# Mechanisms of mitochondrial mutation rate variation across eukaryotes

> **NIH NIH R35** · COLORADO STATE UNIVERSITY · 2023 · $383,645

## Abstract

PROJECT SUMMARY
High mutation rates in mitochondrial DNA (mtDNA) are a major cause of inherited and age-related diseases.
There is a longstanding view that the mutation-prone nature of mitochondrial genomes in humans and animal
models is a byproduct of the intense metabolic activity associated with oxidative phosphorylation and energy
conversion. However, recent evidence has challenged this idea, and there is growing recognition that
differences in the enzymatic machinery responsible for mtDNA replication and repair are a key cause of high
mutation rates in human mtDNA. Variation in mtDNA replication and repair pathways may also explain why
some eukaryotic lineages (e.g., plants) are able to suppress mutation rates in their mitochondrial genomes to
exceptionally low levels. An overarching theme of our research program is to identify the mechanisms
responsible for variation in mitochondrial mutation rates across eukaryotes and thereby help resolve the long-
term uncertainties about why rates are so high in humans. To overcome the technical challenges associated
with investigating rare events like de novo mutations, we have applied multiple innovative sequencing
technologies that can detect new DNA sequence variants present at ultra-low frequencies, essentially
capturing mutations and damaged bases as they occur and mapping them to nucleotide-level resolution. Our
future work will address two major questions. First, how do plant mitochondria achieve some of the lowest
rates of point mutations ever observed (less than one substitution per site per billion years)? This line of
investigation will build off our recent discovery that plant-MSH1 is necessary for maintaining low mutation rates
in plant organelle genomes. MSH1 is enigmatic member of the MutS gene family which was likely acquired by
horizontal transfer from giant viruses. We will test the hypothesis that it is part of a novel mechanism of
mismatch repair that induces double-stranded breaks followed by template-based recombinational repair.
Second, how do mitochondria repair bulky DNA damage introduced by UV? We will test the hypothesis that
mitochondria contain a previously unrecognized repair pathway with similarities to classic nucleotide excision
repair (NER). This hypothesis is motivated by our recent observation that exposure of divergent eukaryotic
model systems to UV light results in the release of mtDNA-derived oligonucleotides that carry damaged bases
at consistent positions and exhibit characteristic length profiles, a hallmark of NER. Overall, this research
program will help determine why mitochondrial genomes exhibit such extreme mutation rate variation across
the eukaryotic tree of life.

## Key facts

- **NIH application ID:** 10549690
- **Project number:** 1R35GM148134-01
- **Recipient organization:** COLORADO STATE UNIVERSITY
- **Principal Investigator:** Daniel Benjamin Sloan
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $383,645
- **Award type:** 1
- **Project period:** 2023-06-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10549690

## Citation

> US National Institutes of Health, RePORTER application 10549690, Mechanisms of mitochondrial mutation rate variation across eukaryotes (1R35GM148134-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10549690. Licensed CC0.

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