We predict housekeeping genes from replicate microarray gene expression data of human lymphoblastoid cells and liver tissue with outliers removed using a scoring scheme, by an algorithm based on statistical hypothesis testing, assuming that such genes are constitutively expressed. A few predicted genes were examined and found to be housekeeping.

BACKGROUND: The over consumption of fossil fuels has led to growing concerns over climate change and global warming. Increasing research activities have been carried out towards alternative viable biofuel sources. Of several different biofuel platforms, cyanobacteria possess great potential, for their ability to accumulate biomass tens of times faster than traditional oilseed crops. The cyanobacterium Cyanothece sp. ATCC 51142 has recently attracted lots of research interest as a model organism for such research. Cyanothece can perform efficiently both photosynthesis and nitrogen fixation within the same cell, and has been recently shown to produce biohydrogen--a byproduct of nitrogen fixation--at very high rates of several folds higher than previously described hydrogen-producing photosynthetic microbes. Since the key enzyme for nitrogen fixation is very sensitive to oxygen produced by photosynthesis, Cyanothece employs a sophisticated temporal separation scheme, where nitrogen fixation occurs at night and photosynthesis at day. At the core of this temporal separation scheme is a robust clocking mechanism, which so far has not been thoroughly studied. Understanding how this circadian clock interacts with and harmonizes global transcription of key cellular processes is one of the keys to realize the inherent potential of this organism. RESULTS: In this paper, we employ several state of the art bioinformatics techniques for studying the core circadian clock in Cyanothece sp. ATCC 51142, and its interactions with other key cellular processes. We employ comparative genomics techniques to map the circadian clock genes and genetic interactions from another cyanobacterial species, namely Synechococcus elongatus PCC 7942, of which the circadian clock has been much more thoroughly investigated. Using time series gene expression data for Cyanothece, we employ gene regulatory network reconstruction techniques to learn this network de novo, and compare the reconstructed network against the interactions currently reported in the literature. Next, we build a computational model of the interactions between the core clock and other cellular processes, and show how this model can predict the behaviour of the system under changing environmental conditions. The constructed models significantly advance our understanding of the Cyanothece circadian clock functional mechanisms.

Learning optimal Bayesian networks (BN) from data is NP-hard in general. Nevertheless, certain BN classes with additional topological constraints, such as the dynamic BN (DBN) models, widely applied in specific fields such as systems biology, can be efficiently learned in polynomial time. Such algorithms have been developed for the Bayesian-Dirichlet (BD), Minimum Description Length (MDL), and Mutual Information Test (MIT) scoring metrics. The BD-based algorithm admits a large polynomial bound, hence it is impractical for even modestly sized networks. The MDL-and MIT-based algorithms admit much smaller bounds, but require a very restrictive assumption that all variables have the same cardinality, thus significantly limiting their applicability. In this paper, we first propose an improvement to the MDL-and MIT-based algorithms, dropping the equicardinality constraint, thus significantly enhancing their generality. We also explore local Markov blanket based algorithms for constructing BN in the context of DBN, and show an interesting result: under the faithfulness assumption, the mutual information test based local Markov blanket algorithms yield the same network as learned by the global optimization MIT-based algorithm. Experimental validation on small and large scale genetic networks demonstrates the effectiveness of our proposed approaches.

BACKGROUND: Dynamic Bayesian network (DBN) is among the mainstream approaches for modeling various biological networks, including the gene regulatory network (GRN). Most current methods for learning DBN employ either local search such as hill-climbing, or a meta stochastic global optimization framework such as genetic algorithm or simulated annealing, which are only able to locate sub-optimal solutions. Further, current DBN applications have essentially been limited to small sized networks. RESULTS: To overcome the above difficulties, we introduce here a deterministic global optimization based DBN approach for reverse engineering genetic networks from time course gene expression data. For such DBN models that consist only of inter time slice arcs, we show that there exists a polynomial time algorithm for learning the globally optimal network structure. The proposed approach, named GlobalMIT+, employs the recently proposed information theoretic scoring metric named mutual information test (MIT). GlobalMIT+ is able to learn high-order time delayed genetic interactions, which are common to most biological systems. Evaluation of the approach using both synthetic and real data sets, including a 733 cyanobacterial gene expression data set, shows significantly improved performance over other techniques. CONCLUSIONS: Our studies demonstrate that deterministic global optimization approaches can infer large scale genetic networks.

MOTIVATION: Dynamic Bayesian networks (DBN) are widely applied in modeling various biological networks including the gene regulatory network (GRN). Due to the NP-hard nature of learning static Bayesian network structure, most methods for learning DBN also employ either local search such as hill climbing, or a meta stochastic global optimization framework such as genetic algorithm or simulated annealing. RESULTS: This article presents GlobalMIT, a toolbox for learning the globally optimal DBN structure from gene expression data. We propose using a recently introduced information theoretic-based scoring metric named mutual information test (MIT). With MIT, the task of learning the globally optimal DBN is efficiently achieved in polynomial time. AVAILABILITY: The toolbox, implemented in Matlab and C++, is available at http://code.google.com/p/globalmit. CONTACT: [email protected]; [email protected] SUPPLEMENTARY INFORMATION: Supplementary data is available at Bioinformatics online.

BACKGROUND: The structure conservation in various α-helix subclasses reveals the sequence and context dependent factors causing distortions in the α-helix. The sequence-structure relationship in these subclasses can be used to predict structural variations in α-helix purely based on its sequence. We train support vector machine(SVM) with dot product kernel function to discriminate between regular α-helix and non-regular α-helices purely based on the sequences, which are represented with various overall and position specific propensities of amino acids. RESULTS: We characterize the structural distortions in five α-helix subclasses. The sequence structure correlation in the subclasses reveals that the increased propensity of proline, histidine, serine, aspartic acid and aromatic amino acids are responsible for the distortions in regular α-helix. The N-terminus of regular α-helix prefers neutral and acidic polar amino acids, while the C-terminus prefers basic polar amino acid. Proline is preferred in the first turn of regular α-helix, while it is preferred to produce kinked and curved subclasses. The SVM discriminates between regular α-helix and the rest with precision of 80.97% and recall of 88.05%. CONCLUSIONS: The correlation between structural variation in helices and their sequences is manifested by the performance of SVM based on sequence features. The results presented here are useful for computational design of helices. The results are also useful for prediction of structural perturbations in helix sequence purely based on its sequence.

MOTIVATION: Characterization of the restricted nature of the protein local conformational space has remained a challenge, thereby necessitating a computationally expensive conformational search in protein modeling. Moreover, owing to the lack of unilateral structural descriptors, conventional data mining techniques, such as clustering and classification, have not been applied in protein structure analysis. RESULTS: We first map the local conformations in a fixed dimensional space by using a carefully selected suite of geometric invariants (GIs) and then reduce the number of dimensions via principal component analysis (PCA). Distribution of the conformations in the space spanned by the first four PCs is visualized as a set of conditional bivariate probability distribution plots, where the peaks correspond to the preferred conformations. The locations of the different canonical structures in the PC-space have been interpreted in the context of the weights of the GIs to the first four PCs. Clustering of the available conformations reveals that the number of preferred local conformations is several orders of magnitude smaller than that suggested previously. SUPPLEMENTARY INFORMATION: www.it.iitb.ac.in/~ashish/bioinfo2005/.