Hierarchical Reconstruction of High-Resolution 3D Models of Large Chromosomes

Eukaryotic chromosomes are often composed of components organized into multiple scales, such as nucleosomes, chromatin fibers, topologically associated domains (TAD), chromosome compartments, and chromosome territories. Therefore, reconstructing detailed 3D models of chromosomes in high resolution is useful for advancing genome research. However, the task of constructing quality high-resolution 3D models is still challenging with existing methods. Hence, we designed a hierarchical algorithm, called Hierarchical3DGenome, to reconstruct 3D chromosome models at high resolution (<=5 Kilobase (KB)). The algorithm first reconstructs high-resolution 3D models at TAD level. The TAD models are then assembled to form complete high-resolution chromosomal models. The assembly of TAD models is guided by a complete low-resolution chromosome model. The algorithm is successfully used to reconstruct 3D chromosome models at 5 KB resolution for the human B-cell (GM12878). These high-resolution models satisfy Hi-C chromosomal contacts well and are consistent with models built at lower (i.e. 1 MB) resolution, and with the data of fluorescent in situ hybridization experiments. The Java source code of Hierarchical3DGenome and its user manual are available here https://github.com/BDM-Lab/Hierarchical3DGenome.