with an accepted framework of the binding of transcription factors to DNA, we consider a simple model of gene regulatory dynamics. In this model, we show that the constraint of having a given function leads to the emergence of minimum connectivities compatible with function. We exhibit mathematically this behavior within a limit of our model and show that it also arises in the full model. As a consequence, functionality in these gene networks is parsimonious, i.e., is concentrated on a sparse number of interactions as measured for instance by their essentiality. Our model thus provides a simple mechanism for the emergence of sparse regulatory networks, and leads to very heterogeneous effects of mutations.

q-bio.MN↗

Investigating the robustness of the classical enzyme kinetic equations in small intracellular compartments

Classical descriptions of enzyme kinetics ignore the physical nature of the intracellular environment. Main implicit assumptions behind such approaches are that reactions occur in compartment volumes which are large enough so that molecular discreteness can be ignored and that molecular transport occurs via diffusion. Starting from a master equation description of enzyme reaction kinetics and assuming metabolic steady-state conditions, we derive novel mesoscopic rate equations which take into account (i) the intrinsic molecular noise due to the low copy number of molecules in intracellular compartments (ii) the physical nature of the substrate transport process, i.e. diffusion or vesicle-mediated transport. These equations replace the conventional macroscopic and deterministic equations in the context of intracellular kinetics. The latter are recovered in the limit of infinite compartment volumes. We find that deviations from the predictions of classical kinetics are pronounced (hundreds of percent in the estimate for the reaction velocity) for enzyme reactions occurring in compartments which are smaller than approximately 200nm, for the case of substrate transport to the compartment being mediated principally by vesicle or granule transport and in the presence of competitive enzyme inhibitors. This has implications for the common approach of modelling large intracellular reaction networks using ordinary differential equations and also for the calculation of the effective dosage of competitive inhibitor drugs.

q-bio.SC↗

Analysis of interaction partners of H4 histone by a new proteomics approach

We describe a modification of the TAP method for purification and analysis of multiprotein complexes, termed here DEF-TAP (for Differential Elution Fractionation after Tandem Affinity Purification). Its essential new feature is the use for last purification step of 6XHis-Ni++ interaction, which is resistant to a variety of harsh washing conditions, including high ionic strength and presence of organic solvents. This allows us to use various fractionation schemes before the protease digestion, which is expected to improve the coverage of the analysed protein mixture and also to provide an additional insight into the structure of the purified macromolecular complex and the nature of protein-protein interactions involved. We illustrate our new approach by analysis of soluble nuclear complexes containing histone H4 purified from HeLa cells. In particular, we observed different fractionation patterns of HAT1 and RbAp46 proteins as compared to RbAp48 protein, all identified as interaction partners of H4 histone. In addition, we report all components of the licensing MCM2-7 complex and the apoptosis-related DAXX protein among the interaction partners of the soluble H4. Finally, we show that HAT1 requires N-terminal tail of H4 for its stable association with this histone.

q-bio.MN↗

Theoretical analyses predict A20 regulates period of NF-kB oscillation

The nuclear-cytoplasmic shuttling of NF-kB is characterized by damped oscillations of the nuclear concentration with a time period of around 1-2 hours. The NF-kB network contains several feedback loops modulating the overall response of NF-kB activity. While IkBa is known to drive and IkBe is known to dampen the oscillations, the precise role of A20 negative feedback remains to be elucidated. Here we propose a model of the NF-kB system focusing on three negative feedback loops (IkBa, IkBe and A20) which capture the experimentally observed responses in wild-type and knockout cells. We find that A20, like IkBe, efficiently dampens the oscillations albeit through a distinct mechanism. In addition, however, we have discovered a new functional role of A20 by which it controls the oscillation period of nuclear NF-kB. The design based on three nested feedback loops allows independent control of period and amplitude decay in the oscillatory response. Based on these results we predict that adjusting the expression level of A20, e.g. by siRNA, the period can be changed by up to a factor 2.

physics.bio-ph↗

Mapping Complex Networks: Exploring Boolean Modeling of Signal Transduction Pathways

In this study, we explored the utility of a descriptive and predictive bionetwork model for phospholipase C-coupled calcium signaling pathways, built with non-kinetic experimental information. Boolean models generated from these data yield oscillatory activity patterns for both the endoplasmic reticulum resident inositol-1,4,5-trisphosphate receptor (IP3R) and the plasma-membrane resident canonical transient receptor potential channel 3 (TRPC3). These results are specific as randomization of the Boolean operators ablates oscillatory pattern formation. Furthermore, knock-out simulations of the IP3R, TRPC3, and multiple other proteins recapitulate experimentally derived results. The potential of this approach can be observed by its ability to predict previously undescribed cellular phenotypes using in vitro experimental data. Indeed our cellular analysis of the developmental and calcium-regulatory protein, DANGER1a, confirms the counter-intuitive predictions from our Boolean models in two highly relevant cellular models. Based on these results, we theorize that with sufficient legacy knowledge and/or computational biology predictions, Boolean networks provide a robust method for predictive-modeling of any biological system.

q-bio.MN↗

Calibration and validation of a genetic regulatory network model describing the production of the gap gene protein Hunchback in \emph{Drosophila} early development

We fit the parameters of a differential equations model describing the production of gap gene proteins Hunchback and Knirps along the antero-posterior axis of the embryo of \emph{Drosophila}. As initial data for the differential equations model, we take the antero-posterior distribution of the proteins Bicoid, Hunchback and Tailless at the beginning of cleavage cycle 14. We calibrate and validate the model with experimental data using single- and multi-objective evolutionary optimization techniques. In the multi-objective optimization technique, we compute the associated Pareto fronts. We analyze the cross regulation mechanism between the gap-genes protein pair Hunchback-Knirps and we show that the posterior distribution of Hunchback follow the experimental data if Hunchback is negatively regulated by the Huckebein protein. This approach enables to predict the posterior localization on the embryo of the protein Huckebein, and we validate with the experimental data the genetic regulatory network responsible for the antero-posterior distribution of the gap gene protein Hunchback. We discuss the importance of Pareto multi-objective optimization techniques in the calibration and validation of biological models.

q-bio.MN↗

A quantum spin approach to histone dynamics

Post-translational modifications of histone proteins are an important factor in epigenetic control that serve to regulate transcription, depending on the particular modification states of the histone proteins. We study the stochastic dynamics of histone protein states, taking into account a feedback mechanism where modified nucleosomes recruit enzymes that diffuse to adjacent nucleosomes. We map the system onto a quantum spin system whose dynamics is generated by a non-Hermitian Hamiltonian. Making an ansatz for the solution as a tensor product state leads to nonlinear partial differential equations that describe the dynamics of the system. Multiple stable histone states appear in a parameter regime whose size increases with increasing number of modification sites. We discuss the role of the spatial dependance, and we consider the effects of spatially heterogeneous enzymatic activity. Finally, we consider multistability in a model of several types of correlated post-translational modifications.

q-bio.MN↗

Enzymatic Logic Gates with Noise-Reducing Sigmoid Response

Biochemical computing is an emerging field of unconventional computing that attempts to process information with biomolecules and biological objects using digital logic. In this work we survey filtering in general, in biochemical computing, and summarize the experimental realization of an AND logic gate with sigmoid response in one of the inputs. The logic gate is realized with electrode-immobilized glucose-6-phosphate dehydrogenase enzyme that catalyzes a reaction corresponding to the Boolean AND functions. A kinetic model is also developed and used to evaluate the extent to which the performance of the experimentally realized logic gate is close to optimal.

cond-mat.soft↗

Inspiration from genetics to promote recognition and protection within ad hoc sensor networks

This work illustrates potentials for recognition within {\em ad hoc} sensor networks if their nodes possess individual inter-related biologically inspired genetic codes. The work takes ideas from natural immune systems protecting organisms from infection. Nodes in the present proposal have individual gene sets fitting into a self organised phylogenetic tree. Members of this population are genetically ''relatives''. Outsiders cannot easily copy or introduce a new node in the network without going through a process of conception between two nodes in the population. Related nodes can locally decide to check each other for their genetic relation without directly revealing their gene sets. A copy/clone of a gene sequence or a random gene set will appear as alien. Nodes go through a cycle of introduction (conception or ''birth'') with parents in the network and later exit from it (''death''). Hence the phylogenetic tree is dynamic or possesses a genetic drift. Typical lifetimes of gene sets and number of offspring from different parents affect this genetic drift and the level of correlation between gene sets. The frequency of mutations similarly affects the gene pool. Correlation between genes of the nodes implies a common secret for cryptographic material for communication and consistency check facilitating intrusion detection and tracing of events. A node can by itself (non-specifically) recognise an adversary if it does not respond properly according to its genes. Nodes can also collaborate to recognise adversaries by communicating response from intruders to check for consistency with the whole gene pool (phylogenetic tree).

cs.CR↗

A survey of statistical network models

Networks are ubiquitous in science and have become a focal point for discussion in everyday life. Formal statistical models for the analysis of network data have emerged as a major topic of interest in diverse areas of study, and most of these involve a form of graphical representation. Probability models on graphs date back to 1959. Along with empirical studies in social psychology and sociology from the 1960s, these early works generated an active network community and a substantial literature in the 1970s. This effort moved into the statistical literature in the late 1970s and 1980s, and the past decade has seen a burgeoning network literature in statistical physics and computer science. The growth of the World Wide Web and the emergence of online networking communities such as Facebook, MySpace, and LinkedIn, and a host of more specialized professional network communities has intensified interest in the study of networks and network data. Our goal in this review is to provide the reader with an entry point to this burgeoning literature. We begin with an overview of the historical development of statistical network modeling and then we introduce a number of examples that have been studied in the network literature. Our subsequent discussion focuses on a number of prominent static and dynamic network models and their interconnections. We emphasize formal model descriptions, and pay special attention to the interpretation of parameters and their estimation. We end with a description of some open problems and challenges for machine learning and statistics.

stat.ME↗

On the Stability of Metabolic Cycles

We investigate the stability properties of two different classes of metabolic cycles using a combination of analytical and computational methods. Using principles from structural kinetic modeling (SKM), we show that the stability of metabolic networks with certain structural regularities can be studied using a combination of analytical and computational techniques. We then apply these techniques to a class of single input, single output metabolic cycles, and find that the cycles are stable under all conditions tested. Next, we extend our analysis to a small autocatalytic cycle, and determine parameter regimes within which the cycle is very likely to be stable. We demonstrate that analytical methods can be used to understand the relationship between kinetic parameters and stability, and that results from these analytical methods can be confirmed with computational experiments. In addition, our results suggest that elevated metabolite concentrations and certain crucial saturation parameters can strongly affect the stability of the entire metabolic cycle. We discuss our results in light of the possibility that evolutionary forces may select for metabolic network topologies with a high intrinsic probability of being stable. Furthermore, our conclusions support the hypothesis that certain types of metabolic cycles may have played a role in the development of primitive metabolism despite the absence of regulatory mechanisms.

q-bio.MN↗