Population dynamics of mitochondrial genomes in Saccharomyces cerevisiae reveal tightly constrained mutational trajectories and a simple relationship between genome content and replicative fitness

Mitochondrial genome (mtDNA) quality is important for cellular function. Eukaryotic cells contain numerous copies of mtDNA which allows for the coexistence of mutant and wild-type mtDNA in individual cells. The fate of these mutant mtDNA depends on their relative replicative fitness as compared to the wild-type genomes. Yet the dynamics of the generation mutant mtDNA as well as their fitness to outcompete wild-type mtDNA remain to be fully understood. The primary challenge has been to track the large structural mutations that alter wild-type mtDNA. To address this, we utilize long read single-molecule sequencing to track the mutational trajectories of mtDNA in Saccharomyces cerevisiae (budding yeast). We show a previously unseen pattern that constrains the mtDNA mutational landscape where new mutations are contingent on previous events. We then propose a phenomenological model of relative fitness – the measure of the replication advantage of mutant genomes over wild-type genomes which depends on biophysical parameters of mutant mtDNA. Finally, we test how well the model explains relative fitness by performing direct competition between mutant and wild-type mtDNA in yeast mating experiments.