Computational inference and analysis of genetic regulatory networks via a supervised combinatorial-optimization pattern

Background

Post-genome era brings about diverse categories of omics data. Inference and analysis of genetic regulatory networks act prominently in extracting inherent mechanisms, discovering and interpreting the related biological nature and living principles beneath mazy phenomena, and eventually promoting the well-beings of humankind.

Results

A supervised combinatorial-optimization pattern based on information and signal-processing theories is introduced into the inference and analysis of genetic regulatory networks. An associativity measure is proposed to define the regulatory strength/connectivity, and a phase-shift metric determines regulatory directions among components of the reconstructed networks. Thus, it solves the undirected regulatory problems arising from most of current linear/nonlinear relevance methods. In case of computational and topological redundancy, we constrain the classified group size of pair candidates within a multiobjective combinatorial optimization (MOCO) pattern.

Conclusions

We testify the proposed approach on two real-world microarray datasets of different statistical characteristics. Thus, we reveal the inherent design mechanisms for genetic networks by quantitative means, facilitating further theoretic analysis and experimental design with diverse research purposes. Qualitative comparisons with other methods and certain related focuses needing further work are illustrated within the discussion section.

     

Computational dynamics of gradient bistable networks

We describe a neural-like, homogeneous network consisting of coupled bistable elements and we study its abilities of learning, pattern recognition and computation. The technique allows new possibilities of pattern recognition, including the memorization and perfect recall of several memory patterns, without interference from spurious states. When the coupling strength between elements exceeds a critical value, the network readily converges to a unique attractor. Below this critical value one could perfectly recall all memorized patterns.     

Computational design of synthetic regulatory networks from a genetic library to characterize the designability of dynamical behaviors

The engineering of synthetic gene networks has mostly relied on the assembly of few characterized regulatory elements using rational design principles. It is of outmost importance to analyze the scalability and limits of such a design workflow. To analyze the design capabilities of libraries of regulatory elements, we have developed the first automated design approach that combines such elements to search the genotype space associated to a given phenotypic behavior. Herein, we calculated the designability of dynamical functions obtained from circuits assembled with a given genetic library. By designing circuits working as amplitude filters, pulse counters and oscillators, we could infer new mechanisms for such behaviors. We also highlighted the hierarchical design and the optimization of the interface between devices. We dissected the functional diversity of a constrained library and we found that even such libraries can provide a rich variety of behaviors. We also found that intrinsic noise slightly reduces the designability of digital circuits, but it increases the designability of oscillators. Finally, we analyzed the robust design as a strategy to counteract the evolvability and noise in gene expression of the engineered circuits within a cellular background, obtaining mechanisms for robustness through non-linear negative feedback loops.     

Computational analysis of human protein interaction networks

Large amounts of human protein interaction data have been produced by experiments and prediction methods. However, the experimental coverage of the human interactome is still low in contrast to predicted data. To gain insight into the value of publicly available human protein network data, we compared predicted datasets, high-throughput results from yeast two-hybrid screens, and literature-curated protein-protein interactions. This evaluation is not only important for further methodological improvements, but also for increasing the confidence in functional hypotheses derived from predictions. Therefore, we assessed the quality and the potential bias of the different datasets using functional similarity based on the Gene Ontology, structural iPfam domain-domain interactions, likelihood ratios, and topological network parameters. This analysis revealed major differences between predicted datasets, but some of them also scored at least as high as the experimental ones regarding multiple quality measures. Therefore, since only small pair wise overlap between most datasets is observed, they may be combined to enlarge the available human interactome data. For this purpose, we additionally studied the influence of protein length on data quality and the number of disease proteins covered by each dataset. We could further demonstrate that protein interactions predicted by more than one method achieve an elevated reliability.     

Computational identification of cellular networks and pathways

In this article we highlight recent developments in computational functional genomics to identify networks of functionally related genes and proteins based on diverse sources of genomic data. Our specific focus is on statistical methods to identify genetic networks. We discuss integrated analysis of microarray datasets, methods to combine heterogeneous data sources, the analysis of high-dimensional phenotyping screens and describe efforts to establish a reliable and unbiased gold standard for method comparison and evaluation.     

Identification of genetic networks

In this report, we propose the use of structural equations as a tool for identifying and modeling genetic networks and genetic algorithms for searching the most likely genetic networks that best fit the data. After genetic networks are identified, it is fundamental to identify those networks influencing cell phenotypes. To accomplish this task we extend the concept of differential expression of the genes, widely used in gene expression data analysis, to genetic networks. We propose a definition for the differential expression of a genetic network and use the generalized T2 statistic to measure the ability of genetic networks to distinguish different phenotypes. However, describing the differential expression of genetic networks is not enough for understanding biological systems because differences in the expression of genetic networks do not directly reflect regulatory strength between gene activities. Therefore, in this report we also introduce the concept of differentially regulated genetic networks, which has the potential to assess changes of gene regulation in response to perturbation in the environment and may provide new insights into the mechanism of diseases and biological processes. We propose five novel statistics to measure the differences in regulation of genetic networks. To illustrate the concepts and methods for reconstruction of genetic networks and identification of association of genetic networks with function, we applied the proposed models and algorithms to three data sets.     

Natural expansion of the genetic code

At the time of its discovery four decades ago, the genetic code was viewed as the result of a "frozen accident." Our current knowledge of the translation process and of the detailed structure of its components highlights the roles of RNA structure (in mRNA and tRNA), RNA modification (in tRNA), and aminoacyl-tRNA synthetase diversity in the evolution of the genetic code. The diverse assortment of codon reassignments present in subcellular organelles and organisms of distinct lineages has 'thawed' the concept of a universal immutable code; it may not be accidental that out of more than 140 amino acids found in natural proteins, only two (selenocysteine and pyrrolysine) are known to have been added to the standard 20-member amino acid alphabet. The existence of phosphoseryl-tRNA (in the form of tRNACys and tRNASec) may presage the discovery of other cotranslationally inserted modified amino acids.     

Computational approaches for modeling regulatory cellular networks

Cellular components interact with each other to form networks that process information and evoke biological responses. A deep understanding of the behavior of these networks requires the development and analysis of mathematical models. In this article, different types of mathematical representations for modeling signaling networks are described, and the advantages and disadvantages of each type are discussed. Two experimentally well-studied signaling networks are then used as examples to illustrate the insight that could be gained through modeling. Finally, the modeling approach is expanded to describe how signaling networks might regulate cellular machines and evoke phenotypic behaviors.     

Computational functions in biochemical reaction networks.

In prior work we demonstrated the implementation of logic gates, sequential computers (universal Turing machines), and parallel computers by means of the kinetics of chemical reaction mechanisms. In the present article we develop this subject further by first investigating the computational properties of several enzymatic (single and multiple) reaction mechanisms: we show their steady states are analogous to either Boolean or fuzzy logic gates. Nearly perfect digital function is obtained only in the regime in which the enzymes are saturated with their substrates. With these enzymatic gates, we construct combinational chemical networks that execute a given truth-table. The dynamic range of a network's output is strongly affected by "input/output matching" conditions among the internal gate elements. We find a simple mechanism, similar to the interconversion of fructose-6-phosphate between its two bisphosphate forms (fructose-1,6-bisphosphate and fructose-2,6-bisphosphate), that functions analogously to an AND gate. When the simple model is supplanted with one in which the enzyme rate laws are derived from experimental data, the steady state of the mechanism functions as an asymmetric fuzzy aggregation operator with properties akin to a fuzzy AND gate. The qualitative behavior of the mechanism does not change when situated within a large model of glycolysis/gluconeogenesis and the TCA cycle. The mechanism, in this case, switches the pathway's mode from glycolysis to gluconeogenesis in response to chemical signals of low blood glucose (cAMP) and abundant fuel for the TCA cycle (acetyl coenzyme A).     

Computational structural analysis of protein interactions and networks

Protein interactions have been at the focus of computational biology in recent years. In particular, interest has come from two different communities--structural and systems biology. Here, we will discuss key systems and structural biology methods that have been used for analysis and prediction of protein-protein interactions and the insight these approaches have provided on the nature and organization of protein-protein interactions inside cells.     

Computational models of signalling networks for non-linear control

Artificial signalling networks (ASNs) are a computational approach inspired by the signalling processes inside cells that decode outside environmental information. Using evolutionary algorithms to induce complex behaviours, we show how chaotic dynamics in a conservative dynamical system can be controlled. Such dynamics are of particular interest as they mimic the inherent complexity of non-linear physical systems in the real world. Considering the main biological interpretations of cellular signalling, in which complex behaviours and robust cellular responses emerge from the interaction of multiple pathways, we introduce two ASN representations: a stand-alone ASN and a coupled ASN. In particular we note how sophisticated cellular communication mechanisms can lead to effective controllers, where complicated problems can be divided into smaller and independent tasks.     

Stochastic synchronization of genetic oscillator networks

Background  

The study of synchronization among genetic oscillators is essential for the understanding of the rhythmic phenomena of living organisms at both molecular and cellular levels. Genetic networks are intrinsically noisy due to natural random intra- and inter-cellular fluctuations. Therefore, it is important to study the effects of noise perturbation on the synchronous dynamics of genetic oscillators. From the synthetic biology viewpoint, it is also important to implement biological systems that minimizing the negative influence of the perturbations.