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. 2015;16 Suppl 2(Suppl 2):S1.
doi: 10.1186/1471-2156-16-S2-S1. Epub 2015 Apr 23.

An integrative framework for the identification of double minute chromosomes using next generation sequencing data

Matthew Hayes, Jing Li

An integrative framework for the identification of double minute chromosomes using next generation sequencing data

Matthew Hayes et al. BMC Genet. 2015.

Abstract

Background: Double minute chromosomes are circular fragments of DNA whose presence is associated with the onset of certain cancers. Double minutes are lethal, as they are highly amplified and typically contain oncogenes. Locating double minutes can supplement the process of cancer diagnosis, and it can help to identify therapeutic targets. However, there is currently a dearth of computational methods available to identify double minutes. We propose a computational framework for the idenfication of double minute chromosomes using next-generation sequencing data. Our framework integrates predictions from algorithms that detect DNA copy number variants, and it also integrates predictions from algorithms that locate genomic structural variants. This information is used by a graph-based algorithm to predict the presence of double minute chromosomes.

Results: Using a previously published copy number variant algorithm and two structural variation prediction algorithms, we implemented our framework and tested it on a dataset consisting of simulated double minute chromosomes. Our approach uncovered double minutes with high accuracy, demonstrating its plausibility.

Conclusions: Although we only tested the framework with three programs (RDXplorer, BreakDancer, Delly), it can be extended to incorporate results from programs that 1) detect amplified copy number and from programs that 2) detect genomic structural variants like deletions, translocations, inversions, and tandem repeats. The software that implements the framework can be accessed here: https://github.com/mhayes20/DMFinder

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Figures

Figure 1
Figure 1
Chromothripsis: the haphazard shattering of the genome during cancer development.
Figure 2
Figure 2
The erroneous repair of the genome in Figure 1 leads to a circular double minute chromosome.
Figure 3
Figure 3
Overview of the framework. The algorithms require as input predictions from structural variant prediction programs and copy number prediction programs.
Figure 4
Figure 4
Algorithm to build the amplicon graph G and auxiliary graph H.
Figure 5
Figure 5
Algorithm to find all double minutes that are represented in the amplicon graph.
Figure 6
Figure 6
Algorithm to find double minutes that may have been missed by algorithms 1 and 2.
Figure 7
Figure 7
Conversion of NGS breakpoints and amplicons to an amplicon graph. The segments in the top image are amplicons with elevated copy number. The colored lines represent SV predictions for a translocation (green line), and a deletion (blue line). The corresponding amplicon graph is depicted in the bottom image. Vertices are amplicons and edges are NGS-based SV breakpoint predictions.
Figure 8
Figure 8
A double minute chromosome found by our algorithms. This is the double minute as it is represented in the amplicon graph G. Each node is an amplicon, and the edges are structural variant breakpoints that connect them. The nodes are annotated with the chromosome number and the start and end position of the amplicon. The graph image was rendered with GraphViz [17].
Figure 9
Figure 9
A predicted DM whose circular structure was not captured in the data. All 10 amplicons are present in this predicted double minute.
See this image and copyright information in PMC

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