The sequence of a genome is insufficient to understand all genomic processes carried out in the cell nucleus. To achieve this, the knowledge of its three-dimensional architecture is necessary. Advances in genomic technologies and the development of new analytical methods, such as Chromosome Conformation Capture (3C) and its derivatives, provide unprecedented insights in the spatial organization of genomes. Here we present TADbit, a computational framework to analyze and model the chromatin fiber in three dimensions. Our package takes as input the sequencing reads of 3C-based experiments and performs the following main tasks: (i) pre-process the reads, (ii) map the reads to a reference genome, (iii) filter and normalize the interaction data, (iv) analyze the resulting interaction matrices, (v) build 3D models of selected genomic domains, and (vi) analyze the resulting models to characterize their structural properties. To illustrate the use of TADbit, we automatically modeled 50 genomic domains from the fly genome revealing differential structural features of the previously defined chromatin colors, establishing a link between the conformation of the genome and the local chromatin composition. TADbit provides three-dimensional models built from 3C-based experiments, which are ready for visualization and for characterizing their relation to gene expression and epigenetic states. TADbit is an open-source Python library available for download from https://github.com/3DGenomes/tadbit.

a b s t r a c tChromosomes are large polymer molecules composed of nucleotides. In some species, such as humans, this polymer can sum up to meters long and still be properly folded within the nuclear space of few microns in size. The exact mechanisms of how the meters long DNA is folded into the nucleus, as well as how the regulatory machinery can access it, is to a large extend still a mystery. However, and thanks to newly developed molecular, genomic and computational approaches based on the Chromosome Conformation Capture (3C) technology, we are now obtaining insight on how genomes are spatially organized. Here we review a new family of computational approaches that aim at using 3C-based data to obtain spatial restraints for modeling genomes and genomic domains.

Genomic interactions reveal the spatial organization of genomes and genomic domains, which is known to play key roles in cell function. Physical proximity can be represented as two‐dimensional heat maps or matrices. From these, three‐dimensional (3D) conformations of chromatin can be computed revealing coherent structures that highlight the importance of nonsequential relationships across genomic features. Mainstream genomic browsers have been classically developed to display compact, stacked tracks based on a linear, sequential, per‐chromosome coordinate system. Genome‐wide comparative analysis demands new approaches to data access and new layouts for analysis. The legibility can be compromised when displaying track‐aligned second dimension matrices, which require greater screen space. Moreover, 3D representations of genomes defy vertical alignment in track‐based genome browsers. Furthermore, investigation at previously unattainable levels of detail is revealing multiscale, multistate, time‐dependent complexity. This article outlines how these challenges are currently handled in mainstream browsers as well as how novel techniques in visualization are being explored to address them. A set of requirements for coherent visualization of novel spatial genomic data is defined and the resulting potential for whole genome visualization is described.