Mapping mitonuclear epistasis using a novel recombinant yeast population.

Genetic variation in mitochondrial and nuclear genomes can perturb mitonuclear interactions and lead to phenotypic differences between individuals and populations. Despite their importance to most complex traits, it has been difficult to identify the interacting mitonuclear loci. Here, we present a novel advanced intercrossed population of Saccharomyces cerevisiae yeasts, called the Mitonuclear Recombinant Collection (MNRC), designed explicitly for detecting mitonuclear loci contributing to complex traits. For validation, we focused on mapping genes that contribute to the spontaneous loss of mitochondrial DNA (mtDNA) that leads to the petite phenotype in yeast. We found that rates of petite formation in natural populations are variable and influenced by genetic variation in nuclear DNA, mtDNA and mitonuclear interactions. We mapped nuclear and mitonuclear alleles contributing to mtDNA stability using the MNRC by integrating a term for mitonuclear epistasis into a genome-wide association model. We found that the associated mitonuclear loci play roles in mitotic growth most likely responding to retrograde signals from mitochondria, while the associated nuclear loci with main effects are involved in genome replication. We observed a positive correlation between growth rates and petite frequencies, suggesting a fitness tradeoff between mitotic growth and mtDNA stability. We also found that mtDNA stability was correlated with a mobile mitochondrial GC-cluster that is present in certain populations of yeast and that selection for nuclear alleles that stabilize mtDNA may be rapidly occurring. The MNRC provides a powerful tool for identifying mitonuclear interacting loci that will help us to better understand genotype-phenotype relationships and coevolutionary trajectories. Author summary: Mitochondrial functions require genes from nuclear and mitochondrial genomes that must work together. These interactions influence organismal fitness and coevolutionary processes yet it is difficult to identify the genes involved. Here, we created a novel collection of yeast designed explicitly for mapping mitonuclear genes. We used this collection to reveal genes influencing the maintenance of mitochondrial DNAs (mtDNAs), a trait important for human health. The mapping population presented here is an important new resource that will help to understand genotype-phenotype relationships and coevolutionary trajectories. Additionally, this work provides insight into mechanisms underlying mtDNA stability. [ABSTRACT FROM AUTHOR]