Adaptive evolution of Topoisomerase II triggers reproductive isolation in Drosophila

A fundamental driver of biological diversification is the evolution of reproductive barriers between species. Instability and mis-regulation of repetitive DNA underlie numerous post-zygotic reproductive barriers, yet the molecular mechanisms are unknown. A long-studied genetic incompatibility between <i>Drosophila melanogaster</i> and <i>D. simulans</i> arises from mis-segregation of the <i>D. melanogaster</i>-specific <i>359bp</i> DNA satellite in hybrid embryos. Here we report that the <i>D. simulans</i> version of the essential enzyme Topoisomerase II/Top2 causes this lethal incompatibility. Combining interspecies gene swaps with cell biology and genetics revealed that <i>D. simulans</i>-specific adaptive divergence of Top2 DNA-interacting domains prevents the resolution of <i>359bp</i>-induced topological stress. Our findings demonstrate that species-specific DNA satellite topology requires species-specific molecular machinery and that even vital housekeeping genes can underlie reproductive isolation between closely related species.