Spontaneous Mutation Rates and Spectra of Respiratory-Deficient Yeast.

The yeast petite mutant was first discovered in the yeast , which shows growth stress due to defects in genes encoding the respiratory chain. In a previous study, we described that deletion of the nuclear-encoded gene leads to mitochondrial genome (mtDNA) loss and the petite phenotype, which can be rescued by acquiring mutations. The strain showed an elevated SNV (single nucleotide variant) rate, suggesting genome instability occurred during the crisis of mtDNA loss. However, the genome-wide mutation landscape and mutational signatures of mitochondrial dysfunction are unknown. In this study we profiled the mutation spectra in yeast strains with the genotype combination of and in their wildtype and mutated status, along with the wildtype and cytoplasmic petite rho0 strains as controls. In addition to the previously described elevated SNV rate, we found the INDEL (insertion/deletion) rate also increased in the strain, reinforcing the occurrence of genome instability. Notably, although both are petites, the and rho0 strains exhibited different INDEL rates and transition/transversion ratios, suggesting differences in the mutational signatures underlying these two types of petites. Interestingly, the petite-related mutagenesis effect disappeared when suppressor mutations were acquired, suggesting a cost-effective mechanism for restoring both fitness and genome stability. Taken together, we present an unbiased genome-wide characterization of the mutation rates and spectra of yeast strains with respiratory deficiency, which provides valuable insights into the impact of respiratory deficiency on genome instability.