Dataset Information

A computational strategy to adjust for copy number in tumor Hi-C data.

ABSTRACT: The Hi-C technology was designed to decode the three-dimensional conformation of the genome. Despite progress towards more and more accurate contact maps, several systematic biases have been demonstrated to affect the resulting data matrix. Here we report a new source of bias that can arise in tumor Hi-C data, which is related to the copy number of genomic DNA. To address this bias, we designed a chromosome-adjusted iterative correction method called caICB. Our caICB correction method leads to significant improvements when compared with the original iterative correction in terms of eliminating copy number bias.The method is available at https://bitbucket.org/mthjwu/hicapp CONTACT: michor@jimmy.harvard.eduSupplementary information: Supplementary data are available at Bioinformatics online.

SUBMITTER: Wu HJ

PROVIDER: S-EPMC6078171 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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A computational strategy to adjust for copy number in tumor Hi-C data.

Wu Hua-Jun HJ Michor Franziska F

Bioinformatics (Oxford, England) 20160816 24

<h4>Motivation</h4>The Hi-C technology was designed to decode the three-dimensional conformation of the genome. Despite progress towards more and more accurate contact maps, several systematic biases have been demonstrated to affect the resulting data matrix. Here we report a new source of bias that can arise in tumor Hi-C data, which is related to the copy number of genomic DNA. To address this bias, we designed a chromosome-adjusted iterative correction method called caICB. Our caICB correctio ...[more]

PMID: 27531101

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Project description:MotivationEukaryotic chromosomes adapt a complex and highly dynamic three-dimensional (3D) structure, which profoundly affects different cellular functions and outcomes including changes in epigenetic landscape and in gene expression. Making the scenario even more complex, cancer cells harbor chromosomal abnormalities [e.g. copy number variations (CNVs) and translocations] altering their genomes both at the sequence level and at the level of 3D organization. High-throughput chromosome conformation capture techniques (e.g. Hi-C), which are originally developed for decoding the 3D structure of the chromatin, provide a great opportunity to simultaneously identify the locations of genomic rearrangements and to investigate the 3D genome organization in cancer cells. Even though Hi-C data has been used for validating known rearrangements, computational methods that can distinguish rearrangement signals from the inherent biases of Hi-C data and from the actual 3D conformation of chromatin, and can precisely detect rearrangement locations de novo have been missing.ResultsIn this work, we characterize how intra and inter-chromosomal Hi-C contacts are distributed for normal and rearranged chromosomes to devise a new set of algorithms (i) to identify genomic segments that correspond to CNV regions such as amplifications and deletions (HiCnv), (ii) to call inter-chromosomal translocations and their boundaries (HiCtrans) from Hi-C experiments and (iii) to simulate Hi-C data from genomes with desired rearrangements and abnormalities (AveSim) in order to select optimal parameters for and to benchmark the accuracy of our methods. Our results on 10 different cancer cell lines with Hi-C data show that we identify a total number of 105 amplifications and 45 deletions together with 90 translocations, whereas we identify virtually no such events for two karyotypically normal cell lines. Our CNV predictions correlate very well with whole genome sequencing data among chromosomes with CNV events for a breast cancer cell line (r = 0.89) and capture most of the CNVs we simulate using Avesim. For HiCtrans predictions, we report evidence from the literature for 30 out of 90 translocations for eight of our cancer cell lines. Furthermore, we show that our tools identify and correctly classify relatively understudied rearrangements such as double minutes and homogeneously staining regions. Considering the inherent limitations of existing techniques for karyotyping (i.e. missing balanced rearrangements and those near repetitive regions), the accurate identification of CNVs and translocations in a cost-effective and high-throughput setting is still a challenge. Our results show that the set of tools we develop effectively utilize moderately sequenced Hi-C libraries (100-300 million reads) to identify known and de novo chromosomal rearrangements/abnormalities in well-established cancer cell lines. With the decrease in required number of cells and the increase in attainable resolution, we believe that our framework will pave the way towards comprehensive mapping of genomic rearrangements in primary cells from cancer patients using Hi-C.Availability and implementationCNV calling: https://github.com/ay-lab/HiCnv, Translocation calling: https://github.com/ay-lab/HiCtrans and Hi-C simulation: https://github.com/ay-lab/AveSim.Supplementary informationSupplementary data are available at Bioinformatics online.

Dataset Information

A computational strategy to adjust for copy number in tumor Hi-C data.

Publications

A computational strategy to adjust for copy number in tumor Hi-C data.

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