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Systems Biological Determination of the Epi-Genomic Structure Function Relation:Despite our knowledge of the sequence of the human genome, the relation of its three-dimensional dynamic architecture with its function – the storage and expression of genetic information – remains one of the central unresolved issues of our age. It became very clear meanwhile that this link is crucial for the entire holistic function of the genome on all genomic coding levels from the DNA sequence to the entire chromosomes. To fulfil the dreams for better diagnostics and treatment in the 21st century (e.g. by gene therapy by inserting a gene into a new global context), we propose here in a unique interdisciplinary project to combine experiment with theory to analyze the (epi-)genomic structure function relationships within the dynamic organization of the -Globin locus, the Immuno Globin loci, and the Tumor Necrosis Factor Alpha regulated SAMD4 region in mouse and human active and inactive cell states, and their global genomic context. The project consists of five work packages (WP1-WP5) and corresponding tasks connected in a system biological approach with iterative use of data, modelling, simulation and experiments via a unique data sharing and visualization platform: In WP1 (Längst, Rippe, Wedemann, Knoch/Grosfeld; T1-T5) to investigate nucleosomal association changes in relation to the DNA sequence and the activity of ATP-driven chromatin remodelling complexes, nucleosome positions will be determined by high-throughput sequencing. The resulting nucleosomal localization probability maps will be evaluated by a novel combination of analysis tools and innovative generic data ontologies. The relation to epigenetic modifications, to the activity of ATP-driven remodelling complexes and compaction degree of nucleosomes will be analysed to understand chromatin morphogenesis and fiber formation. In parallel, in WP2 (Grosveld/Knoch, Cook, Rippe, Längst; T1-T3) we determine by high-throughput monitoring of intra/inter chromosomal contacts and architecture absolute DNA-DNA interaction probability maps for the individual loci and their global context using a novel chromosome conformation capture approach based on deep sequencing. From these the 3D conformation of the chromatin fiber and its higher-order folding into loops and loop clusters can be derived using algorithms recently developed by us. WP3 (Cook, Grosveld/Knoch, Längst; T1-T5) focuses on the determination of transcription rates and structure by qRT-PCR, DNA and RNA fluorescence in situ hybridization using intronic probes and high-resolution laser-scanning and single molecule imaging with advanced image analysis tools. Transcription-dependent changes of active and inactive loci as well as rapid synchronous transcription alteration against the unchanged background is one main interest here. This will yield results in a detailed cartography of the structure-transcription-function dependency and its importance. To rationalize the experimental results theoretically, in WP4 (Wedemann Knoch/Grosveld, Rippe; T1-T3) simulations are made of nucleosomal structure, chromatin fiber conformation and chromosomal architecture using parallel and grid super-computers with ~10.000 CPUs. The impact of different nucleosomal positions and epigenetic modifications on the nucleosomal structure and the chromatin fiber conformation will be assessed by novel Monte Carlo approaches. To understand the higher-order architecture Brownian Dynamics simulations of entire cell nuclei with molecular resolution, morphogenic processes and transcriptional states will be made. This results in a virtual multi-scale model with unseen spatial and time resolution providing novel insights into genome organization. All the resulting virtual architectures will be compared to experiment to prompt again new experiments and vice versa in reiterative cycles. In WP5 (Knoch/Grosveld, Cook, Rippe, Längst, Wedemann; T1-T5) all partners together will integrate the experimental and theoretic results to achieve a system biological model with existing genome-wide data in the GLOBE 3D Genome Browser – a novel platform developed by us for the analysis, manipulation and understanding of multi-dimensional complex genome wide data in an easy to understand 3D visualization environment. The entire experimental data will be archived, all simulations and analysis on high-performance computing infrastructures (e.g. German MediGRID, Dutch Erasmus Computing Grid) will be controlled by a new management system. Together with a novel generic correlation finder and a process/pathway data base this will result together with our Portable Genome Format (PGF) in a unique system biological platform publicly available to understand genome complexity. We are strongly convinced, that the reiterative combination of quantitative experiment with theory leads to a virtual system biological model of the (epi-)genomic structure-function relationship with major impact and great valorization opportunities in research, training, diagnosis and treatment due to the uniqueness, novelty, and frontier position (~20 academic, ~10 industry collaborations underway). This is stressed by our i) scientific excellence, ii) interdisciplinary experience, iii) participative (SOP) management, and iv) IP valorization successes, embedded within strong education/training regimes and famous infrastructures. Consequently, our “EpiGenSys” virtual laboratory is a prime example for systems biology combining high-throughput/performance techniques of cell biology, mathematics, physics and informatics to solve one of the most fundamental issues of personalized genomic medicine. Beyond, we believe to make a major contribution to e-Science, e-Health, e-Learning, as well as e-Commerce creating a novel awareness and understanding of genomic complexity within society.
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DNA Sequence Patterns – A Successful Example of Grid Computing in Genome Research and Building Virtual Super-Computers for the Research Commons of e-SocietiesThe 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 coefficients show a species specific multi-scaling behaviour: close to random correlations on the scale of a few base pairs, a first maximum from 40 to 3400 bp (for Arabidopsis thaliana and Drosophila melanogaster divided in two submaxima), and often a region of one or more second maxima from 105 to 3x105 bp. Within this multi-scaling behaviour, an additional fine-structure is present and attributable to codon usage in all except the human sequences, where it is related to nucleosomal binding. Computer-generated random sequences assuming a block organization of genomes, the codon usage, and nucleosomal binding explain these results. Mutation by sequence reshuffling destroyed all correlations. Thus, the stability of correlations seems evolutionarily tightly controlled and connected to the spatial genome organization. In summary, genomes show a complex sequential organization related closely to their three-dimensional organization. Consequently, grids can be established by solving the Grid Inverse Tragedy of the Commons using a e-Human Grid Ecology rational and indeed be used as e.g. in genome research for DNA sequence pattern analysis very successfully to determine for decades unresolved questions which demand very heavy IT support. Thus, indeed the solutions for the demand requirements in the research commons of e-Societies can be tackled successfully by such a systemic approach.
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The Erasmus Computing Grid – Building a Super-Computer for FreeToday advances in scientific research as well as clinical diagnostics and treatment are inevitably connected with information solutions concerning computation power and information storage. The needs for information technology are enormous and are in many cases the limiting factor for new scientific results or clinical diagnostics and treatment. At the Hogeschool Rotterdam and the Erasmus MC there is a massive need for computation power on a scale of 10,000 to 15,000 computers equivalent to ~20 to ~30 Tflops (1012 floating point operations per second) for a variety of work areas ranging from e.g. MRI and CT scan and microscopic image anlysis to DNA sequence analysis, protein and other structural simulations and analysis. Both institutions have already 13,000 computers, i.e. ~18 Tflops of computer power, available! To make the needed computer power accessible, we started to build the Erasmus Computing Grid (ECG), which is connecting local computers in each institution via central management systems. The system guaranties security and any privacy rules through the used software as well as through our set-up and a NAN and ISO certification process being under way. Similar systems run already world-wide on entire institutions including secured environments like government institutions or banks. Currently, the ECG has a computational power of ~5 Tflops and is one of or already the largest desktop grid in the world. At the Hogeschool Rotterdam meanwhile all computers were included in the ECG. Currently, 10 departments with ~15 projects at the Erasmus MC depend on using the ECG and are preparing or prepared their analysis programs or are already in production state. The Erasmus Computing Grid office and an advisory and control board were set-up. To sustain the ECG now further infrastructure measures have to be taken. Central hardware and specialist personal needs to be put in place for capacity, security and usability reasons for the application at Erasmus MC. This is also necessary in respect to NAN and ISO certification towards diagnostic and commercial ECG use, for which there is great need and potential. Beyond the link to the Dutch BigGrid Initiative and the German MediGRID should be prepared for and realized due to the great interest for cooperation. There is also big political interest from the government to relieve the pressure on computational needs in The Netherlands and to strengthen the Dutch position in the field of high performance computing. In both fields the ECG should be brought into a leading position by establishing the Erasmus MC a centre of excellence for high-performance computing in the medical field in respect to Europe and world-wide. Consequently, we successfully started to build a super-computer at the Hogeschool Rotterdam and Erasmus MC with great opportunities for scientific research, clinical diagnostics and research as well as student training. This will put both institutions in the position to play a major world-wide role in high-performance computing. This will open entire new possibilities for both institutions in terms of recognition and new funding possibilities and is of major importance for The Netherlands and the EU.