Controlling the Effects of External Perturbations on a Gene Regulatory Network Using Proportional-Integral-Derivative Controller.

Gene regulatory networks are biologically robust, which imparts resilience to living systems against most external perturbations affecting them. However, there is a limit to this and disturbances beyond this limit can impart unwanted signalling on one or more master regulators in a network. Certain disturbances may affect the functioning of other constituent genes of the same network. In most cases, this phenomenon can have some effect on the functioning of the living organism. In this investigation, we have proposed a methodology to mitigate the effects of external perturbations on a genetic network using a proportional-integral-derivative controller. The proposed controller has been used to perturb one or more of the other unaffected master regulators such that the most affected gene/s of the network revert to their normal state. The only required condition of such type of manoeuvring is that there should be multiple master regulators in a network. The proposed technique has been experimented on a 10-gene DREAM4 benchmark network and also on a larger 20-gene network, where only downregulation has been considered due to data constraints. Simulation results indicate that the most vulnerable genes can be reverted to their normal expression levels in 10 out of the 16 simulations performed.

Modified Half-System Based Method for Reverse Engineering of Gene Regulatory Networks.

The accurate reconstruction of gene regulatory networks for proper understanding of the intricacies of complex biological mechanisms still provides motivation for researchers. Due to accessibility of various gene expression data, we can now attempt to computationally infer genetic interactions. Among the established network inference techniques, S-system is preferred because of its efficiency in replicating biological systems though it is computationally more expensive. This provides motivation for us to develop a similar system with lesser computational load. In this work, we have proposed a novel methodology for reverse engineering of gene regulatory networks based on a new technique: half-system. Half-systems use half the number of parameters compared to S-systems and thus significantly reduce the computational complexity. We have implemented our proposed technique for reconstructing four benchmark networks from their corresponding temporal expression profiles: an 8-gene, a 10-gene, and two 20-gene networks. Being a new technique, to the best of our knowledge, there are no comparable results for this in the contemporary literature. Therefore, we have compared our results with those obtained from the contemporary literature using other methodologies, including the state-of-the-art method, GENIE3. The results obtained in this work stack favourably against the competition, even showing quantifiable improvements in some cases.

An approach for reduction of false predictions in reverse engineering of gene regulatory networks.

A gene regulatory network discloses the regulatory interactions amongst genes, at a particular condition of the human body. The accurate reconstruction of such networks from time-series genetic expression data using computational tools offers a stiff challenge for contemporary computer scientists. This is crucial to facilitate the understanding of the proper functioning of a living organism. Unfortunately, the computational methods produce many false predictions along with the correct predictions, which is unwanted. Investigations in the domain focus on the identification of as many correct regulations as possible in the reverse engineering of gene regulatory networks to make it more reliable and biologically relevant. One way to achieve this is to reduce the number of incorrect predictions in the reconstructed networks. In the present investigation, we have proposed a novel scheme to decrease the number of false predictions by suitably combining several metaheuristic techniques. We have implemented the same using a dataset ensemble approach (i.e. combining multiple datasets) also. We have employed the proposed methodology on real-world experimental datasets of the SOS DNA Repair network of Escherichia coli and the IMRA network of Saccharomyces cerevisiae. Subsequently, we have experimented upon somewhat larger, in silico networks, namely, DREAM3 and DREAM4 Challenge networks, and 15-gene and 20-gene networks extracted from the GeneNetWeaver database. To study the effect of multiple datasets on the quality of the inferred networks, we have used four datasets in each experiment. The obtained results are encouraging enough as the proposed methodology can reduce the number of false predictions significantly, without using any supplementary prior biological information for larger gene regulatory networks. It is also observed that if a small amount of prior biological information is incorporated here, the results improve further w.r.t. the prediction of true positives.

Construction of Gene Regulatory Networks Using Recurrent Neural Networks and Swarm Intelligence.

We have proposed a methodology for the reverse engineering of biologically plausible gene regulatory networks from temporal genetic expression data. We have used established information and the fundamental mathematical theory for this purpose. We have employed the Recurrent Neural Network formalism to extract the underlying dynamics present in the time series expression data accurately. We have introduced a new hybrid swarm intelligence framework for the accurate training of the model parameters. The proposed methodology has been first applied to a small artificial network, and the results obtained suggest that it can produce the best results available in the contemporary literature, to the best of our knowledge. Subsequently, we have implemented our proposed framework on experimental (in vivo) datasets. Finally, we have investigated two medium sized genetic networks (in silico) extracted from GeneNetWeaver, to understand how the proposed algorithm scales up with network size. Additionally, we have implemented our proposed algorithm with half the number of time points. The results indicate that a reduction of 50% in the number of time points does not have an effect on the accuracy of the proposed methodology significantly, with a maximum of just over 15% deterioration in the worst case.

Reverse engineering of gene regulatory networks based on S-systems and Bat algorithm.

The correct inference of gene regulatory networks for the understanding of the intricacies of the complex biological regulations remains an intriguing task for researchers. With the availability of large dimensional microarray data, relationships among thousands of genes can be simultaneously extracted. Among the prevalent models of reverse engineering genetic networks, S-system is considered to be an efficient mathematical tool. In this paper, Bat algorithm, based on the echolocation of bats, has been used to optimize the S-system model parameters. A decoupled S-system has been implemented to reduce the complexity of the algorithm. Initially, the proposed method has been successfully tested on an artificial network with and without the presence of noise. Based on the fact that a real-life genetic network is sparsely connected, a novel Accumulative Cardinality based decoupled S-system has been proposed. The cardinality has been varied from zero up to a maximum value, and this model has been implemented for the reconstruction of the DNA SOS repair network of Escherichia coli. The obtained results have shown significant improvements in the detection of a greater number of true regulations, and in the minimization of false detections compared to other existing methods.

Large-Scale Recurrent Neural Network Based Modelling of Gene Regulatory Network Using Cuckoo Search-Flower Pollination Algorithm.

The accurate prediction of genetic networks using computational tools is one of the greatest challenges in the postgenomic era. Recurrent Neural Network is one of the most popular but simple approaches to model the network dynamics from time-series microarray data. To date, it has been successfully applied to computationally derive small-scale artificial and real-world genetic networks with high accuracy. However, they underperformed for large-scale genetic networks. Here, a new methodology has been proposed where a hybrid Cuckoo Search-Flower Pollination Algorithm has been implemented with Recurrent Neural Network. Cuckoo Search is used to search the best combination of regulators. Moreover, Flower Pollination Algorithm is applied to optimize the model parameters of the Recurrent Neural Network formalism. Initially, the proposed method is tested on a benchmark large-scale artificial network for both noiseless and noisy data. The results obtained show that the proposed methodology is capable of increasing the inference of correct regulations and decreasing false regulations to a high degree. Secondly, the proposed methodology has been validated against the real-world dataset of the DNA SOS repair network of Escherichia coli. However, the proposed method sacrifices computational time complexity in both cases due to the hybrid optimization process.