How Genomes Emerge, Function, and Evolve: Living Systems Emergence-Genotype-Phenotype-Multilism-Genome/Systems Ecology.

What holds together the world in its innermost, what life is, how it emerges, functions, and evolves, has not only been an epic matter of endless romantic sunset poetry and philosophy, but also manifests explicitly in its perhaps most central organization unit-genomes. Their 3D architecture and dynamics, including the interaction networks of regulatory elements, obviously co-evolved as inseparable systems allowing the physical storage, expression, and replication of genetic information. Since we were able to fill finally the much-debated centennial gaps in their 3D architecture and dynamics, now entire new perspectives open beyond epigenetics reaching as far as a general understanding of living systems: besides the previously known DNA double helix and nucleosome structure, the latter compact into a chromatin quasi-fibre folded into stable loops forming stable multi-loop aggregates/rosettes connected by linkers, creating hence the again already known chromosome arms and entire chromosomes forming the cell nucleus. Instantly and for the first time this leads now to a consistent and cross-proven systems statistical mechanics genomics framework elucidating genome intrinsic function and regulation including various components. It balances stability/flexibility ensuring genome integrity, enabling expression/regulation of genetic information, as well as genome replication/spread. Furthermore, genotype and phenotype are multiplisticly entangled being evolutionarily the outcome of both Darwinian natural selection and Lamarckian self-referenced manipulation-all embedded in even broader genome ecology (autopoietic) i(!)n- and environmental scopes. This allows formulating new meta-level functional semantics of genomics, i.e. notions as communication of genes, genomes, and information networks, architectural and dynamic spaces for creativity and innovation, or genomes as central geno-/phenotype entanglements. Beyond and most fundamentally, the paradoxical-seeming local equilibrium substance stability in its entity though far from a universal heat-death-like equilibrium is solved, and system irreversibility, time directionality, and thus the emergence of existence are clarified. Consequently, real deep understandings of genomes, life, and complex systems in general appear in evolutionary perspectives as well as from systems analyses, via system damage/disease (its repair/cure and manipulation) as far as the understanding of extraterrestrial life, the de novo creation and thus artificial life, and even the raison d'etre.

Simulation of Different Three-Dimensional Models of Whole Interphase Nuclei Compared to Experiments - A Consistent Scale-Bridging Simulation Framework for Genome Organization.

The three-dimensional architecture of chromosomes, their arrangement, and dynamics within cell nuclei are still subject of debate. Obviously, the function of genomes-the storage, replication, and transcription of genetic information-has closely coevolved with this architecture and its dynamics, and hence are closely connected. In this work a scale-bridging framework investigates how of the 30 nm chromatin fibre organizes into chromosomes including their arrangement and morphology in the simulation of whole nuclei. Therefore, mainly two different topologies were simulated with corresponding parameter variations and comparing them to experiments: The Multi-Loop-Subcompartment (MLS) model, in which (stable) small loops form (stable) rosettes, connected by chromatin linkers, and the Random-Walk/Giant-Loop (RW/GL) model, in which large loops are attached to a flexible non-protein backbone, were simulated for various loop and linker sizes. The 30 nm chromatin fibre was modelled as a polymer chain with stretching, bending and excluded volume interactions. A spherical boundary potential simulated the confinement to nuclei with different radii. Simulated annealing and Brownian Dynamics methods were applied in a four-step decondensation procedure to generate from metaphase decondensated interphase configurations at thermodynamical equilibrium. Both the MLS and the RW/GL models form chromosome territories, with different morphologies: The MLS rosettes result in distinct subchromosomal domains visible in electron and confocal laser scanning microscopic images. In contrast, the big RW/GL loops lead to a mostly homogeneous chromatin distribution. Even small changes of the model parameters induced significant rearrangements of the chromatin morphology. The low overlap of chromosomes, arms, and subchromosomal domains observed in experiments agrees only with the MLS model. The chromatin density distribution in CLSM image stacks reveals a bimodal behaviour in agreement with recent experiments. Combination of these results with a variety of (spatial distance) measurements favour an MLS like model with loops and linkers of 63 to 126 kbp. The predicted large spaces between the chromatin fibres allow typically sized biological molecules to reach nearly every location in the nucleus by moderately obstructed diffusion and is in disagreement with the much simplified assumption that defined channels between territories for molecular transport as in the Interchromosomal Domain (ICD) hypothesis exist and are necessary for transport. All this is also in agreement with recent selective high-resolution chromosome interaction capture (T2C) experiments, the scaling behaviour of the DNA sequence, the dynamics of the chromatin fibre, the diffusion of molecules, and other measurements. Also all other chromosome topologies can in principle be excluded. In summary, polymer simulations of whole nuclei compared to experimental data not only clearly favour only a stable loop aggregate/rosette like genome architecture whose local topology is tightly connected to the global morphology and dynamics of the cell nucleus and hence can be used for understanding genome organization also in respect to diagnosis and treatment. This is in agreement with and also leads to a general novel framework of genome emergence, function, and evolution.

Simulation of different three-dimensional polymer models of interphase chromosomes compared to experiments-an evaluation and review framework of the 3D genome organization.

Despite all the efforts the three-dimensional higher-order architecture and dynamics in the cell nucleus are still debated. The regulation of genes, their transcription, replication, as well as differentiation in Eukarya is, however, closely connected to this architecture and dynamics. Here, an evaluation and review framework is setup to investigate the folding of a 30 nm chromatin fibre into chromosome territories by comparing computer simulations of two different chromatin topologies to experiments: The Multi-Loop-Subcompartment (MLS) model, in which small loops form rosettes connected by chromatin linkers, and the Random-Walk/Giant-Loop (RW/GL) model, in which large loops are attached to a flexible non-protein backbone, were simulated for various loop, rosette, and linker sizes. The 30 nm chromatin fibre was modelled as a polymer chain with stretching, bending, and excluded volume interactions. A spherical boundary potential simulated the confinement by other chromosomes and the nuclear envelope. Monte Carlo and Brownian Dynamics methods were applied to generate chain configurations at thermodynamic equilibrium. Both the MLS and the RW/GL models form chromosome territories, with different morphologies: The MLS rosettes form distinct subchromosomal domains, compatible in size as those from light microscopic observations. In contrast, the big RW/GL loops lead to a more homogeneous chromatin distribution. Only the MLS model agrees with the low overlap of chromosomes, their arms, and subchromosomal domains found experimentally. A review of experimental spatial distance measurements between genomic markers labelled by FISH as a function of their genomic separation from different publications and comparison to simulated spatial distances also favours an MLS-like model with loops and linkers of 63 to 126 kbp. The chromatin folding topology also reduces the apparent persistence length of the chromatin fibre to a value significantly lower than the free solution persistence length, explaining the low persistence lengths found various experiments. The predicted large spaces between the chromatin fibres allow typically sized biological molecules to reach nearly every location in the nucleus by moderately obstructed diffusion and disagrees with the much simplified assumption that defined channels between territories for molecular transport as in the Interchromosomal Domain (ICD) hypothesis exist. All this is also in agreement with recent selective high-resolution chromosome interaction capture (T2C) experiments, the scaling behaviour of the DNA sequence, the dynamics of the chromatin fibre, the nuclear diffusion of molecules, as well as other experiments. In summary, this polymer simulation framework compared to experimental data clearly favours only a quasi-chromatin fibre forming a stable multi-loop aggregate/rosette like genome organization and dynamics whose local topology is tightly connected to the global morphology and dynamics of the cell nucleus.

A Guided Protocol for Array Based T2C: A High-Quality Selective High-Resolution High-Throughput Chromosome Interaction Capture.

After now more than 170 years of research the dynamic three-dimensional chromatin architecture of genomes and the co-evolved interaction networks of regulatory elements which create genome function - i.e. the storage, expression, and finally replication of genetic information - involves ever more investigative efforts in respect to not only the pure understanding of living organisms, but also diagnosis, treatment, and even future genome engineering. To study genomic interactions, we developed a novel and superior high-quality selective high-resolution, high-throughput chromosome interaction capture method - T2C (targeted chromatin capture) - which allows to arbitrarily balance resolution, frequency range of interactions, and the investigated general genetic region or single interactions in a highly cost-effective manner in respect to the obtainable result and compared to other techniques. Beyond, T2C has such a high signal-to-noise ratio at high resolution that the "genomic" statistical mechanics level can be reached. With the guided T2C protocol described here, we were already able to finally determine the chromatin quasi-fiber conformation and its folding into stable multi-loop aggregates/rosettes connected by a linker. Actually, this guided T2C protocol provides the means for architectural genome sequencing from the level of the single base pair to the entire cell nucleus and thus to analyze genetic interactions in respect to genome function in a systems biological manner in general as well as in settings ranging from basic research, via diagnostics and treatment, to genome engineering. © 2018 by John Wiley & Sons, Inc.

Investigation of the spatial structure and interactions of the genome at sub-kilobase-pair resolution using T2C.

Chromosome conformation capture (3C) and its derivatives (e.g., 4C, 5C and Hi-C) are used to analyze the 3D organization of genomes. We recently developed targeted chromatin capture (T2C), an inexpensive method for studying the 3D organization of genomes, interactomes and structural changes associated with gene regulation, the cell cycle, and cell survival and development. Here, we present the protocol for T2C based on capture, describing all experimental steps and bio-informatic tools in full detail. T2C offers high resolution, a large dynamic interaction frequency range and a high signal-to-noise ratio. Its resolution is determined by the resulting fragment size of the chosen restriction enzyme, which can lead to sub-kilobase-pair resolution. T2C's high coverage allows the identification of the interactome of each individual DNA fragment, which makes binning of reads (often used in other methods) basically unnecessary. Notably, T2C requires low sequencing efforts. T2C also allows multiplexing of samples for the direct comparison of multiple samples. It can be used to study topologically associating domains (TADs), determining their position, shape, boundaries, and intra- and inter-domain interactions, as well as the composition of aggregated loops, interactions between nucleosomes, individual transcription factor binding sites, and promoters and enhancers. T2C can be performed by any investigator with basic skills in molecular biology techniques in ∼7-8 d. Data analysis requires basic expertise in bioinformatics and in Linux and Python environments.

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

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 chromosomal interaction capture (T2C), polymer simulations, and scaling analysis of the 3D architecture and the DNA sequence. RESULTS: The genome is compacted into a chromatin quasi-fibre with ~5 ± 1 nucleosomes/11 nm, folded into stable ~30-100 kbp loops forming stable loop aggregates/rosettes connected by similar sized linkers. Minor but significant variations in the architecture are seen between cell types and functional states. The architecture and the DNA sequence show very similar fine-structured multi-scaling behaviour confirming their co-evolution and the above. CONCLUSIONS: This architecture, its dynamics, and accessibility, balance stability and flexibility ensuring genome integrity and variation enabling gene expression/regulation by self-organization of (in)active units already in proximity. Our results agree with the heuristics of the field and allow "architectural sequencing" at a genome mechanics level to understand the inseparable systems genomic properties.

Dynamic properties of independent chromatin domains measured by correlation spectroscopy in living cells.

BACKGROUND: Genome organization into subchromosomal topologically associating domains (TADs) is linked to cell-type-specific gene expression programs. However, dynamic properties of such domains remain elusive, and it is unclear how domain plasticity modulates genomic accessibility for soluble factors. RESULTS: Here, we combine and compare a high-resolution topology analysis of interacting chromatin loci with fluorescence correlation spectroscopy measurements of domain dynamics in single living cells. We identify topologically and dynamically independent chromatin domains of ~1 Mb in size that are best described by a loop-cluster polymer model. Hydrodynamic relaxation times and gyration radii of domains are larger for open (161 ± 15 ms, 297 ± 9 nm) than for dense chromatin (88 ± 7 ms, 243 ± 6 nm) and increase globally upon chromatin hyperacetylation or ATP depletion. CONCLUSIONS: Based on the domain structure and dynamics measurements, we propose a loop-cluster model for chromatin domains. It suggests that the regulation of chromatin accessibility for soluble factors displays a significantly stronger dependence on factor concentration than search processes within a static network.

Binding of nuclear factor κB to noncanonical consensus sites reveals its multimodal role during the early inflammatory response.

Mammalian cells have developed intricate mechanisms to interpret, integrate, and respond to extracellular stimuli. For example, tumor necrosis factor (TNF) rapidly activates proinflammatory genes, but our understanding of how this occurs against the ongoing transcriptional program of the cell is far from complete. Here, we monitor the early phase of this cascade at high spatiotemporal resolution in TNF-stimulated human endothelial cells. NF-κB, the transcription factor complex driving the response, interferes with the regulatory machinery by binding active enhancers already in interaction with gene promoters. Notably, >50% of these enhancers do not encode canonical NF-κB binding motifs. Using a combination of genomics tools, we find that binding site selection plays a key role in NF-κΒ-mediated transcriptional activation and repression. We demonstrate the latter by describing the synergy between NF-κΒ and the corepressor JDP2. Finally, detailed analysis of a 2.8-Mbp locus using sub-kbp-resolution targeted chromatin conformation capture and genome editing uncovers how NF-κΒ that has just entered the nucleus exploits pre-existing chromatin looping to exert its multimodal role. This work highlights the involvement of topology in cis-regulatory element function during acute transcriptional responses, where primary DNA sequence and its higher-order structure constitute a regulatory context leading to either gene activation or repression.

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 ß-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 ß-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 ß-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.

Cohesin and CTCF differentially affect chromatin architecture and gene expression in human cells.

Recent studies of genome-wide chromatin interactions have revealed that the human genome is partitioned into many self-associating topological domains. The boundary sequences between domains are enriched for binding sites of CTCC-binding factor (CTCF) and the cohesin complex, implicating these two factors in the establishment or maintenance of topological domains. To determine the role of cohesin and CTCF in higher-order chromatin architecture in human cells, we depleted the cohesin complex or CTCF and examined the consequences of loss of these factors on higher-order chromatin organization, as well as the transcriptome. We observed a general loss of local chromatin interactions upon disruption of cohesin, but the topological domains remain intact. However, we found that depletion of CTCF not only reduced intradomain interactions but also increased interdomain interactions. Furthermore, distinct groups of genes become misregulated upon depletion of cohesin and CTCF. Taken together, these observations suggest that CTCF and cohesin contribute differentially to chromatin organization and gene regulation.

TNFα signalling primes chromatin for NF-κB binding and induces rapid and widespread nucleosome repositioning.

BACKGROUND: The rearrangement of nucleosomes along the DNA fiber profoundly affects gene expression, but little is known about how signalling reshapes the chromatin landscape, in three-dimensional space and over time, to allow establishment of new transcriptional programs. RESULTS: Using micrococcal nuclease treatment and high-throughput sequencing, we map genome-wide changes in nucleosome positioning in primary human endothelial cells stimulated with tumour necrosis factor alpha (TNFα) - a proinflammatory cytokine that signals through nuclear factor kappa-B (NF-κB). Within 10 min, nucleosomes reposition at regions both proximal and distal to NF-κB binding sites, before the transcription factor quantitatively binds thereon. Similarly, in long TNFα-responsive genes, repositioning precedes transcription by pioneering elongating polymerases and appears to nucleate from intragenic enhancer clusters resembling super-enhancers. By 30 min, widespread repositioning throughout megabase pair-long chromosomal segments, with consequential effects on three-dimensional structure (detected using chromosome conformation capture), is seen. CONCLUSIONS: Whilst nucleosome repositioning is viewed as a local phenomenon, our results point to effects occurring over multiple scales. Here, we present data in support of a TNFα-induced priming mechanism, mostly independent of NF-κB binding and/or elongating RNA polymerases, leading to a plastic network of interactions that affects DNA accessibility over large domains.

Super-resolution imaging reveals three-dimensional folding dynamics of the ß-globin locus upon gene activation.

The chromatin architecture is constantly changing because of cellular processes such as proliferation, differentiation and changes in the expression profile during gene activation or silencing. Unravelling the changes that occur in the chromatin structure during these processes has been a topic of interest for many years. It is known that gene activation of large gene loci is thought to occur by means of an active looping mechanism. It was also shown for the ß-globin locus that the gene promoter interacts with an active chromatin hub by means of an active looping mechanism. This means that the locus changes in three-dimensional (3D) nuclear volume and chromatin shape. As a means of visualizing and measuring these dynamic changes in chromatin structure of the ß-globin locus, we used a 3D DNA-FISH method in combination with 3D image acquisition to volume render fluorescent signals into 3D objects. These 3D chromatin structures were geometrically analysed, and results prior to and after gene activation were quantitatively compared. Confocal and super-resolution imaging revealed that the inactive locus occurs in several different conformations. These conformations change in shape and surface structure upon cell differentiation into a more folded and rounded structure that has a substantially smaller size and volume. These physical measurements represent the first non-biochemical evidence that, upon gene activation, an actively transcribing chromatin hub is formed by means of additional chromatin looping.

Enhancers and silencers: an integrated and simple model for their function.

Regulatory DNA elements such as enhancers, silencers and insulators are embedded in metazoan genomes, and they control gene expression during development. Although they fulfil different roles, they share specific properties. Herein we discuss some examples and a parsimonious model for their function is proposed. All are transcription units that tether their target promoters close to, or distant from, transcriptional hot spots (or 'factories').

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 respective chromosome region, which is of major importance to estimate the hybridization probe dynamics. Beyond, even several people at different locations could work on the same process in a team wise manner. Consequently, we present how a complex interactive process can profit from grid infrastructure technology using our unique GLOBE 3D Genome Platform gateway towards a real interactive curative diagnosis planning and therapy monitoring.

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.

Development of an information platform for new grid users in the biomedical field.

Bringing new users into grids is a top priority for all grid initiatives and one of the most challenging tasks. Especially in life sciences it is essential to have a certain amount of users to establish a critical mass for a sustainable grid and give feedback back to the technological middleware layer. Based on the presumable lack of grid IT knowledge it is notably more arduous to satisfy user demands although here the requirements are especially demanding. Therefore, the development of an information- and learning platform could support the efforts of grid experts to guide new users. By providing a platform about grid technology and their feasibilities for users of the community of biomedicine potential, users could be supported using the high potential of their discipline.

Tagged mutagenesis by efficient Minos-based germ line transposition.

Germ line gene transposition technology has been used to generate "libraries" of flies and worms carrying genomewide mutations. Phenotypic screening and DNA sequencing of such libraries provide functional information resulting from insertional events in target genes. There is also a great need to have a fast and efficient way to generate mouse mutants in vivo to model developmental defects and human diseases. Here we describe an optimized mammalian germ line transposition system active during early mouse spermatogenesis using the Minos transposon. Transposon-positive progeny carry on average more than 2 new transpositions, and 45 to 100% of the progeny carry an insertion in a gene. The optimized Minos-based system was tested in a small rapid dominant functional screen to identify mutated genes likely to cause measurable cardiovascular "disease" phenotypes in progeny/embryos. Importantly this system allows rapid screening for modifier genes.

GRIMP: a web- and grid-based tool for high-speed analysis of large-scale genome-wide association using imputed data.

The current fast growth of genome-wide association studies (GWAS) combined with now common computationally expensive imputation requires the online access of large user groups to high-performance computing resources capable of analyzing rapidly and efficiently millions of genetic markers for ten thousands of individuals. Here, we present a web-based interface--called GRIMP--to run publicly available genetic software for extremely large GWAS on scalable super-computing grid infrastructures. This is of major importance for the enlargement of GWAS with the availability of whole-genome sequence data from the 1000 Genomes Project and for future whole-population efforts.

The GLOBE 3D Genome Platform - towards a novel system-biological paper tool to integrate the huge complexity of genome organization and function.

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.

Perspectives of MediGRID.

Sustainability is a top priority for nearly all grid communities. The German grid communities in the area of life sciences are continuing their dissemination efforts in order to bring the grid to scientists. With cloud computing another concept for distributed IT infrastructures is on the rise. In this regard the grid has a different focus and matches better with life science compute power demands. A comparison of both grid and cloud in addition to the background and present status of the German life science grid give a contemporary impression of the future perspectives of MediGRID.