# Investigating natural epigenetic variation and the origins and inheritance of spontaneous epimutations

> **NIH NIH R01** · UNIVERSITY OF GEORGIA · 2020 · $371,854

## Abstract

PROJECT SUMMARY
The goal of this proposal is to determine how interindividual variation in heterochromatin abundance and
mechanisms required for its maintenance lead to the formation and differential accumulation of spontaneous
epimutations. There is exists vast amounts of heterochromatin in genomes, which varies in abundance
depending on the population being studied. We hypothesize that changes to overall sequences that lead to
heterochromatin formation will influence the formation of stable epimutations and therefore create novel allelic
variants. Although the formation of spontaneous epimutations are documented and they are linked to a range
of developmental abnormalities and diseases, the mechanisms underlying their origins is unknown.
Spontaneous epimutations are rare, but this is mostly an ascertainment bias because there are have not been
systematic efforts dedicated to their discovery. In this proposal we are using mutation accumulation
populations from distinct genotypes including both natural variation and experimental variation as a result of
induced mutations as experimental models. These experimental evolution populations make detection of
spontaneous epimutations routine. At the same time, we have designed experiments to modulate the rate of
epimutation formation based on varying total abundance of heterochromatin. Combined, these approaches and
unique experimental populations will allow us to dissect the mechanistic origins of spontaneous epimutations,
which will provide the basis for the design of drugs that can target their reversal. We expect that the proposed
studies will elucidate how the mis-regulation of heterochromatin establishment or maintenance leads to
spontaneous epimutations that are associated with human diseases. Heterochromatin is a critical aspect of
chromosomes that is important for chromosome segregation, silencing of transposable elements and repetitive
DNA sequences. Errors in proper formation of heterochromatin and its maintenance upon DNA replication are
associated with a number of cellular abnormalities and human diseases. This proposal addresses a key
hypothesis that posits rare epimutations in genes form as a byproduct of enzymatic activities of proteins that
are required for the maintenance of heterochromatin and that they are impacted by genomic variation. These
spontaneous epimutations result in a stable and inherited change in gene expression states, which is often
associated with a change in DNA methylation and chromatin status. Due to the absence of changes to the
DNA sequences, these spontaneous epimutations can be reversed potentially mitigating associated diseases.

## Key facts

- **NIH application ID:** 9994345
- **Project number:** 5R01GM134682-02
- **Recipient organization:** UNIVERSITY OF GEORGIA
- **Principal Investigator:** Robert J. Schmitz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $371,854
- **Award type:** 5
- **Project period:** 2019-08-15 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9994345

## Citation

> US National Institutes of Health, RePORTER application 9994345, Investigating natural epigenetic variation and the origins and inheritance of spontaneous epimutations (5R01GM134682-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9994345. Licensed CC0.

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