Completed Genetics & Molecular Biology Pregnancy, Children & Inherited Conditions

Epigenetic inheritance: the influence of variable silencing of the repeat genome.

Funder Wellcome Charity-funded
Recipient organisation University of Cambridge
Funding £2.9M
Period Dec 2018 — Nov 2024

In plain English

AI plain-English summary

A mouse’s coat colour can reveal whether its parents’ environment altered the activity of ancient viral DNA stitched into the genome. This matters because scientists have long suspected that experiences such as diet or stress might leave non-genetic marks that pass to offspring, but the mechanisms remain unknown in mammals. The Agouti mouse offers a clear example: a dormant retrovirus inserted near a coat-colour gene switches on unpredictably depending on its DNA methylation, and that methylation pattern can be inherited. The researchers will test whether other endogenous retroviruses—which make up roughly 12 percent of the mouse genome—behave similarly, and whether they act as environmental sensors that influence offspring traits. If this fundamental science succeeds, it will reveal a previously hidden layer of inheritance. Understanding how these viral remnants are silenced or activated could eventually explain why genetically identical individuals differ in disease susceptibility, and whether a parent’s environment leaves a molecular record in their children. The work is curiosity-driven, but similar discoveries about non-genetic inheritance have reshaped how researchers think about evolution, development, and the origins of complex disease.

View original technical description
Evidence from epidemiological studies and experiments in animal models suggests that effects of environment and lifestyle can be transmitted across generations via non-genetic mechanisms. Such mechanisms are challenging to unravel in mouse and man. In mammals, non-genetic inheritance is best exemplified by the Agouti viable yellow (Avy) mouse where phenotypic differences in genetically identical animals are caused by insertion of a retrotransposon - an endogenous retrovirus (ERV) that provides a cryptic promoter driving ectopic expression of agouti. This ERV is variably DNA methylated in different individuals causing inter-individual variation in coat colour – a non-genetic influence on phenotype. Remarkably, a memory of parental coat colour is transmitted to subsequent generations. Variable expressivity can be modulated by in utero environmental exposures. ERVs represent ~12% of the mouse genome. Inspired by Avy, we propose a research programme, supported by preliminary data, to address the following questions: Aim 1 – To what extent do mammalian ERVs exhibit variable epigenetic silencing and what is the mechanism? Aim 2 – Is this transmitted as non-genetic memory across generations? Aim 3 – Are they sensors of environmental compromise? Aim 4 – Are there implications for phenotype? Aim 5 – Does a related phenomenon occur in humans?

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Researchers

Anne Ferguson-Smith (EPMC Awardee)

Related Research

Grants with similar aims, by meaning.

A human genome-wide screen for transgenerational epigenetic inheritance
Uncovering signals regulating epigenetic establishment and maintenance in mammals
Epigenetic mechanisms underlying the influence of paternal drug experience on offspring behavior
A systems-level study of the role of epigenetics in mediating in utero environmental influences on genome function and transgenerational effects
Epigenetic processes in transmission of prenatally-induced phenotypes between generations

Original classification

Investigator Award in Science

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