A Consistent Systems Mechanics Model of the 3D Architecture and Dynamics of Genomes

Already for thousands of years mankind is aware of inheritance and its manipulation by mating and breeding. The discovery of the cell nucleus by A. van Leeuwenhook in the 17th century marks a start to elucidate the epically discussed evolutionary transfer of information in detail. Now after more than 170 years of research on the 3D architecture and dynamics of genomes and the co-evolved interaction networks of regulatory elements creating genome function - i.e. the storage, replication, and expression of genetic information—a consistent systems statistical mechanics genomics framework emerges for the first time. Obviously the structure and function of genomes co-evolved as an inseparable system allowing the physical storage, expression, and replication of genetic information. The DNA double helix and the nucleosome had been determined structurally at the very highest level already, including genome sequences and epigenetic histone modifications. That chromosomes form territories with functional relevant positioning within the cell nucleus and that chromosomal subdomains exist has been also determined to a fair degree of detail. Only recently, however, we were finally able to fill the much debated gap in-between by establishing that nucleosomes compact into a quasi-fibre folded into stable loops which form stable multi-loop aggregates/rosettes connected by linkers and hence creating chromosome arms and entire chromosomes. Interestingly, this has lead immediately to a consistent and cross-proven systems statistical mechanics genomic framework which is balancing stability/flexibility ensuring genome integrity, enabling expression/regulation of genetic information, as well as genome replication - all this in evolutionary perspectives as the natural outcome of Darwinian natural selection and Lamarkian self-referenced manipulation. Thus, genotype and phenotype are multilisticly entangled and beyond are embedded in genome ecology i(!)n- and environments. This not only opens the door to a true universal sequencing of genetic information, but also is the key for a general understanding of genomes, their function and evolution, as well as for applied diagnostics and treatment of disease, for future genome manipulation and engineering efforts, as far as the creation of artificial or extra-terrestrial live contexts

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

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')

Dynamic behavior of GFP–CLIP-170 reveals fast protein turnover on microtubule plus ends

Microtubule (MT) plus end–tracking proteins (+TIPs) specifically recognize the ends of growing MTs. +TIPs are involved in diverse cellular processes such as cell division, cell migration, and cell polarity. Although +TIP tracking is important for these processes, the mechanisms underlying plus end specificity of mammalian +TIPs are not completely understood. Cytoplasmic linker protein 170 (CLIP-170), the prototype +TIP, was proposed to bind to MT ends with high affinity, possibly by copolymerization with tubulin, and to dissociate seconds later. However, using fluorescence-based approaches, we show that two +TIPs, CLIP-170 and end-binding protein 3 (EB3), turn over rapidly on MT ends. Diffusion of CLIP-170 and EB3 appears to be rate limiting for their binding to MT plus ends. We also report that the ends of growing MTs contain a surplus of sites to which CLIP-170 binds with relatively low affinity. We propose that the observed loss of fluorescent +TIPs at plus ends does not reflect the behavior of single molecules but is a result of overall structural changes of the MT end

The Erasmus Computing Grid – Building a Super-Computer for Free

Today 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

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

Fine-structured multi-scaling long-range correlations in completely sequenced genomes—features, origin, and classification

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 is still a largely unresolved problem. Long-range power-law correlations were found using correlation analysis on almost the entire observable scale of 132 completely sequenced chromosomes of 0.5 × 106 to 3.0 × 107 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 3,400 bp (for Arabidopsis thaliana and Drosophila melanogaster divided in two submaxima), and often a region of one or more second maxima from 105 to 3 × 105 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 to be evolutionarily tightly controlled and connected to the spatial genome organization, especially on large scales. In summary, genomes show a complex sequential organization related closely to their three-dimensional organization