Variable DNA methylation in the mouse genome: repetitive elements, unique regions and functional implications
type: CreativeWork
description: Approximately 10% of the mouse genome consists of endogenous retroviruses (ERVs), a class of retrotransposon, which includes the murine-specific intracisternal A particle (IAP) elements. To prevent their mobilisation and suppress the function of the TE- encoded regulatory sequences, TEs are generally targeted by repressive histone modifications and DNA methylation. The Avy allele results from an IAP insertion into the endogenous Agouti gene locus which is variably silenced between isogenic individuals. Variable DNA methylation at the IAP inversely correlates with ectopic expression of Agouti, resulting in a spectrum of coat colours between littermates. This, and other similarly behaving loci, are termed metastable epialleles, or variably methylated IAPs (VM-IAPs), and are widely cited as the best examples of mammalian epigenetic inheritance. A recent screen in the C57BL/6J mouse strain identified over 100 candidate VM-IAPs providing novel insights into metastable epialleles. In this thesis, I revisit the phenotypic and epigenetic heritability associated with the classic metastable epiallele Avy and further characterise novel variably methylated loci in the mouse genome through transcriptional and cross-strain comparative analyses. First, breeding-intensive experiments of the Avy allele in two genetic backgrounds (C57BL/6J and C3H/HeJ) show that coat colour is weakly heritable upon maternal transmission, while DNA methylation is only weakly heritable upon paternal transmission. This implies that coat colour cannot be used as a phenotypic read-out of an epigenetic state as previously reported, since DNA methylation and coat colour appear to be uncoupled at this locus. Additionally, both coat colour and DNA methylation at Avy are subject to genetic background effects. Second, thorough experimental validations of candidate variably methylated regions result in the identification of a novel class of VM-IAP with tissue-specific variability and the potential to affect neig…
abstract: Approximately 10% of the mouse genome consists of endogenous retroviruses (ERVs), a class of retrotransposon, which includes the murine-specific intracisternal A particle (IAP) elements. To prevent their mobilisation and suppress the function of the TE- encoded regulatory sequences, TEs are generally targeted by repressive histone modifications and DNA methylation. The Avy allele results from an IAP insertion into the endogenous Agouti gene locus which is variably silenced between isogenic individuals. Variable DNA methylation at the IAP inversely correlates with ectopic expression of Agouti, resulting in a spectrum of coat colours between littermates. This, and other similarly behaving loci, are termed metastable epialleles, or variably methylated IAPs (VM-IAPs), and are widely cited as the best examples of mammalian epigenetic inheritance. A recent screen in the C57BL/6J mouse strain identified over 100 candidate VM-IAPs providing novel insights into metastable epialleles. In this thesis, I revisit the phenotypic and epigenetic heritability associated with the classic metastable epiallele Avy and further characterise novel variably methylated loci in the mouse genome through transcriptional and cross-strain comparative analyses. First, breeding-intensive experiments of the Avy allele in two genetic backgrounds (C57BL/6J and C3H/HeJ) show that coat colour is weakly heritable upon maternal transmission, while DNA methylation is only weakly heritable upon paternal transmission. This implies that coat colour cannot be used as a phenotypic read-out of an epigenetic state as previously reported, since DNA methylation and coat colour appear to be uncoupled at this locus. Additionally, both coat colour and DNA methylation at Avy are subject to genetic background effects. Second, thorough experimental validations of candidate variably methylated regions result in the identification of a novel class of VM-IAP with tissue-specific variability and the potential to affect neig…
author: Elmer, Jessica
language: eng
keywords: metastable epiallele, endogenous retrovirus, intracisternal A particle, Agouti viable yellow, epigenetic inheritance, DNA methylation
license: https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/646b4837-fd1a-4150-a852-a9b6c08a56f4/download
license: https://www.rioxx.net/licenses/all-rights-reserved/
date published: 2020-12-01
date modified: 2026-07-22T22:24:21Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.66303