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Analysis of gene systems across brain disorders

Bach, Snow orcid logoORCID: 0000-0001-9615-2735 (2021) Analysis of gene systems across brain disorders. Master of Science thesis, Dublin City University.

Abstract
This thesis analyses data from genetic and epigenetic studies of brain disorders, in order to establish potential convergences of mechanisms across different conditions. Current research highlights the common symptoms across a wide range of brain disorders. We analyse the properties of the gene regulator: Methyl-CpG binding protein 2 (MeCP2), a chromatin-binding protein and a modulator of gene expression and we establish a DNA binding model: Matrix-GC, to predict MeCP2 targets. We evaluate Matrix-GC’s performance using receiver operating characteristic curves while varying a determinant binding factor: guanine-cytosine nucleotide enrichment (GC content). We show by combining a DNA binding sequence with GC content, that Matrix-GC is able to capture genes bound by MeCP2 better than random chance and binding sequence alone. Matrix-GC is applied to various brain disorders associated with MeCP2, followed by downstream enrichment analysis of molecular pathways and processes. We show three main processes to be under the control of MeCP2 across several brain disorders: neuronal transmission, development, and immunoreactivity. We further validate the performance of Matrix-GC at the single gene level by comparing MeCP2-bound genes with existing high-throughput transcriptome analysis and show that our results are statistically significant. We carry out stringent control analysis by Monte Carlo permutation to strengthen the reliability of our results. We propose the Matrix-GC as an in silico procedure to identify putative MeCP2 target genes and shed light on mechanisms overlapping across different brain disorders. Our method of identifying target genes has broad applications and can be implemented with other proteins that influence gene regulation. Importantly, this research provides a framework for analysing genetic data with statistical rigour which can be applied to downstream gene set analysis.
Metadata
Item Type:Thesis (Master of Science)
Date of Award:November 2021
Refereed:No
Supervisor(s):Guasoni, Paolo and Tropea, Daniela
Subjects:Biological Sciences > Neuroscience
Mathematics > Mathematical models
DCU Faculties and Centres:DCU Faculties and Schools > Faculty of Science and Health > School of Mathematical Sciences
Use License:This item is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 License. View License
Funders:Science Foundation Ireland
ID Code:26193
Deposited On:29 Oct 2021 10:25 by Paolo Guasoni . Last Modified 29 Oct 2021 10:25
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