3D genome structure reconstruction from chromosomal contact data
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[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Different cell types of an organism have the same DNA sequence, but they can function differently because their difference in 3D organization allows them to express different genes and has different cellular functions. Understanding the 3D organization of the genome is the key to understand functions of the cell. Chromosome conformation capture techniques like Hi-C and TCC that can capture interactions between proximal chromosome fragments have allowed the study of 3D genome organization in high resolution and high through-put. My work focuses on developing computational methods to reconstruct 3D genome structures from Hi-C data. I presented three methods to reconstruct 3D genome and chromosome structures. The first method can build 3D genome models from soft constraints of contacts and non-contacts. This method utilizes the concept of contact and non-contact to reconstruct 3D models without translating interaction frequencies into physical distances. The translation is commonly used by other methods even though it makes a strong assumption about the relationship between interaction frequencies and physical distances. In synthetic dataset, when the relationship was known, my method performed comparably with other methods assuming the relationship. This shows the potential of my method for real Hi-C datasets where the relationship is unknown. The limitation of the method is that it has parameters requiring manual adjustment. I developed the second method to reconstruct 3D genome models. This method utilizes a commonly used function to translate interaction frequencies to physical distances to build 3D models. I proposed a novel way to derive soft constraints to handle inconsistency in the data and to make the method robust. Building 3D models at high resolution is a more challenging problem as the number of constraints is small and the feasible space is larger. I introduced a third method to build 3D chromosome models at high resolution. The method reconstructs models at low resolution and then uses them to guide the reconstruction of models at high resolution. The last part of my work is the development of a comprehensive tool with intuitive graphic user interface to analyze Hi-C data, reconstruct and analyze 3D models.
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