# Mitonuclear genetics of complex traits in Drosophila

> **NIH NIH R35** · BROWN UNIVERSITY · 2022 · $385,797

## Abstract

Mitochondrial dysfunction is a common source of disease, affecting 1 in ~5000 individuals. The
United Mitochondrial Disease Foundation states “every 30 minutes a child is born who will develop a
mitochondrial disease by age 10” (www.umdf.org). The biology of mitochondria makes these problems
tremendously complex. Mitochondrial function requires the coordinated expression of 37 genes
encoded in mitochondrial DNA (mtDNA) inside mitochondria, and over 1000 nuclear-encoded genes
whose products must be transported into mitochondria. The high mutation rate for mtDNA and the large
target of nuclear genes for mutations ensures that every individual has a unique ‘mito-nuclear
genotype’ that can alter fitness. Development in different environments can alter how different
genotypes express adult traits. Thus, these sources of complexity are responsible for key gaps in our
understanding of the genetic bases of mitochondrial disease, and more generally, the genetic variation
for mitochondrial performance in natural populations.
 The Drosophila model we have developed provides a powerful genetic approach to dissect this
complexity. We have introduced different mtDNAs into controlled nuclear genetic backgrounds and
identified genetic interactions (‘mitonuclear epistases’) affecting fitness traits and gene expression. We
have discovered that many of the genes with differential expression resulting from mitonuclear genetic
interactions also show differential expression in response environmental perturbations. Our working
hypothesis is that mitochondria integrate genetic pathways regulating changes in both the internal
cellular, and external physical, environments.
 We will pursue three general questions. First, what signaling pathways underlie the shared gene
expression responses to altered mitonuclear genotypes and altered physical environments? This will be
addressed with gene expression and epigenetic experiments pairing mitonuclear genotypes and
environmental stressors. Second, which nuclear genes regulate mtDNA effects on phenotypes? This
will be addressed with genetic screens of the nuclear genome across a panel of variable mtDNAs.
Third, do mtDNA mutations affect males more than females? The maternal inheritance of mtDNA
allows direct selection in females but prevents selection in males. Male-specific deleterious mutations
could accumulate in populations, a phenomenon known as Mother’s Curse. This will be addressed
using sex-based phenotypic assays in a panel of mtDNA genotypes that span a range of genetic
divergences. Each of these questions is relevant to current challenges in quantitative and medical
genetics. The findings from this research could be informative regarding genetic questions in the
identification of appropriate donors for mitochondrial replacement therapies.

## Key facts

- **NIH application ID:** 10377905
- **Project number:** 5R35GM139607-02
- **Recipient organization:** BROWN UNIVERSITY
- **Principal Investigator:** DAVID M RAND
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $385,797
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10377905

## Citation

> US National Institutes of Health, RePORTER application 10377905, Mitonuclear genetics of complex traits in Drosophila (5R35GM139607-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10377905. Licensed CC0.

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