A Tale of Two Genomes: The Complex Interplay between the Mitochondrial and the Nuclear Genomes

Mitochondria, the product of an ancient endosymbiotic event are pivotal to eukaryotic cells by synthesizing the majority of the cell’s ATP output. However, modern- day mitochondria are completely dependent on more than one thousand nuclear-encoded products for their function and the maintenance of their genomes. The fundamentally different ways in which the mitochondrial (mtDNA) and the nuclear (nucDNA) genomes are replicated and inherited lead to captivating coevolutionary dynamics between them. The aims of this dissertation are to investigate the coevolutionary dynamics between the mitochondrial and nuclear genomes at three distinct biological scales. At the organismal level, we use a Drosophila strain with a characterized mitochondrial-nuclear incompatibility to test for the functional effects of mitochondrial-nuclear interactions on male reproductive fitness, in the context of both gene-environment interactions and the female-specific selective sieve that operates on mtDNA. We find that the mitochondrial- nuclear incompatibility negatively affects male fertility, although these effects are largely context-dependent. At the molecular level, using sequence and structural comparisons, we classify and characterize mutations associated with human mitochondrial disorders in the mtDNA and nucDNA as compensated or uncompensated based on whether the mutant amino acid is observed in a non-human species. We find that mtDNA, relative to nucDNA harbors a higher proportion of compensated mutations and this pattern is likely driven by the higher mtDNA background substitution rate. At the phylogenomic level, we estimate rates of evolutionary change for mtDNA- and nucDNA-encoded genes and compare correlations between the rates of mtDNA-encoded genes and three nuclear- encoded gene sets with differing extent of overlapping interactions with the mtDNA genes. We find that the patterns of rate correlations are consistent with the extent of overlap between the mtDNA and nucDNA genes with nucDNA genes that directly interact with mtDNA exhibiting the strongest correlations. In summary, we find that the higher rate of mutation in mtDNA appears to be driving mitochondrial-nuclear coevolutionary dynamics with the effects of mitochondrial-nuclear interactions being largely context-dependent