# Causes of Extreme Mitochondrial Mutation Rate Variation

> **NIH NIH R01** · COLORADO STATE UNIVERSITY · 2021 · $315,117

## Abstract

PROJECT SUMMARY
Mitochondrial mutations occur at a very high rate in humans and are a major cause of inherited and age-
related diseases. Although elevated mutation rates have long been considered a byproduct of the intense
metabolic activity that occurs within mitochondria, recent evidence has called this view into question, creating
enormous uncertainty in the field about the causes of mitochondrial mutations. In contrast to humans, some
eukaryotes exhibit extremely low rates of mutation in their mitochondrial DNA. Answering the question of how
some organisms are able to maintain low mitochondrial mutation rates has the potential to inform our
understanding of what causes them to be so high in humans. Remarkably, however, little effort has been made
to address this fundamental question of eukaryotic genetics. The proposed research will focus on flowering
plants as a model for understanding the mechanisms responsible for variation in mitochondrial mutation rate.
Rates of mitochondrial (and plastid) DNA substitutions in plants are generally lower than in plant nuclear
genomes and orders of magnitude lower than in animal mitochondria. However, plants also exhibit extreme
fluctuations in rates of mitochondrial sequence evolution even among closely related species. Progress in
understanding the mechanisms responsible for the extremely low rates in most plant species has been
impeded by the inherent technical difficulties in studying rare mutation events. The advent of new
methodologies that leverage deep sequencing and quantitative PCR technologies to directly measure rare
mutations and quantify rates of DNA damage presents an exciting opportunity to overcome these historical
barriers. The proposed research will apply these methodologies to both wild-type and mutant backgrounds in
the model angiosperm Arabidopsis thaliana to test a suite of alternative hypotheses, relating to the fidelity of
DNA polymerases, the efficacy of recombinational repair mechanisms, the effects of biased gene conversion,
and exposure/susceptibility to DNA damage in plant organelles. Analyses will be conducted on both vegetative
and meristematic tissues to distinguish mutations that simply accumulate in plant tissues from those that are
actually transmitted to offspring. The research will also be extended to related species of flowering plants in
which there has been a recent and massive acceleration in rates of mitochondrial sequence evolution. These
investigations will elucidate the mechanisms responsible for variation in mitochondrial mutation rates across
eukaryotes and inform ongoing debates about the role of oxidative damage as a mutagenic force in human
mitochondria.

## Key facts

- **NIH application ID:** 10218200
- **Project number:** 5R01GM118046-05
- **Recipient organization:** COLORADO STATE UNIVERSITY
- **Principal Investigator:** Daniel Benjamin Sloan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $315,117
- **Award type:** 5
- **Project period:** 2017-09-06 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10218200

## Citation

> US National Institutes of Health, RePORTER application 10218200, Causes of Extreme Mitochondrial Mutation Rate Variation (5R01GM118046-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10218200. Licensed CC0.

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