We present ScaleTrotter, a conceptual framework for an interactive, multi-scale visualization of biological mesoscale data and, specifically, genome data. ScaleTrotter allows viewers to smoothly transition from the nucleus of a cell to the atomistic composition of the DNA, while bridging several orders of magnitude in scale. The challenges in creating an interactive visualization of genome data are fundamentally different in several ways from those in other domains like astronomy that require a multi-scale representation as well. First, genome data has intertwined scale levels---the DNA is an extremely long, connected molecule that manifests itself at all scale levels. Second, elements of the DNA do not disappear as one zooms out---instead the scale levels at which they are observed group these elements differently. Third, we have detailed information and thus geometry for the entire dataset and for all scale levels, posing a challenge for interactive visual exploration. Finally, the conceptual scale levels for genome data are close in scale space, requiring us to find ways to visually embed a smaller scale into a coarser one. We address these challenges by creating a new multi-scale visualization concept. We use a scale-dependent camera model that controls the visual embedding of the scales into their respective parents, the rendering of a subset of the scale hierarchy, and the location, size, and scope of the view. In traversing the scales, ScaleTrotter is roaming between 2D and 3D visual representations that are depicted in integrated visuals. We discuss, specifically, how this form of multi-scale visualization follows from the specific characteristics of the genome data and describe its implementation. Finally, we discuss the implications of our work to the general illustrative depiction of multi-scale data.
We investigate multi-scale representations of the DNA, which relates to work in bio-molecular visualization. Several surveys have summarized work in this field @cite_14 @cite_3 @cite_25 @cite_17 , so below we only point out selected approaches. In addition, a large body of work by professional illustrators on mesoscale cell depiction inspired us such as visualizing the human chromosome down to the detail of individual parts of the molecule @cite_15 .
@cite_14 @cite_3 @cite_15 @cite_25 @cite_17
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Abstract We provide a high-level survey of multiscale molecular visualization techniques, with a focus on application-domain questions, challenges, and tasks. We provide a general introduction to molecular visualization basics and describe a number of domain-specific tasks that drive this work. These tasks, in turn, serve as the general structure of the following survey. First, we discuss methods that support the visual analysis of molecular dynamics simulations. We discuss, in particular, visual abstraction and temporal aggregation. In the second part, we survey multiscale approaches that support the design, analysis, and manipulation of DNA nanostructures and related concepts for abstraction, scale transition, scale-dependent modeling, and navigation of the resulting abstraction spaces. In the third part of the survey, we showcase approaches that support interactive exploration within large structural biology assemblies up to the size of bacterial cells. We describe fundamental rendering techniques as well as approaches for element instantiation, visibility management, visual guidance, camera control, and support of depth perception. We close the survey with a brief listing of important tools that implement many of the discussed approaches and a conclusion that provides some research challenges in the field. Abstract Modeling and visualization of the cellular mesoscale, bridging the nanometer scale of molecules to the micrometer scale of cells, is being studied by an integrative approach. Data from structural biology, proteomics, and microscopy are combined to simulate the molecular structure of living cells. These cellular landscapes are used as research tools for hypothesis generation and testing, and to present visual narratives of the cellular context of molecular biology for dissemination, education, and outreach. Structural properties of molecules are of primary concern in many fields. This report provides a comprehensive overview on techniques that have been developed in the fields of molecular graphics and visualization with a focus on applications in structural biology. The field heavily relies on computerized geometric and visual representations of three-dimensional, complex, large and time-varying molecular structures. The report presents a taxonomy that demonstrates which areas of molecular visualization have already been extensively investigated and where the field is currently heading. It discusses visualizations for molecular structures, strategies for efficient display regarding image quality and frame rate, covers different aspects of level of detail and reviews visualizations illustrating the dynamic aspects of molecular simulation data. The survey concludes with an outlook on promising and important research topics to foster further success in the development of tools that help to reveal molecular secrets. Large-scale comparison of genomic DNA is of fundamental importance in annotating functional elements of genomes. To perform large comparisons efficiently, BLAST (Methods: Companion Methods Enzymol 266 (1996) 460, J. Mol. Biol. 215 (1990) 403, Nucleic Acids Res. 25(17) (1997) 3389) and other widely used tools use seeded alignment, which compares only sequences that can be shown to share a common pattern or ''seed'' of matching bases. The literature suggests that the choice of seed substantially affects the sensitivity of seeded alignment, but designing and evaluating seeds is computationally challenging. This work addresses the problem of designing a seed to optimize performance of seeded alignment. We give a fast, simple algorithm based on finite automata for evaluating the sensitivity of a seed in a Markov model of ungapped alignments, along with extensions to mixtures and inhomogeneous Markov models. We give intuition and theoretical results on which seeds are good choices. Finally, we describe Mandala, a software tool for seed design, and show that it can be used to improve the sensitivity of alignment in practice. Background Understanding complicated networks of interactions and chemical components is essential to solving contemporary problems in modern biology, especially in domains such as cancer and systems research. In these domains, biological pathway data is used to represent chains of interactions that occur within a given biological process. Visual representations can help researchers understand, interact with, and reason about these complex pathways in a number of ways. At the same time, these datasets offer unique challenges for visualization, due to their complexity and heterogeneity. Preface Introduction Molecular Biology Mathematics, Statistics, and Computer Science Some Molecular Biology DNA and Proteins The Central Dogma The Genetic Code Transfer RNA and Protein Sequences Genes Are Not Simple Biological Chemistry Restriction Maps Introduction Graphs Interval Graphs Measuring Fragment Sizes Multiple Maps Double Digest Problem Classifying Multiple Solutions Algorithms for DDP Algorithms and Complexity DDP is N P-Complete Approaches to DDP Simulated Annealing: TSP and DDP Mapping with Real Data Cloning and Clone Libraries A Finite Number of Random Clones Libraries by Complete Digestion Libraries by Partial Digestion Genomes per Microgram Physical Genome Maps: Oceans, Islands, and Anchors Mapping by Fingerprinting Mapping by Anchoring An Overview of Clone Overlap Putting It Together Sequence Assembly Shotgun Sequencing Sequencing by Hybridization Shotgun Sequencing Revisited Databases and Rapid Sequence Analysis DNA and Protein Sequence Databases A Tree Representation of a Sequence Hashing a Sequence Repeats in a Sequence Sequence Comparison by Hashing Sequence Comparison with at most l Mismatches Sequence Comparison by Statistical Content Dynamic Programming Alignment of Two Sequences The Number of Alignments Shortest and Longest Paths in a Network Global Distance Alignment Global Similarity Alignment Fitting One Sequence into Another Local Alignment and Clumps Linear Space Algorithms Tracebacks Inversions Map Alignment Parametric Sequence Comparisons Multiple Sequence Alignment The Cystic Fibrosis Gene Dynamic Programming in r-Dimensions Weighted-Average Sequences Profile Analysis Alignment by Hidden Markov Models Consensus Word Analysis Probability and Statistics for Sequence Alignment Global Alignment Local Alignment Extreme Value Distributions The Chein-Stein Method Poisson Approximation and Long Matches Sequence Alignment with Scores Probability and Statistics for Sequence Patterns A Central Limit Theorem Nonoverlapping Pattern Counts Poisson Approximation Site Distributions RNA Secondary Structure Combinatorics Minimum Free-energy Structures Consensus folding Trees and Sequences Trees Distance Parsimony Maximum Likelihood Trees Sources and Perspectives Molecular Biology Physical Maps and Clone Libraries Sequence Assembly Sequence Comparisons Probability and Statistics RNA Secondary Structure Trees and Sequences References Problem Solutions and Hints Mathematical Notation Algorithm Index Author Index Subject Index Biologists pioneering the new field of comparative functional genomics attempt to infer the mechanisms of gene regulation by looking for similarities and differences of gene activity over time across multiple species. They use three kinds of data: functional data such as gene activity measurements, pathway data that represent a series of reactions within a cellular process, and phylogenetic relationship data that describe the relatedness of species. No existing visualization tool can visually encode the biologically interesting relationships between multiple pathways, multiple genes, and multiple species. We tackle the challenge of visualizing all aspects of this comparative functional genomics dataset with a new interactive tool called Pathline. In addition to the overall characterization of the problem and design of Pathline, our contributions include two new visual encoding techniques. One is a new method for linearizing metabolic pathways that provides appropriate topological information and supports the comparison of quantitative data along the pathway. The second is the curvemap view, a depiction of time series data for comparison of gene activity and metabolite levels across multiple species. Pathline was developed in close collaboration with a team of genomic scientists. We validate our approach with case studies of the biologists' use of Pathline and report on how they use the tool to confirm existing findings and to discover new scientific insights. An operation preceding most human DNA analyses is read mapping, which aligns millions of short sequences (called reads) to a reference genome. This step involves an enormous amount of computation (evaluating edit distances for millions upon billions of sequence pairs) and thus needs to be outsourced to low-cost commercial clouds. This asks for scalable techniques to protect sensitive DNA information, a demand that cannot be met by any existing techniques (e.g., homomorphic encryption, secure multiparty computation). In this paper, we report a new step towards secure and scalable read mapping on the hybrid cloud, which includes both the public commercial cloud and the private cloud within an organization. Inspired by the famous “seed-and-extend” method, our approach strategically splits a mapping task: the public cloud seeks exact matches between the keyed hash values of short read substrings (called seeds) and those of reference sequences to roughly position reads on the genome; the private cloud extends the seeds from these positions to find right alignments. Our novel seed-combination technique further moves most workload of this task to the public cloud. The new approach is found to work effectively against known inference attacks, and also easily scale to millions of reads. We introduce a novel projection-based visualization method for high-dimensional data sets by combining concepts from MDS and the geometry of the hyperbolic spaces. This approach hyperbolic multi-dimensional scaling (H-MDS) is a synthesis of two important concepts for explorative data analysis and visualization: (i) multi-dimensional scaling uses proximity or pair distance data to generate a low-dimensional, spatial presentation of the data; (ii) previous work on the "hyperbolic tree browser" demonstrated the extraordinary advantages for an interactive display of graph-like data in the two-dimensional hyperbolic space (H2).In the new approach, H-MDS maps proximity data directly into the H2. This removes the restriction to "quasihierarchical", graph-based data--a major limitation of (ii). Since a suitable distance function can convert all kinds of data to proximity (or distance-based) data, this type of data can be considered the most general.We review important properties of the hyperbolic space and, in particular, the circular Poincare model of the H2. It enables effective human-computer interaction: by mouse dragging the "focus", the user can navigate in the data without loosing the context. In H2 the "fish-eye" behavior originates not simply by a non-linear view transformation but rather by extraordinary, non-Euclidean properties of the H2. Especially, the exponential growth of length and area of the underlying space makes the H2 a prime target for mapping hierarchical and (now also) high-dimensional data.Several high-dimensional mapping examples including synthetic and real-world data are presented. Since high-dimensional data produce "ring"-shaped displays, we present methods to enhance the display by modulating the dissimilarity contrast. This is demonstrated for an application for unstructured text: i.e., by using multiple film critiques from news:rec.art.movies.reviews and www.imdb.com, each movie is placed within the H2--creating a "space of movies" for interactive exploration. Structural properties of molecules are of primary concern in many fields. This report provides a comprehensive overview on techniques that have been developed in the fields of molecular graphics and visualization with a focus on applications in structural biology. The field heavily relies on computerized geometric and visual representations of three-dimensional, complex, large, and time-varying molecular structures. The report presents a taxonomy that demonstrates which areas of molecular visualization have already been extensively investigated and where the field is currently heading. It discusses visualizations for molecular structures, strategies for efficient display regarding image quality and frame rate, covers different aspects of level of detail, and reviews visualizations illustrating the dynamic aspects of molecular simulation data. The report concludes with an outlook on promising and important research topics to enable further success in advancing the knowledge about interaction of molecular structures. Systems biologists and cancer researchers require interactive visualization tools that enable them to more easily navigate and discover patterns at different levels of the biological hierarchy of signaling pathways. Furthermore, biologists are often interested in understanding and exploring the causal biochemical links between processes. When exploring the literature of particular biological pathways or specific proteins within those pathways, biologists find it useful to know the contexts in which biochemical links are active and, importantly, to be aware of potential conflicts when different experiments introduce alternative interpretations of the function of a pathway or biochemical reaction. We introduce BioLinker, a interactive visualization system that helps users to perform bottom-up exploration of complex protein interaction networks. Five interconnected views provide the user with a range of ways to explore pathway data, including views that show potential conflicts within pathway databases and publications and that highlight contextual information about individual proteins. Additionally, we discuss system details to show how our system manages the large amount of protein interactions extracted from the literature of biological pathways. Development of high throughput analytical methods has given physicians the potential access to extensive and patient-specific data sets, such as gene sequences, gene expression profiles or metabolite footprints. This opens for a new approach in health care, which is both personalized and based on system-level analysis. Genome-scale metabolic networks provide a mechanistic description of the relationships between different genes, which is valuable for the analysis and interpretation of large experimental data-sets. Here we describe the generation of genome-scale active metabolic networks for 69 different cell types and 16 cancer types using the INIT (Integrative Network Inference for Tissues) algorithm. The INIT algorithm uses cell type specific information about protein abundances contained in the Human Proteome Atlas as the main source of evidence. The generated models constitute the first step towards establishing a Human Metabolic Atlas, which will be a comprehensive description (accessible online) of the metabolism of different human cell types, and will allow for tissue-level and organism-level simulations in order to achieve a better understanding of complex diseases. A comparative analysis between the active metabolic networks of cancer types and healthy cell types allowed for identification of cancer-specific metabolic features that constitute generic potential drug targets for cancer treatment. Background The interpretation of the results from genome-scale experiments is a challenging and important problem in contemporary biomedical research. Biological networks that integrate experimental results with existing knowledge from biomedical databases and published literature can provide a rich resource and powerful basis for hypothesizing about mechanistic explanations for observed gene-phenotype relationships. However, the size and density of such networks often impede their efficient exploration and understanding. The three dimensional structure of DNA in the nucleus (chromatin) plays an important role in many cellular processes. Recent experimental advances have led to high-throughput methods of capturing information about chromatin conformation on genome-wide scales. New models are needed to quantitatively interpret this data at a global scale. Here we introduce the use of tools from topological data analysis to study chromatin conformation. We use persistent homology to identify and characterize conserved loops and voids in contact map data and identify scales of interaction. We demonstrate the utility of the approach on simulated data and then look data from both a bacterial genome and a human cell line. We identify substantial multiscale topology in these datasets. Genome-scale models of metabolism and macromolecular expression (ME-models) explicitly compute the optimal proteome composition of a growing cell. ME-models expand upon the well-established genome-scale models of metabolism (M-models), and they enable a new fundamental understanding of cellular growth. ME-models have increased predictive capabilities and accuracy due to their inclusion of the biosynthetic costs for the machinery of life, but they come with a significant increase in model size and complexity. This challenge results in models which are both difficult to compute and challenging to understand conceptually. As a result, ME-models exist for only two organisms (Escherichia coli and Thermotoga maritima) and are still used by relatively few researchers. To address these challenges, we have developed a new software framework called COBRAme for building and simulating ME-models. It is coded in Python and built on COBRApy, a popular platform for using M-models. COBRAme streamlines computation and analysis of ME-models. It provides tools to simplify constructing and editing ME-models to enable ME-model reconstructions for new organisms. We used COBRAme to reconstruct a condensed E. coli ME-model called iJL1678b-ME. This reformulated model gives functionally identical solutions to previous E. coli ME-models while using 1 5 the number of free variables and solving in less than 10 minutes, a marked improvement over the 6 hour solve time of previous ME-model formulations. Errors in previous ME-models were also corrected leading to 52 additional genes that must be expressed in iJL1678b-ME to grow aerobically in glucose minimal in silico media. This manuscript outlines the architecture of COBRAme and demonstrates how ME-models can be created, modified, and shared most efficiently using the new software framework. Modeling biological systems to understand their mechanistic behavior is an important activity in molecular systems biology. Mathematical modeling typically requires deep mathematical or computing knowledge, and this limits the spread of modeling tools among biologists. Graphical modeling languages have been introduced to minimize this limit. Here, we survey the main graphical formalisms (supported by software tools) available to model biological systems with a primary focus on their usability, within the framework of modeling reaction pathways with two-dimensional (2D) (possibly nested) compartments. Considering the main characteristics of the surveyed formalisms, we synthesise a new proposal (Style) and report the results of an online survey conducted among biologists to assess usability of available graphical formalisms. We consider this proposal a guideline developed from what we learned in the survey, which can inform development of graphical formalisms to model reaction pathways in 2D space. Biological pathway maps are highly relevant tools for many tasks in molecular biology. They reduce the complexity of the overall biological network by partitioning it into smaller manageable parts. While this reduction of complexity is their biggest strength, it is, at the same time, their biggest weakness. By removing what is deemed not important for the primary function of the pathway, biologists lose the ability to follow and understand cross-talks between pathways. Considering these cross-talks is, however, critical in many analysis scenarios, such as judging effects of drugs. In this paper we introduce Entourage, a novel visualization technique that provides contextual information lost due to the artificial partitioning of the biological network, but at the same time limits the presented information to what is relevant to the analyst's task. We use one pathway map as the focus of an analysis and allow a larger set of contextual pathways. For these context pathways we only show the contextual subsets, i.e., the parts of the graph that are relevant to a selection. Entourage suggests related pathways based on similarities and highlights parts of a pathway that are interesting in terms of mapped experimental data. We visualize interdependencies between pathways using stubs of visual links, which we found effective yet not obtrusive. By combining this approach with visualization of experimental data, we can provide domain experts with a highly valuable tool. We demonstrate the utility of Entourage with case studies conducted with a biochemist who researches the effects of drugs on pathways. We show that the technique is well suited to investigate interdependencies between pathways and to analyze, understand, and predict the effect that drugs have on different cell types. From bacteria following simple chemical gradients to the brain distinguishing complex odour information, the ability to recognize molecular patterns is essential for biological organisms. This type of information-processing function has been implemented using DNA-based neural networks, but has been limited to the recognition of a set of no more than four patterns, each composed of four distinct DNA molecules. Winner-take-all computation has been suggested as a potential strategy for enhancing the capability of DNA-based neural networks. Compared to the linear-threshold circuits and Hopfield networks used previously, winner-take-all circuits are computationally more powerful, allow simpler molecular implementation and are not constrained by the number of patterns and their complexity, so both a large number of simple patterns and a small number of complex patterns can be recognized. Here we report a systematic implementation of winner-take-all neural networks based on DNA-strand-displacement reactions. We use a previously developed seesaw DNA gate motif, extended to include a simple and robust component that facilitates the cooperative hybridization that is involved in the process of selecting a ‘winner’. We show that with this extended seesaw motif DNA-based neural networks can classify patterns into up to nine categories. Each of these patterns consists of 20 distinct DNA molecules chosen from the set of 100 that represents the 100 bits in 10 × 10 patterns, with the 20 DNA molecules selected tracing one of the handwritten digits ‘1’ to ‘9’. The network successfully classified test patterns with up to 30 of the 100 bits flipped relative to the digit patterns ‘remembered’ during training, suggesting that molecular circuits can robustly accomplish the sophisticated task of classifying highly complex and noisy information on the basis of similarity to a memory. Analyses of biomedical images often rely on demarcating the boundaries of biological structures (segmentation). While numerous approaches are adopted to address the segmentation problem including collecting annotations from domain-experts and automated algorithms, the lack of comparative benchmarking makes it challenging to determine the current state-of-art, recognize limitations of existing approaches, and identify relevant future research directions. To provide practical guidance, we evaluated and compared the performance of trained experts, crowd sourced non-experts, and algorithms for annotating 305 objects coming from six datasets that include phase contrast, fluorescence, and magnetic resonance images. Compared to the gold standard established by expert consensus, we found the best annotators were experts, followed by non-experts, and then algorithms. This analysis revealed that online paid crowd sourced workers without domain-specific backgrounds are reliable annotators to use as part of the laboratory protocol for segmenting biomedical images. We also found that fusing the segmentations created by crowd sourced internet workers and algorithms yielded improved segmentation results over segmentations created by single crowd sourced or algorithm annotations respectively. We invite extensions of our work by sharing our data sets and associated segmentation annotations (http: www.cs.bu.edu betke Biomedical Image Segmentation). High-throughput studies of biological systems are rapidly accumulating a wealth of 'omics'-scale data. Visualization is a key aspect of both the analysis and understanding of these data, and users now have many visualization methods and tools to choose from. The challenge is to create clear, meaningful and integrated visualizations that give biological insight, without being overwhelmed by the intrinsic complexity of the data. In this review, we discuss how visualization tools are being used to help interpret protein interaction, gene expression and metabolic profile data, and we highlight emerging new directions.