MOTIVATION: Modern biological screens yield enormous numbers of measurements, and identifying and interpreting statistically significant associations among features are essential. In experiments featuring multiple high-dimensional datasets collected from the same set of samples, it is useful to identify groups of associated features between the datasets in a way that provides high statistical power and false discovery rate (FDR) control. RESULTS: Here, we present a novel hierarchical framework, HAllA (Hierarchical All-against-All association testing), for structured association discovery between paired high-dimensional datasets. HAllA efficiently integrates hierarchical hypothesis testing with FDR correction to reveal significant linear and non-linear block-wise relationships among continuous and/or categorical data. We optimized and evaluated HAllA using heterogeneous synthetic datasets of known association structure, where HAllA outperformed all-against-all and other block-testing approaches across a range of common similarity measures. We then applied HAllA to a series of real-world multiomics datasets, revealing new associations between gene expression and host immune activity, the microbiome and host transcriptome, metabolomic profiling and human health phenotypes. AVAILABILITY AND IMPLEMENTATION: An open-source implementation of HAllA is freely available at http://huttenhower.sph.harvard.edu/halla along with documentation, demo datasets and a user group. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

BACKGROUND: sgnesR (Stochastic Gene Network Expression Simulator in R) is an R package that provides an interface to simulate gene expression data from a given gene network using the stochastic simulation algorithm (SSA). The package allows various options for delay parameters and can easily included in reactions for promoter delay, RNA delay and Protein delay. A user can tune these parameters to model various types of reactions within a cell. As examples, we present two network models to generate expression profiles. We also demonstrated the inference of networks and the evaluation of association measure of edge and non-edge components from the generated expression profiles. RESULTS: The purpose of sgnesR is to enable an easy to use and a quick implementation for generating realistic gene expression data from biologically relevant networks that can be user selected. CONCLUSIONS: sgnesR is freely available for academic use. The R package has been tested for R 3.2.0 under Linux, Windows and Mac OS X.

Transcription kinetics is limited by its initiation steps, which differ between promoters and with intra- and extracellular conditions. Regulation of these steps allows tuning both the rate and stochasticity of RNA production. We used time-lapse, single-RNA microscopy measurements in live Escherichia coli to study how the rate-limiting steps in initiation of the Plac/ara-1 promoter change with temperature and induction scheme. For this, we compared detailed stochastic models fit to the empirical data in maximum likelihood sense using statistical methods. Using this analysis, we found that temperature affects the rate limiting steps unequally, as nonlinear changes in the closed complex formation suffice to explain the differences in transcription dynamics between conditions. Meanwhile, a similar analysis of the PtetA promoter revealed that it has a different rate limiting step configuration, with temperature regulating different steps. Finally, we used the derived models to explore a possible cause for why the identified steps are preferred as the main cause for behavior modifications with temperature: we find that transcription dynamics is either insensitive or responds reciprocally to changes in the other steps. Our results suggests that different promoters employ different rate limiting step patterns that control not only their rate and variability, but also their sensitivity to environmental changes.

MOTIVATION: Cell growth and division affect the kinetics of internal cellular processes and the phenotype diversity of cell populations. Since the effects are complex, e.g. different cellular components are partitioned differently in cell division, to account for them in silico, one needs to simulate these processes in great detail. RESULTS: We present SGNS2, a simulator of chemical reaction systems according to the Stochastic Simulation Algorithm with multi-delayed reactions within hierarchical, interlinked compartments which can be created, destroyed and divided at runtime. In division, molecules are randomly segregated into the daughter cells following a specified distribution corresponding to one of several partitioning schemes, applicable on a per-molecule-type basis. We exemplify its use with six models including a stochastic model of the disposal mechanism of unwanted protein aggregates in Escherichia coli, a model of phenotypic diversity in populations with different levels of synchrony, a model of a bacteriophage's infection of a cell population and a model of prokaryotic gene expression at the nucleotide and codon levels. AVAILABILITY: SGNS2, instructions and examples available at www.cs.tut.fi/~lloydpri/sgns2/ (open source under New BSD license). CONTACT: [email protected]. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

BACKGROUND: In prokaryotes, transcription and translation are dynamically coupled, as the latter starts before the former is complete. Also, from one transcript, several translation events occur in parallel. To study how events in transcription elongation affect translation elongation and fluctuations in protein levels, we propose a delayed stochastic model of prokaryotic transcription and translation at the nucleotide and codon level that includes the promoter open complex formation and alternative pathways to elongation, namely pausing, arrests, editing, pyrophosphorolysis, RNA polymerase traffic, and premature termination. Stepwise translation can start after the ribosome binding site is formed and accounts for variable codon translation rates, ribosome traffic, back-translocation, drop-off, and trans-translation. RESULTS: First, we show that the model accurately matches measurements of sequence-dependent translation elongation dynamics. Next, we characterize the degree of coupling between fluctuations in RNA and protein levels, and its dependence on the rates of transcription and translation initiation. Finally, modeling sequence-specific transcriptional pauses, we find that these affect protein noise levels. CONCLUSIONS: For parameter values within realistic intervals, transcription and translation are found to be tightly coupled in Escherichia coli, as the noise in protein levels is mostly determined by the underlying noise in RNA levels. Sequence-dependent events in transcription elongation, e.g. pauses, are found to cause tangible effects in the degree of fluctuations in protein levels.

UNLABELLED: We present CellLine, a simulator of the dynamics of gene regulatory networks (GRN) in the cells of a lineage. From user-defined reactions and initial substance quantities, it generates cell lineages, i.e. genealogic pedigrees of cells related through mitotic division. Each cell's dynamics is driven by a delayed stochastic simulation algorithm (delayed SSA), allowing multiple time delayed reactions. The cells of the lineage can be individually subject to 'perturbations', such as gene deletion, duplication and mutation. External interventions, such as adding or removing a substance at a given moment, can be specified. Cell differentiation lineages, where differentiation is stochastically driven or externally induced, can be modeled as well. Finally, CellLine can generate and simulate the dynamics of multiple copies of any given cell of the lineage. As examples of CellLine use, we simulate the following systems: cell lineages containing a model of the P53-Mdm2 feedback loop, a differentiation lineage where each cell contains a 4 gene repressilator (a bistable circuit), a model of the differentiation of the cells of the retinal mosaic required for color vision in Drosophila melanogaster, where the differentiation pathway depends on one substance's concentration that is controlled by a stochastic process, and a 9 gene GRN to illustrate the advantage of using CellLine rather than simulating multiple independent cells, in cases where the cells of the lineage are dynamically correlated. AVAILABILITY: The CellLine program, instructions and examples are available at www.ucalgary.ca/~aribeiro/CellLine/CellLine.html

UNLABELLED: We present SGNSim, 'Stochastic Gene Networks Simulator', a tool to model gene regulatory networks (GRN) where transcription and translation are modeled as multiple time delayed events and its dynamics is driven by a stochastic simulation algorithm (SSA) able to deal with multiple time delayed events. The delays can be drawn from several distributions and the reaction rates from complex functions or from physical parameters. SGNSim can generate ensembles of GRNs, within a set of user-defined parameters, such as topology. It can also be used to model specific GRNs and systems of chemical reactions. Perturbations, e.g. gene deletion, over-expression, copy and mutation, can be modeled as well. As examples, we present a model of a toggle switch without cooperative binding subject to perturbations, a system of reactions within a compartmentalized environment where membrane crossing is controlled by a negative feedback mechanism and a simulation based on the yeast transcriptional network. AVAILABILITY: SGNSim program, instructions and examples available at www.ucalgary.ca/~aribeiro/SGNtheSim/SGNtheSim.html.