An efficient biological pathway layout algorithm combining grid-layout and spring embedder for complicated cellular location information

<p>Abstract</p> <p>Background</p> <p>Graph drawing is one of the important techniques for understanding biological regulations in a cell or among cells at the pathway level. Among many available layout algorithms, the spring embedder algorithm is widely used not only for pathway drawing but also for circuit placement and www visualization and so on because of the harmonized appearance of its results. For pathway drawing, location information is essential for its comprehension. However, complex shapes need to be taken into account when torus-shaped location information such as nuclear inner membrane, nuclear outer membrane, and plasma membrane is considered. Unfortunately, the spring embedder algorithm cannot easily handle such information. In addition, crossings between edges and nodes are usually not considered explicitly.</p> <p>Results</p> <p>We proposed a new grid-layout algorithm based on the spring embedder algorithm that can handle location information and provide layouts with harmonized appearance. In grid-layout algorithms, the mapping of nodes to grid points that minimizes a cost function is searched. By imposing positional constraints on grid points, location information including complex shapes can be easily considered. Our layout algorithm includes the spring embedder cost as a component of the cost function. We further extend the layout algorithm to enable dynamic update of the positions and sizes of compartments at each step.</p> <p>Conclusions</p> <p>The new spring embedder-based grid-layout algorithm and a spring embedder algorithm are applied to three biological pathways; endothelial cell model, Fas-induced apoptosis model, and <it>C. elegans </it>cell fate simulation model. From the positional constraints, all the results of our algorithm satisfy location information, and hence, more comprehensible layouts are obtained as compared to the spring embedder algorithm. From the comparison of the number of crossings, the results of the grid-layout-based algorithm tend to contain more crossings than those of the spring embedder algorithm due to the positional constraints. For a fair comparison, we also apply our proposed method without positional constraints. This comparison shows that these results contain less crossings than those of the spring embedder algorithm. We also compared layouts of the proposed algorithm with and without compartment update and verified that latter can reach better local optima.</p

Simulation-based model checking approach to cell fate specification during Caenorhabditis elegans vulval development by hybrid functional Petri net with extension

<p>Abstract</p> <p>Background</p> <p>Model checking approaches were applied to biological pathway validations around 2003. Recently, Fisher <it>et al</it>. have proved the importance of model checking approach by inferring new regulation of signaling crosstalk in <it>C. elegans </it>and confirming the regulation with biological experiments. They took a discrete and state-based approach to explore all possible states of the system underlying vulval precursor cell (VPC) fate specification for desired properties. However, since both discrete and continuous features appear to be an indispensable part of biological processes, it is more appropriate to use quantitative models to capture the dynamics of biological systems. Our key motivation of this paper is to establish a quantitative methodology to model and analyze <it>in silico </it>models incorporating the use of model checking approach.</p> <p>Results</p> <p>A novel method of modeling and simulating biological systems with the use of model checking approach is proposed based on hybrid functional Petri net with extension (HFPNe) as the framework dealing with both discrete and continuous events. Firstly, we construct a quantitative VPC fate model with 1761 components by using HFPNe. Secondly, we employ two major biological fate determination rules – Rule I and Rule II – to VPC fate model. We then conduct 10,000 simulations for each of 48 sets of different genotypes, investigate variations of cell fate patterns under each genotype, and validate the two rules by comparing three simulation targets consisting of fate patterns obtained from <it>in silico </it>and <it>in vivo </it>experiments. In particular, an evaluation was successfully done by using our VPC fate model to investigate one target derived from biological experiments involving hybrid lineage observations. However, the understandings of hybrid lineages are hard to make on a discrete model because the hybrid lineage occurs when the system comes close to certain thresholds as discussed by Sternberg and Horvitz in 1986. Our simulation results suggest that: Rule I that cannot be applied with qualitative based model checking, is more reasonable than Rule II owing to the high coverage of predicted fate patterns (except for the genotype of <it>lin-15ko; lin-12ko </it>double mutants). More insights are also suggested.</p> <p>Conclusion</p> <p>The quantitative simulation-based model checking approach is a useful means to provide us valuable biological insights and better understandings of biological systems and observation data that may be hard to capture with the qualitative one.</p

Ontology-based instance data validation for high-quality curated biological pathways

<p>Abstract</p> <p>Background</p> <p>Modeling in systems biology is vital for understanding the complexity of biological systems across scales and predicting system-level behaviors. To obtain high-quality pathway databases, it is essential to improve the efficiency of model validation and model update based on appropriate feedback.</p> <p>Results</p> <p>We have developed a new method to guide creating novel high-quality biological pathways, using a rule-based validation. Rules are defined to correct models against biological semantics and improve models for dynamic simulation. In this work, we have defined 40 rules which constrain event-specific participants and the related features and adding missing processes based on biological events. This approach is applied to data in Cell System Ontology which is a comprehensive ontology that represents complex biological pathways with dynamics and visualization. The experimental results show that the relatively simple rules can efficiently detect errors made during curation, such as misassignment and misuse of ontology concepts and terms in curated models.</p> <p>Conclusions</p> <p>A new rule-based approach has been developed to facilitate model validation and model complementation. Our rule-based validation embedding biological semantics enables us to provide high-quality curated biological pathways. This approach can serve as a preprocessing step for model integration, exchange and extraction data, and simulation.</p

Time-dependent structural transformation analysis to high-level Petri net model with active state transition diagram

<p>Abstract</p> <p>Background</p> <p>With an accumulation of <it>in silico </it>data obtained by simulating large-scale biological networks, a new interest of research is emerging for elucidating how living organism functions over time in cells.</p> <p>Investigating the dynamic features of current computational models promises a deeper understanding of complex cellular processes. This leads us to develop a method that utilizes structural properties of the model over all simulation time steps. Further, user-friendly overviews of dynamic behaviors can be considered to provide a great help in understanding the variations of system mechanisms.</p> <p>Results</p> <p>We propose a novel method for constructing and analyzing a so-called <it>active state transition diagram </it>(ASTD) by using time-course simulation data of a high-level Petri net. Our method includes two new algorithms. The first algorithm extracts a series of subnets (called <it>temporal subnets</it>) reflecting biological components contributing to the dynamics, while retaining positive mathematical qualities. The second one creates an ASTD composed of unique temporal subnets. ASTD provides users with concise information allowing them to grasp and trace how a key regulatory subnet and/or a network changes with time. The applicability of our method is demonstrated by the analysis of the underlying model for circadian rhythms in <it>Drosophila</it>.</p> <p>Conclusions</p> <p>Building ASTD is a useful means to convert a hybrid model dealing with discrete, continuous and more complicated events to finite time-dependent states. Based on ASTD, various analytical approaches can be applied to obtain new insights into not only systematic mechanisms but also dynamics.</p

A Nucleosome-Guided Map of Transcription Factor Binding Sites in Yeast

Finding functional DNA binding sites of transcription factors (TFs) throughout the genome is a crucial step in understanding transcriptional regulation. Unfortunately, these binding sites are typically short and degenerate, posing a significant statistical challenge: many more matches to known TF motifs occur in the genome than are actually functional. However, information about chromatin structure may help to identify the functional sites. In particular, it has been shown that active regulatory regions are usually depleted of nucleosomes, thereby enabling TFs to bind DNA in those regions. Here, we describe a novel motif discovery algorithm that employs an informative prior over DNA sequence positions based on a discriminative view of nucleosome occupancy. When a Gibbs sampling algorithm is applied to yeast sequence-sets identified by ChIP-chip, the correct motif is found in 52% more cases with our informative prior than with the commonly used uniform prior. This is the first demonstration that nucleosome occupancy information can be used to improve motif discovery. The improvement is dramatic, even though we are using only a statistical model to predict nucleosome occupancy; we expect our results to improve further as high-resolution genome-wide experimental nucleosome occupancy data becomes increasingly available

ClipCrop: a tool for detecting structural variations with single-base resolution using soft-clipping information

<p>Abstract</p> <p>Background</p> <p>Structural variations (SVs) change the structure of the genome and are therefore the causes of various diseases. Next-generation sequencing allows us to obtain a multitude of sequence data, some of which can be used to infer the position of SVs.</p> <p>Methods</p> <p>We developed a new method and implementation named ClipCrop for detecting SVs with single-base resolution using soft-clipping information. A soft-clipped sequence is an unmatched fragment in a partially mapped read. To assess the performance of ClipCrop with other SV-detecting tools, we generated various patterns of simulation data – SV lengths, read lengths, and the depth of coverage of short reads – with insertions, deletions, tandem duplications, inversions and single nucleotide alterations in a human chromosome. For comparison, we selected BreakDancer, CNVnator and Pindel, each of which adopts a different approach to detect SVs, e.g. discordant pair approach, depth of coverage approach and split read approach, respectively.</p> <p>Results</p> <p>Our method outperformed BreakDancer and CNVnator in both discovering rate and call accuracy in any type of SV. Pindel offered a similar performance as our method, but our method crucially outperformed for detecting small duplications. From our experiments, ClipCrop infer reliable SVs for the data set with more than 50 bases read lengths and 20x depth of coverage, both of which are reasonable values in current NGS data set.</p> <p>Conclusions</p> <p>ClipCrop can detect SVs with higher discovering rate and call accuracy than any other tool in our simulation data set.</p