Towards a Holistic Understanding of the Human Genome by Determination and Integration of Its Sequential and Three-Dimensional Organization

Summary Genomes are one of the major foundations of life due to their role in information storage, process regulation and evolution. However, the sequential and three-dimensional structure of the human genome in the cell nucleus as well as its interplay with and embedding into the cell and organism only arise scarcely from the unknown, despite recent successes e.g. in the linear sequencing efforts and growing evidence for seven genomic organization levels. To achieve a deeper understanding of the human genome the structural, scaling and dynamic properties in the simulation of interphase chromosomes and cell nuclei are determined and combined with the analysis of long-range correlations in completely sequenced genomes as well as the analysis of the chromatin distribution in vivo: This integrative approach reveals that the chromatin fiber is most likely folded according to the Multi-Loop-Subcompartment (MLS) model in which the chromatin fiber bents into 63–126 kbp big loops aggregated to rosettes connected by again 63–126 kbp linkers. The MLS model exhibits fine-structured multi-scaling and predicts correctly the transport of molecules by moderately obstructed/anomalous diffusion. On the basic sequence level, genomes show fine-structured positive long-range correlations, allowing classification and tree construction. This, DNA fragment distributions after carbon ion irradiation and on the highest structural level, the nuclear morphology visualized by histone autofluorescent protein fusions in vivo, agrees again best with the MLS model. Thus, the local, global and dynamic characteristics of cell nuclei are not only tightly inter-connected, but also are integrated holisticly to fulfill the overall function of the genome.