Characteristics of spontaneous epimutations
File(s)
Author(s)
Wilson, Rachel
Type
Thesis or dissertation
Abstract
Epimutations are changes in the state of epigenetic modifications which are heritable, independent of variation in underlying DNA, and which have the potential to alter gene expression patterns. If epimutations persist transgenerationally, they might be subject to selection and could therefore drive distinct phenotypes. This hypothesis corresponds with the paradigm of heritable genetic variation as a source of trait diversity underlying adaptive evolution. Epimutation-based inheritance requires transmission of altered states of epigenetic modifications. Epimutations might be found as changes in the coverage of DNA by methyl groups, the abundance of small non coding RNAs (sRNAs) or the extent to which DNA wrapped around histone proteins is compacted into chromatin. In this thesis, I use Mutation Accumulation techniques to show for the first time in an animal model that heritable chromatin-based epimutations arise spontaneously under controlled conditions. I show that gene expression changes which are inherited across multiple generations are frequently accompanied by epimutations, suggesting a ‘driver’ role for epimutations in transgenerational inheritance of expression changes. I show that whilst the majority of epimutations are short-lived, significantly long-lived subsets of sRNA and chromatin-based epimutations are present. Finally, I show that long-lived spontaneous epimutations are enriched at genes involved in nematode defence against xenobiotics which supports the notion that epimutations may contribute to potentially adaptive phenotypes.
Version
Open Access
Date Issued
2023-06
Date Awarded
2024-02
Copyright Statement
Creative Commons Attribution NonCommercial NoDerivatives Licence
Advisor
Sarkies, Peter
Sponsor
Medical Research Council (Great Britain)
Publisher Department
Institute of Clinical Sciences
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)