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HolistIC: leveraging Hi-C and whole genome shotgun sequencing for double minute chromosome discovery
Matthew Hayes1, Angela Nguyen2, Rahib Islam2
1Department of Physics and Computer Science, Xavier University of Louisiana, New Orleans, LA 70125, USA.
Motivation:
Double minute (DM) chromosomes are acentric extrachromosomal DNA artifacts that are frequently observed in the cells of numerous cancers. They are highly amplified and contain oncogenes and drug-resistance genes, making their presence a challenge for effective cancer treatment. Algorithmic discovery of DM can potentially improve bench-derived therapies for cancer treatment. A hindrance to this task is that DMs evolve, yielding circular chromatin that shares segments from progenitor DMs. This creates DMs with overlapping amplicon coordinates. Existing DM discovery algorithms use whole genome shotgun sequencing (WGS) in isolation, which can potentially incorrectly classify DMs that share overlapping coordinates.
Results:
In this study, we describe an algorithm called 'HolistIC' that can predict DMs in tumor genomes by integrating WGS and Hi-C sequencing data. The consolidation of these sources of information resolves ambiguity in DM amplicon prediction that exists in DM prediction with WGS data used in isolation. We implemented and tested our algorithm on the tandem Hi-C and WGS datasets of three cancer datasets and a simulated dataset. Results on the cancer datasets demonstrated HolistIC's ability to predict DMs from Hi-C and WGS data in tandem. The results on the simulated data showed the HolistIC can accurately distinguish DMs that have overlapping amplicon coordinates, an advance over methods that predict extrachromosomal amplification using WGS data in isolation.
Availability And Implementation:
Our software, named 'HolistIC', is available at http://www.github.com/mhayes20/HolistIC.
Supplementary Information:
Supplementary data are available at Bioinformatics online.
Insights
We developed HolistIC, an algorithm that integrates Whole Genome Shotgun sequencing and Hi-C data to accurately detect double minute (DM) chromosomes in cancer genomes. This method improves upon existing techniques by resolving overlapping amplicon coordinates, crucial for cancer treatment.
Area of Science:
- Genomics
- Cancer Biology
- Bioinformatics
Background:
- Double minute (DM) chromosomes are extrachromosomal DNA elements frequently found in cancer cells.
- DMs contain amplified oncogenes and drug-resistance genes, posing challenges for cancer therapy.
- The evolution of DMs leads to overlapping amplicon coordinates, complicating their algorithmic discovery using only Whole Genome Shotgun (WGS) sequencing.
Purpose of the Study:
- To develop a novel algorithm for accurate prediction of double minute (DM) chromosomes in tumor genomes.
- To address the limitations of existing methods in handling DMs with overlapping amplicon coordinates.
Main Methods:
- Integration of Whole Genome Shotgun (WGS) sequencing and Hi-C data.
- Development and implementation of the HolistIC algorithm.
- Testing the algorithm on three cancer datasets and one simulated dataset.
Main Results:
- HolistIC successfully predicted DMs by integrating both WGS and Hi-C data on cancer datasets.
- The algorithm accurately distinguished DMs with overlapping amplicon coordinates in simulated data.
- This represents an advancement over methods relying solely on WGS data.
Conclusions:
- The HolistIC algorithm effectively predicts double minute (DM) chromosomes by combining WGS and Hi-C sequencing data.
- HolistIC overcomes the challenge of overlapping amplicon coordinates, improving DM detection in cancer genomes.
- The developed software is publicly available for use in cancer research and treatment development.
