# Genetic and epigenetic architecture of natural telomere length variation

> **NIH NIH R01** · MARSHALL UNIVERSITY · 2020 · $272,682

## Abstract

Project Summary
 Telomeres are evolutionarily conserved protein-DNA complexes at the physical ends of
linear eukaryotic chromosomes. Telomeres shorten with age in most human cells, and their
initial length pre-determines cellular lifespan. Mutations in telomere maintenance genes lead to
cancer, premature aging and a number of age-related disorders. While mean telomere length in
humans shows considerable inter-individual variation and appears to be under strong genetic
control, the exact nature of factors establishing telomere length set point remains elusive. In our
preliminary results using the model plant Arabidopsis thaliana we identify a major effect QTL in
a recombinant inbred population that explains 48% of telomere length variation and map this
QTL to a candidate gene, NOP2A. Notably, expression of the human NOP2 ortholog is linked to
tumorigenesis and serves as a prognostic marker of tumor development. In this proposal, we
will utilize genetic, genomic, biochemical and epigenetic approaches to decipher the mechanism
of AtNOP2A function, and to uncover additional genetic and epigenetic factors involved in
telomere length control. In Aim 1, through a series of quantitative transgenic rescue experiments
we will identify the causal SNP and explore the mechanism by which NOP2A impacts telomere
length. We will also employ powerful Arabidopsis genetic, genomic and transcriptomic tools to
identify and characterize NOP2A-dependent genes and trans-regulators. In Aim 2, we will
perform GWAS in 1,001 Arabidopsis genotypes and fine-map additional QTL in a bi-parental
Arabidopsis RIL population to identify novel polymorphisms that affect telomere length. We will
then perform a series of knock-out and transgenic rescue experiments to functionally
characterize candidate genes and validate their role in telomere biology. In Aim 3, we will utilize
a unique A. thaliana epigenetic recombinant inbred population with almost identical DNA
sequences, but variable methylation and gene expression profiles, to fine-map two previously
identified large-effect epi-QTL governing telomere length, and analyze how heritable epigenetic
variation directly affects telomere length. Overall, the results of this study are expected to
significantly increase understanding of genetic differences underlying telomere length
polymorphism in natural Arabidopsis populations. Because modes of telomere regulation are
highly conserved, our data may also provide novel insight into the molecular basis for different
rates of aging and predisposition to diseases associated with telomere abnormalities in humans.

## Key facts

- **NIH application ID:** 9923707
- **Project number:** 5R01GM127402-04
- **Recipient organization:** MARSHALL UNIVERSITY
- **Principal Investigator:** Eugene V Shakirov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $272,682
- **Award type:** 5
- **Project period:** 2018-08-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9923707

## Citation

> US National Institutes of Health, RePORTER application 9923707, Genetic and epigenetic architecture of natural telomere length variation (5R01GM127402-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9923707. Licensed CC0.

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