# Cytosolic DNA, Telomeres/Subtelomeres, and Epigenetics: A Longitudinal Twin Study to Assess the Role of Genetics and Environment on their Frequency and Inter-relationships

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2024 · $854,797

## Abstract

Cystolic DNA (cyDNA), which is acquired in somatic cells, is emerging as an instigator/integrator of cellular
functions associated with aging, yet the causes/consequences of cyDNA are poorly understood. Do individuals
have a genetic predisposition to develop cyDNA or is its frequency most heavily influenced by environmental
factors? Is cyDNA an early trigger for the acquisition of other age-related biomarker hallmarks, or does it arise
in response to perturbations involving a subset of these hallmarks? To answer these primary questions, we will
complete a longitudinal study (10 to 15 years timeframe) of 100 twin pairs [70 identical (MZ) and 30 fraternal
(DZ) twin pairs; 200 individuals] who are discordant (35 MZ; 15 DZ) or concordant (35 MZ; 15 DZ) for cyDNA
frequencies. The twin pairs will vary in age (currently 22 to at least 80 y.o) to allow us to chronicle associations
between aging hallmarks and the acquisition of cyDNA. For each time point we will determine: (a) cyDNA
levels, (b) chromosome specific-telomere/subtelomere lengths, (c) senescence markers, and (d) DNA
methylation patterns in cells from two different tissues (blood and buccal mucosa cells [to assess potential
soma-related differences]). Two measures of cyDNA will be quantified: (1) micronuclei (MN) frequency; and (2)
extrachromosomal circular DNA (eccDNA) frequency. The MN frequencies will be identified for each of the 24
human chromosomes using a novel assay we developed that combines spectral karyotyping and fluorescence
in situ hybridization technologies. The genetic contents of the eccDNA will be determined using our rolling
circle amplification and sequencing protocol. Chromosome-specific telomere and subtelomere lengths will be
determined using our Q-FISH method and our newly developed nanomapping method that exploits atomic
force microscopy, CRISPR-Cas9, and our novel genome sequence algorithm to provide unprecedented
resolution of telomere/subtelomere measures. We will also use “state of the art” tools we developed/optimized,
to quantify telomere dysfunction; senescence (SADS, classical, and transcriptome studies), and genome-wide
DNA methylation patterns. Using a method of robust variance component estimation (implemented in the
FISHER quantitative genetics package), this study will provide the first measure of the extent to which
individual differences in cyDNA and subtelomere lengths (which are associated with TERRA) are determined
by additive genetic, common environmental, and specific environmental effects. We will also use “state of the
art” statistical modeling and bioinformatic tools that we developed/optimized to analyze biomarker patterns
within individuals, between co-twins, and among twin pairs to determine the stability of patterns with aging, and
to identify temporal, as well as driver/mediator, relationships among cyDNA and other aging hallmarks
(telomeres/subtelomeres, DNA methylation, senescence). The information gained from this study could also
lead to...

## Key facts

- **NIH application ID:** 10929518
- **Project number:** 5R01AG082811-02
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** COLLEEN K JACKSON-COOK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $854,797
- **Award type:** 5
- **Project period:** 2023-09-15 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10929518

## Citation

> US National Institutes of Health, RePORTER application 10929518, Cytosolic DNA, Telomeres/Subtelomeres, and Epigenetics: A Longitudinal Twin Study to Assess the Role of Genetics and Environment on their Frequency and Inter-relationships (5R01AG082811-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10929518. Licensed CC0.

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