The system-biological GLOBE 3D Genome Platform.

Genomes are tremendous co-evolutionary holistic systems for molecular storage, processing and fabrication of information. Their system-biological complexity remains, however, still largely mysterious, despite immense sequencing achievements and huge advances in the understanding of the general sequential, three-dimensional and regulatory organization. Here, we present the GLOBE 3D Genome Platform a completely novel grid based virtual “paper” tool and in fact the first system-biological genome browser integrating the holistic complexity of genomes in a single easy comprehensible platform: Based on a detailed study of biophysical and IT requirements, every architectural level from sequence to morphology of one or several genomes can be approached in a real and in a symbolic representation simultaneously and navigated by continuous scale-free zooming within a unique three-dimensional OpenGL and grid driven environment. In principle an unlimited number of multi-dimensional data sets can be visualized, customized in terms of arrangement, shape, colour, and texture etc. as well as accessed and annotated individually or in groups using internal or external data bases/facilities. Any information can be searched and correlated by importing or calculating simple relations in real-time using grid resources. A general correlation and application platform for more complex correlative analysis and a front-end for system-biological simulations both using again the huge capabilities of grid infrastructures is currently under development. Hence, the GLOBE 3D Genome Platform is an example of a grid based approach towards a virtual desktop for genomic work combining the three fundamental distributed resources: i) visual data representation, ii) data access and management, and iii) data analysis and creation. Thus, the GLOBE 3D Genome Platform is the novel system-biology oriented information system urgently needed to access, present, annotate, and to simulate the holistic genome complexity in a unique gateway towards a real understanding, educative presentation and curative manipulation planning of this tremendous evolutionary information grail – genomes

Parallel high-performance grid computing: Capabilities and opportunities of a novel demanding service and business class allowing highest resource efficiency

Especially in the life-science and the health-care sectors the huge IT requirements are imminent due to the large and complex systems to be analysed and simulated. Grid infrastructures play here a rapidly increasing role for research, diagnostics, and treatment, since they provide the necessary large-scale resources efficiently. Whereas grids were first used for huge number crunching of trivially parallelizable problems, increasingly parallel high-performance computing is required. Here, we show for the prime example of molecular dynamic simulations how the presence of large grid clusters including very fast network interconnects within grid infrastructures allows now parallel high-performance grid computing efficiently and thus combines the benefits of dedicated super-computing centres and grid infrastructures. The demands for this service class are the highest since the user group has very heterogeneous requirements: i) two to many thousands of CPUs, ii) different memory architectures, iii) huge storage capabilities, and iv) fast communication via network interconnects, are all needed in different combinations and must be considered in a highly dedicated manner to reach highest performance efficiency. Beyond, advanced and dedicated i) interaction with users, ii) the management of jobs, iii) accounting, and iv) billing, not only combines classic with parallel high-performance grid usage, but more importantly is also able to increase the efficiency of IT resource providers. Consequently, the mere "yes-we- can" becomes a huge opportunity like e.g. the life-science and health-care sectors as well as grid infrastructures by reaching higher level of resource efficiency

Visualization, analysis, and design of COMBO-FISH probes in the grid-based GLOBE 3D genome platform

The genome architecture in cell nuclei plays an important role in modern microscopy for the monitoring of medical diagnosis and therapy since changes of function and dynamics of genes are interlinked with changing geometrical parameters. The planning of corresponding diagnostic experiments and their imaging is a complex and often interactive IT intensive challenge and thus makes high-performance grids a necessity. To detect genetic changes we recently developed a new form of fluorescence in situ hybridization (FISH) - COMBinatorial Oligonucleotide FISH (COMBO-FISH) - which labels small nucleotide sequences clustering at a desired genomic location. To achieve a unique hybridization spot other side clusters have to be excluded. Therefore, we have designed an interactive pipeline using the grid-based GLOBE 3D Genome Viewer and Platform to design and display different labelling variants of candidate probe sets. Thus, we have created a grid-based virtual "paper" tool for easy interactive calculation, analysis, management, and representation for COMBO-FISH probe design with many an advantage: Since all the calculations and analysis run in a grid, one can instantly and with great visual ease locate duplications of gene subsequences to guide the elimination of side clustering sequences during the probe design process, as well as get at least an impression of the 3D architectural embedding of the respecti

DNA Sequence Patterns – A Successful Example of Grid Computing in Genome Research and Building Virtual Super-Computers for the Research Commons of e-Societies

The amount of information is growing exponentially with ever-new technologies emerging and is believed to be always at the limit. In contrast, huge resources are obviously available, which are underused in the IT sector, similar as e.g. in the renewable energy sector. Genome research is one of the boosting areas, which needs an extreme amount of IT resources to analyse the sequential organization of genomes, i.e. the relations between distant base pairs and regions within sequences, and its connection to the three-dimensional organization of genomes, which is still a largely unresolved problem. The underusage of resources as those accessible by grid with its fast turnover rates is very astonishing considering the barriers for further development put forward by the inability to satisfy the need for such resources. The phenomenon is a typical example of the Inverse Tragedy of the Commons, i.e. resources are underexploited in contrast to the unsustainable and destructing overexploitation in the Classic Tragedy of the Commons. An analysis of IT and the grid sector which attempts to share resources for better usage efficiency, reveals two challenges, which lead to the heart of the paradox: i) From a macro perspective all grid infrastructures involve not only mere technical solutions but also dominantly all of the autopoietic social sub-systems ranging from religion to policy. ii) On the micro level the individual players and their psychology and risk behaviour are of major importance for acting within the macro autopoietic framework. Consequently, the challenges of grid implementation are similar to those of other pressing global issues as e.g. climate protection. This is well described by extending the Human Ecology triangle to a rectangle: invironment-individual-society-environment. By applying this extension of this classical field of interdisciplinary basic and applied research to the grid sector, i.e. by further extension to an e-Human Grid Ecology rational, the Grid Inverse Tragedy of the Commons can be understood and approached regarding the internalization challenge into e-Society and e-Life, from which then guidelines for the day-to-day management can be derived. This is of general importance for many complex fields and thus with similar paradoxes and challenges. By using grid Long-range power-law correlations were found using correlation analysis on almost the entire observable scale of 132 completely sequenced chromosomes of 0.5x106 to 3.0x107 bp from Archaea, Bacteria, Arabidopsis thaliana, Saccharomyces cerevisiae, Schizosaccharomyces pombe, Drosophila melanogaster and Homo sapiens. The local correlation coeffi

Targeted Chromatin Capture (T2C): A novel high resolution high throughput method to detect genomic interactions and regulatory elements.

Background: Significant efforts have recently been put into the investigation of the spatial organization and the chromatin-interaction networks of genomes. Chromosome conformation capture (3C) technology and its derivatives are important tools used in this effort. However, many of these have limitations, such as being limited to one viewpoint, expensive with moderate to low resolution, and/or requiring a large sequencing effort. Techniques like Hi-C provide a genome-wide analysis. However, it requires massive sequencing effort with considerable costs. Here we describe a new technique termed Targeted Chromatin Capture (T2C), to interrogate large selected regions of the genome. T2C provides an unbiased view of the spatial organization of selected loci at superior resolution (single restriction fragment resolution, from 2 to 6 kbp) at much lower costs than Hi-C due to the lower sequencing effort. Results: We applied T2C on well-known model regions, the mouse β-globin locus and the human H19/IGF2 locus. In both cases we identified all known chromatin interactions. Furthermore, we compared the human H19/IGF2 locus data obtained from different chromatin conformation capturing methods with T2C data. We observed the same compartmentalization of the locus, but at a much higher resolution (single restriction fragments vs. the common 40 kbp bins) and higher coverage. Moreover, we compared the β-globin locus in two different biological samples (mouse primary erythroid cells and mouse fetal brain), where it is either actively transcribed or not, to identify possible transcriptional dependent interactions. We identified the known interactions in the β-globin locus and the same topological domains in both mouse primary erythroid cells and in mouse fetal brain with the latter having fewer interactions probably due to the inactivity of the locus. Furthermore, we show that interactions due to the important chromatin proteins, Ldb1 and Ctcf, in both tissues can be analyzed easily to reveal their role on transcriptional interactions and genome folding. Conclusions: T2C is an efficient, easy, and affordable with high (restriction fragment) resolution tool to address both genome compartmentalization and chromatin-interaction networks for specific genomic regions at high resolution for both clinical and non-clinical research

The GLOBE 3D Genome Platform Live Movie of the Presentation

The combination of genome sequence and structure, its annotation and experimental data in an accessible and comprehensible way is a major challenge. Increasingly, there are a large number of extremely divergent data sets: the sequence itself, genes, regulatory regions, various forms of reoccurring sequence features and clone sets etc. Currently, one possibility to represent this information in a visual form - and thus to reveal its scientific meaning - is to use genome browsers such as "Ensembl" or "The UCSC Genome Browser". These browsers have been beneficial in the understanding of the complex organization of genomes. However, there are also huge limitations concerning their focus on linear presentation, standardized input and data bank accessibility. Also customisability by a remote user with special requirements is difficult. Therefore, the GLOBE-Consortium has developed the next generation genome viewer - the GLOBE 3D-Viewer - to visualize multi-dimensional data sets from various sources in an easy intuitive manor while accounting for the complexity of genome organization. Together with an easily accessible data-warehouse for archiving (un- )published experimental data and the Erasmus Computing Grid (ECG) for fast interactive large-scale (correlative) analysis the GLOBE-Consortium creates an intuitive holistic environment for genome research. Thus, the GLOBE 3D-Viewer sets the new standard to integrate complex genomic data sets within a single holistic display system and thus is major advance for scientific and clinical genome research

The GLOBE 3D Genome Platform

The combination of genome sequence and structure, its annotation and experimental data in an accessible and comprehensible way is a major challenge. Increasingly, there are a large number of extremely divergent data sets: the sequence itself, genes, regulatory regions, various forms of reoccurring sequence features and clone sets etc. Currently, one possibility to represent this information in a visual form - and thus to reveal its scientific meaning - is to use genome browsers such as "Ensembl" or "The UCSC Genome Browser". These browsers have been beneficial in the understanding of the complex organization of genomes. However, there are also huge limitations concerning their focus on linear presentation, standardized input and data bank accessibility. Also customisability by a remote user with special requirements is difficult. Therefore, the GLOBE-Consortium has developed the next generation genome viewer - the GLOBE 3D-Viewer - to visualize multi-dimensional data sets from various sources in an easy intuitive manor while accounting for the complexity of genome organization. Together with an easily accessible data-warehouse for archiving (un- )published experimental data and the Erasmus Computing Grid (ECG) for fast interactive large-scale (correlative) analysis the GLOBE-Consortium creates an intuitive holistic environment for genome research. Thus, the GLOBE 3D-Viewer sets the new standard to integrate complex genomic data sets within a single holistic display system and thus is major advance for scientific and clinical genome research

The Detailed 3D Multi-Loop Aggregate/Rosette Chromatin Architecture and Functional Dynamic Organization of the Human and Mouse Genomes. - BioRxiv Version

The dynamic three-dimensional chromatin architecture of genomes and its coevolutionary connection to its function – the storage, expression, and replication of genetic information – is still one of the central issues in biology. Here, we describe the much debated 3D-architecture of the human and mouse genomes from the nucleosomal to the megabase pair level by a novel approach combining selective high-throughput high-resolution chromosomal interaction capture (T2C), polymer simulations, and scaling analysis of the 3D-architecture and the DNA sequence: The genome is compacted into a chromatin quasi-fibre with ~5±1 nucleosomes/11nm, folded into stable ~30-100 kbp loops forming stable loop aggregates/

The detailed 3D multi-loop aggregate/rosette chromatin architecture and functional dynamic organization of the human and mouse genomes. - Epigenetics & Chromatin Version

Background: The dynamic three-dimensional chromatin architecture of genomes and its co-evolutionary connection to its function - the storage, expression, and replication of genetic information - is still one of the central issues in biology. Here, we describe the much debated 3D architecture of the human and mouse genomes from the nucleosomal to the megabase pair level by a novel approach combining selective high-throughput high-resolution chromoso