title: Handling realistic assumptions in hypothesis testing of 3D co-localization of genomic elements.
abstract: The study of chromatin 3D structure has recently gained much focus owing to novel techniques for detecting genome-wide chromatin contacts using next-generation sequencing. A deeper understanding of the architecture of the DNA inside the nucleus is crucial for gaining insight into fundamental processes such as transcriptional regulation, genome dynamics and genome stability. Chromatin conformation capture-based methods, such as Hi-C and ChIA-PET, are now paving the way for routine genome-wide studies of chromatin 3D structure in a range of organisms and tissues. However, appropriate methods for analyzing such data are lacking. Here, we propose a hypothesis test and an enrichment score of 3D co-localization of genomic elements that handles intra- or interchromosomal interactions, both separately and jointly, and that adjusts for biases caused by structural dependencies in the 3D data. We show that maintaining structural properties during resampling is essential to obtain valid estimation of P-values. We apply the method on chromatin states and a set of mutated regions in leukemia cells, and find significant co-localization of these elements, with varying enrichment scores, supporting the role of chromatin 3D structure in shaping the landscape of somatic mutations in cancer.
authors.affiliation: Section for Medical Informatics, The Norwegian Radium Hospital, Oslo University Hospital, PO Box 4950, Nydalen, N-0424 Oslo, Norway.
authors.forename: Jonas
authors.initials: J
authors.lastname: Paulsen
authors.forename: Tonje G
authors.initials: TG
authors.lastname: Lien
authors.forename: Geir Kjetil
authors.initials: GK
authors.lastname: Sandve
authors.forename: Lars
authors.initials: L
authors.lastname: Holden
authors.forename: Ornulf
authors.initials: O
authors.lastname: Borgan
authors.forename: Ingrid K
authors.initials: IK
authors.lastname: Glad
authors.forename: Eivind
authors.initials: E
authors.lastname: Hovig
mesh_terms: D045744:Cell Line, Tumor; D002843:Chromatin / Q000737:chemistry*; D002877:Chromosomes, Human / Q000737:chemistry; D003627:Data Interpretation, Statistical; D016678:Genome; D006801:Humans; D007938:Leukemia / Q000235:genetics; D009154:Mutation; D009690:Nucleic Acid Conformation; D017422:Sequence Analysis, DNA
chemical_list: D002843:Chromatin