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Table of contents
Chapter 1 : Introduction
1.1 DNA damage and mutation in stem and progenitor cells in the context of aging and cancer
Stem cells and tissue dynamics
DNA damage and how it leads to mutation
Mechanisms protecting the stem cell and tissue from the effects of DNA damage
When protection mechanisms fail: acquisition of mutation
DNA damage and somatic mutation in adult tissues: roles in cancer initiation and aging
Contributions of persistent DNA damage to stem cell decline
Towards an understanding of DNA damage and mutation in adult tissues
Concluding remarks
1.2 Loss of heterozygosity (LOH): a common cause of genome alteration in somatic cells Mitotic recombination-driven LOH
DSBs: Drivers of MR
Yeast: a paradigm for studying mechanisms of MR
Another cause of LOH: Aneuploidy
Concluding remarks
1.3 The Drosophila intestine: A model to study genome alterations such as LOH in stem cells
A dynamic tissue in a powerful in vivo model
Structure of the Drosophila intestine
The role of Notch in regulating cell fate
The aging gut
Impact of the environment on the Drosophila midgut
Advantages of using the Drosophila midgut as a model system to study genome instability in adult stem cells
Chapter 2 : Results
Results Overview
2.1 Mitotic Recombination as a Mechanism Driving Spontaneous Loss of Heterozygosity in Drosophila Intestinal Stem Cells (article in preparation).
Abstract
Introduction
Results
Spontaneous loss of heterozygosity increases with age
Whole genome sequencing to determine the mechanism of LOH
LOH arises through mitotic recombination in both males and females.
LOH through mitotic recombination also happens on other chromosome arms
Rad51 promotes loss of heterozygosity
Whole-genome sequencing data supports cross over via a double-Holliday structure
Mapping of LOH initiation regions provides insight into potential sequence drivers of MR
Infection with the pathogenic enteric bacteria Ecc15 increases loss of heterozygosity
Discussion
2.2 Aneuploidy as a mechanism driving spontaneous loss of heterozygosity in Drosophila intestinal stem cells
Context
Results
Sequencing evidence for aneuploidy-driven LOH
The H4K16ac histone mark is a good readout for activation of dosage compensation in the Drosophila intestine
Loss of X (aneuploidy) is detected in aging N55E11/+ females
Discussion
Chapter 3: Discussion
Discussion Overview
3.1 Technical evaluation of the work and experimental caveats
Sample size of sequenced tumours
Tumour purity
Controversy surrounding R-loops
Additional biological repeats and RNAi lines
3.2 Discussion of results
Exploiting the clonal nature of LOH neoplasia in the Drosophila intestine: the novelty
Mechanisms of LOH
Genomic Drivers of MR
Impact of the stem cell niche and environment on LOH
LOH with age
3.3 Implications of the research and conclusions
Implications of the research and perspectives
Conclusions
