Improving 3D Genome Reconstructions Using Orthologous and Functional Constraints

The study of the 3D architecture of chromosomes has been advancing rapidly in recent years. While a number of methods for 3D reconstruction of genomic models based on Hi-C data were proposed, most of the analyses in the field have been performed on different 3D representation forms (such as graphs). Here, we reproduce most of the previous results on the 3D genomic organization of the eukaryote Saccharomyces cerevisiae using analysis of 3D reconstructions. We show that many of these results can be reproduced in sparse reconstructions, generated from a small fraction of the experimental data (5% of the data), and study the properties of such models. Finally, we propose for the first time a novel approach for improving the accuracy of 3D reconstructions by introducing additional predicted physical interactions to the model, based on orthologous interactions in an evolutionary-related organism and based on predicted functional interactions between genes. We demonstrate that this approach indeed leads to the reconstruction of improved models.Author Summary: Understanding the importance of genome architecture, the arrangement of genes within the genome and how this organization evolved has been intensively studied in recent years. Despite rapid progress in the field, accurate 3D modeling of genome organization remains a challenge. While a number of methods for 3D reconstruction of genomic models based on genome-wide experimental data were proposed, most of the analyses in the field have been performed on different 3D representation forms (such as graphs). Here, we reproduce most of the previous results on the 3D genome organization of the eukaryote Saccharomyces cerevisiae using analysis of 3D reconstructions. We show that many of these results can be reproduced in sparse reconstructions, generated from a small fraction of the experimental data (5% of the data), and study the properties of such models. Finally, we propose for the first time a novel approach for improving the accuracy of 3D reconstructions by introducing additional predicted physical interactions to the model, based on orthologous interactions in a different organism and based on predicted functional interactions between genes. Our proposed approach can facilitate future studies of 3D genome organization via improved models.