Incompatibility between Nuclear and Mitochondrial Genomes Contributes to an Interspecies Reproductive Barrier

Vertebrate cells carry two different genomes, nuclear (nDNA) and mitochondrial (mtDNA), both encoding proteins involved in oxidative phosphorylation. Because of the extensive interactions, adaptive coevolution of the two genomes must occur to ensure normal mitochondrial function. To investigate whether incompatibilities between these two genomes could contribute to interspecies reproductive barriers, we performed reciprocal mtDNA replacement (MR) in zygotes between widely divergent Mus m. domesticus (B6) and conplastic Mus m. musculus (PWD) mice. Transfer of MR1 cybrid embryos (B6nDNA-PWDmtDNA) supported normal development of F1 offspring with reduced male fertility but unaffected reproductive fitness in females. Furthermore, donor PWD mtDNA was faithfully transmitted through the germline into F2 and F3 generations. In contrast, reciprocal MR2 (PWDnDNA-B6mtDNA) produced high embryonic loss and stillborn rates, suggesting an association between mitochondrial function and infertility. These results strongly suggest that functional incompatibility between nuclear and mitochondrial genomes contributes to interspecies reproductive isolation in mammals. [Display omitted] •mtDNA replacement (MR) between B6 and PWD mice supports preimplantation development•MR in PWD zygotes, but not in B6, caused post-implantation embryonic lethality•Divergence of mtDNA contributes to interspecies reproductive isolation in mammals Compatibility between nuclear and mitochondrial genomes is important for normal reproductive fitness. Mitalipov and colleagues show that reciprocal mtDNA replacement in zygotes between two mouse strains (B6 and PWD) results in post-implantation embryonic lethality, suggesting that mtDNA sequence divergence between mammalian species contributes to a reproductive barrier.