Inheritance bias of deletion-harbouring mtDNA in yeast: the role of copy number and intracellular selection

Eukaryotic cells contain multiple copies of mitochondrial DNA (mtDNA) molecules that replicate independently. Cell mtDNA content and variability contributes to the overall cell fitness. During sexual reproduction, fungi usually inherit mtDNA from both parents, however, the distribution of the mtDNA in the progeny can be biased toward some mtDNA variants. For example, crossing Saccharomyces cerevisiae strain carrying wild type ( rho ⁺ ) mtDNA with the strain carrying mutant mtDNA variant with large deletion ( rho ⁻ ) can produce up to 99-100% of rho ⁻ diploid progeny. Two factors could contribute to this phenomenon. First, rho ⁻ cells may accumulate more copies of mtDNA molecules per cell than wild-type cells, making rho ⁻ mtDNA a prevalent mtDNA molecule in zygotes. This consequently leads to a high portion of rho ⁻ diploid cells in the offspring. Second, rho ⁻ mtDNA may have a competitive advantage within heteroplasmic cells, and therefore could displace rho ⁺ mtDNA in a series of generations, regardless of their initial ratio. To assess the contribution of these factors, we investigated the genotypes and phenotypes of twenty two rho ⁻ yeast strains. We found that indeed rho ⁻ cells have a higher mtDNA copy number per cell than rho ⁺ strains. Using an in silico modelling of mtDNA selection and random drift in heteroplasmic yeast cells, we assessed the intracellular fitness of mutant mtDNA variants. Our model indicates that both higher copy numbers and intracellular fitness advantage of the rho ^- mtDNA contribute to the biased inheritance of rho ⁻ mtDNA.