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

Abstract

1BackgroundMany 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.\n\nResultsWe 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 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.\n\nConclusionsOverall, 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.