Modeling the evolution space of breakage fusion bridge cycles with a stochastic folding process

CD Greenman, SL Cooke, J Marshall, MR Stratton, PJ Campbell

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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. The process has parallels with paper folding sequences that arise when a piece of paper is folded several times and then unfolded. Here we adapt such methods to study the breakage-fusion-bridge structures in detail. We firstly consider discrete representations of this space with 2-d trees to demonstrate that there are 2^(n(n-1)/2) qualitatively distinct evolutions involving n breakage-fusion-bridge cycles. Secondly we consider the stochastic nature of the fold positions, to determine evolution likelihoods, and also describe how amplicons become localised. Finally we highlight these methods by inferring the evolution of breakage-fusion-bridge cycles with data from primary tissue cancer samples.
Original languageEnglish
Pages (from-to)47-86
Number of pages40
JournalJournal of Mathematical Biology
Volume72
Issue number1
Early online date2 Apr 2015
DOIs
Publication statusPublished - Jan 2016

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