Abstract
Breakage–fusion–bridge cycles in cancer arise when a broken segment of DNA is duplicated and an end from each copy joined together. This structure then ‘unfolds’ into a new piece of palindromic DNA. This is one mechanism responsible for the localised amplicons observed in cancer genome data. Here we study the evolution space of breakage–fusion–bridge structures in detail. We firstly consider discrete representations of this space with 2-d trees to demonstrate that there are 2^{frac{n(n-1)}{2}} qualitatively distinct evolutions involving n breakage–fusion–bridge cycles. Secondly we consider the stochastic nature of the process to show these evolutions are not equally likely, and also describe how amplicons become localized. Finally we highlight these methods by inferring the evolution of breakage–fusion–bridge cycles with data from primary tissue cancer samples.
Highlights
Breakage–fusion–bridge (BFB) cycles potentially arise whenever a stretch of DNA is broken and a cell division cycle takes place
Spindles attach to centromeres, which contract during cell division to pull a chromosome into each daughter cell
This process of duplication, end repair and DNA breaking can continue with each cell division and the process repeat itself in a cascade of BFB cycles
Summary
Breakage–fusion–bridge (BFB) cycles potentially arise whenever a stretch of DNA is broken and a cell division cycle takes place. The cells checkpoint machinery will look for mistakes and the two exposed ends may be erroneously joined together by double stranded break repair This results in a palindromic sequence of DNA, often containing a duplicated centromere (see Fig. 1a). If each centromere of this dicentric chromosome is to successfully relocate to distinct daughter cells, the DNA between the centromeres has to snap, and so each daughter cell will have a centromere on a DNA segment with an exposed (broken) end This process of duplication, end repair and DNA breaking can continue with each cell division and the process repeat itself in a cascade of BFB cycles. The term fold and the folded structure relative to the reference will be Modeling the evolution space of breakage fusion bridge cycles
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