SonHi-C: a set of non-procedural approaches for predicting 3D genome organization from Hi-C data

Abstract

Background: Many computational methods have been developed that leverage the results from biological experiments (such as Hi-C) to infer the 3D organization of the genome.Formally, this is referred to as the 3D genome reconstruction problem (3D-GRP). None of the existing methods for solving the 3D-GRP have utilized a non-procedural programming approach (such as constraint programming or integer programming) despite the established advantages and successful applications of such approaches for predicting the 3D structure of other biomolecules. Our objective was to develop a set of mathematical models and corresponding non-procedural implementations for solving the 3D-GRP to realize the same advantages.Results: We present a set of non-procedural approaches for predicting 3D genome organization from Hi-C data (collectively referred to as SonHi-C and pronounced "sonic").Specifically, this set is comprised of three mathematical models based on constraint programming (CP), graph matching (GM) and integer programming (IP). All of the mathematical models were implemented using non-procedural languages and tested with Hi-C data from Schizosaccharomyces pombe (fission yeast). The CP implementation could not optimally solve the problem posed by the fission yeast data after several days of execution time. The . CC-BY-NC 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/392407 doi: bioRxiv preprint first posted online Aug. 16, 2018; GM and IP implementations were able to predict a 3D model of the fission yeast genome in 1.088 and 294.44 seconds, respectively. These 3D models were then biologically validated through literature search which verified that the predictions were able to recapitulate key documented features of the yeast genome.Conclusions: Overall, the mathematical models and programs developed here demonstrate the power of non-procedural programming and graph theoretic techniques for quickly and accurately modelling the 3D genome from Hi-C data. Additionally, they highlight the practical differences observed when differing non-procedural approaches are utilized to solve the 3D-GRP.Key Words: 3D Genome Reconstruction Problem, Mathematical Modelling, Constraint Programming, Graph Matching, Integer Programming BackgroundWithin the nucleus, a cell's genetic information undergoes extensive folding and reorganization throughout normal physiological processes. Just like in origami where the same piece of paper folded in different ways allows the paper to take on different forms and potential functions, it is possible that different genomic organizations are related to various nuclear functions. Until recently, it has been extremely difficult to comprehensively investigate this relationship due to the lack of high-resolution and high-throughput techniques for identifying genomic organizations. The development of a techn...