Abstract
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.
Highlights
The interaction frequencies between pairs of chromosomal fragments are often summarized as a symmetric matrix, called contact matrix
To figure out if domain models were well adjusted to satisfy inter-domain contacts, we extracted contact sub-matrices for every two adjacent domains consisting of both inter- and intra-domain contacts, reconstructed 3D models of the two adjacent domains from the matrices, and compared them with the corresponding models of the two domains extracted from the full-chromosome models at 5 KB resolution
We investigated if the high resolution chromosomal models were consistent with the FISH data[8]
Summary
The interaction frequencies between pairs of chromosomal fragments are often summarized as a symmetric matrix, called contact matrix (or map). Some of these methods utilize a function that approximates the inverse relationship between interaction frequencies (IFs) and spatial distances between fragments and uses the distances as restraints to build 3D models via spatial optimization. Rieber, L. and Mahony, S23, developed an approximate multidimensional scaling (MDS) algorithm called miniMDS, capable of constructing the 3D structure of chromosomes and genome at high resolution from Hi-C datasets better than most of the existing methods. One way to reduce the search space is to require that high-resolution models have a structural topology similar to that of low-resolution models whose structure can be more stably constructed due to the availability of more contact data between larger fragments. Our results show that the high-resolution chromosome models reconstructed by our method satisfied input chromosomal contacts well, and are consistent with the experimental FISH data
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