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Bayesian inference supports a location and neighbour-dependent model of DNA methylation propagation at the MGMT gene promoter in lung tumours

Lookup NU author(s): Professor Sir John Burn, Dr Ian Wilson, Dr Mauro Santibanez Koref

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Abstract

We exploit model-based Bayesian inference methodologies to analyse lung tumour-derived methylation data from a CpG island in the O6-methylguanine-DNA methyltransferase (MGMT) promoter. Interest is in modelling the changes in methylation patterns in a CpG island in the first exon of the promoter during lung tumour development. We propose four competils of methylation state propagation based on two mechanisms. The first is the location-dependence mechanism in which the probability of a gain or loss of methylation at a CpG within the promoter depends upon its location in the CpG sequence. The second mechanism is that of neighbour-dependence in which gain or loss of methylation at a CpG depends upon the methylation status of the immediately preceding CpG. Our data comprises the methylation status at 12 CpGs near the 5' end of the CpG island in two lung tumour samples for both alleles of a nearby polymorphism. We use approximate Bayesian computation, a computationally intensive rejection-sampling algorithm to infer model parameters and compare models without the need to evaluate the likelihood function. We compare the four proposed models using two criteria: the approximate Bayes factors and the distribution of the Euclidean distance between the summary statistics of the observed and simulated datasets. Our model-based analysis demonstrates compelling evidence for both location and neighbour dependence in the process of aberrant DNA methylation of this MGMT promoter CpG island in lung tumours. We find equivocal evidence to support the hypothesis that the methylation patterns of the two alleles evolve independently. (C) 2013 Elsevier Ltd. All rights reserved.


Publication metadata

Author(s): Bonello N, Sampson J, Burn J, Wilson IJ, McGrown G, Margison GP, Thorncroft M, Crossbie P, Povey AC, Santibanez-Koref M, Walters K

Publication type: Article

Publication status: Published

Journal: Journal of Theoretical Biology

Year: 2013

Volume: 336

Pages: 87-95

Print publication date: 07/11/2013

Online publication date: 30/07/2013

Acceptance date: 19/07/2013

ISSN (print): 0022-5193

ISSN (electronic): 1095-8541

Publisher: Academic Press

URL: http://dx.doi.org/10.1016/j.jtbi.2013.07.019

DOI: 10.1016/j.jtbi.2013.07.019


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