# The Role of Somatic Transposition in Age-associated Genomic Instability

> **NIH NIH R01** · BROWN UNIVERSITY · 2022 · $366,096

## Abstract

Project Summary
Retrotransposable elements (RTEs) comprise approximately 45% of the human genome. RTEs are mobile DNA
elements that can insert into new genomic positions using a copy and paste mechanism. This process, termed
retrotransposition, can be deleterious at multiple levels by causing mutagenesis and genome structural
instability, triggering epigenetic changes, and disrupting normal patterns of gene regulation. Numerous single-
gene mutations in humans have been documented to result from germline retrotransposition. Organisms have
evolved multiple transcriptional and post-transcriptional silencing mechanisms to protect their genomes against
RTEs. Until recently RTEs were thought to be silent in the soma, however, new evidence points to activity in the
brain and in cancer cells. Indeed, initial indications are that somatic retrotransposition is much more frequent
than previously anticipated. We have reported that retrotransposition is activated during aging and cellular
senescence, and hypothesized that it may represent a hitherto unappreciated molecular aging process. The
long-term goal of our research is to determine the impact of retrotransposition on our genomes and
transcriptomes during aging. As a first step, our objective in this proposal is to study, using high-throughput DNA
and RNA sequencing methods, the mobilization of RTEs during cellular senescence and aging, and their impact
on the transcriptome. In Aim 1 we will perform genome-wide high-throughput DNA sequencing of in senescent
cells to determine where new insertions occur and to evaluate whether these events have the potential to exert
deleterious effects by disrupting regions of the genome important for cell function. We have evidence that many
new insertions likely occur in individual post-mitotic cells after they have ceased dividing. To comprehensively
profile the spectrum and frequency of these events we will use single-cell whole genome DNA sequencing. In
Aim 2 we will perform these same studies in the mouse to investigate to what degree different tissues are affected
by increased retrotransposition with age. In Aim 3 we will investigate the effects of RTEs derepression and
transposition on the transcriptome of senescent cells and in the aging mouse. Throughout our research plan we
will apply interventive methods to modulate RTE activity to investigate the consequences on the landscape of
somatic transposition as well as on the physiological function of the cells. Our research will employ innovative
state-of-the-art high-throughput sequencing strategies, and we will develop new bioinformatic tools to integrate
and validate the output from multiple algorithms. The information obtained will address the question: To what
extent is retrotransposition damaging to the genomes of somatic cells in our bodies, and is this a plausible
mechanism of aging? The experience gained and tools developed will be highly informative for future studies
aimed at examining these processes d...

## Key facts

- **NIH application ID:** 10143148
- **Project number:** 5R01AG050582-05
- **Recipient organization:** BROWN UNIVERSITY
- **Principal Investigator:** NICOLA NERETTI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $366,096
- **Award type:** 5
- **Project period:** 2017-09-15 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10143148

## Citation

> US National Institutes of Health, RePORTER application 10143148, The Role of Somatic Transposition in Age-associated Genomic Instability (5R01AG050582-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10143148. Licensed CC0.

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