Aberrant X chromosome dosage compensation causes hybrid male inviability in <i>Caenorhabditis</i>

Zygotic reproductive isolation frequently initiates with hybrid incompatibility in the heterogametic sex, such as males in XX/XY systems. The genetic basis of hybrid male incompatibility has long remained elusive. Here, we show that crosses of <i>Caenorhabditis nigoni</i> males with <i>C. briggsae</i> females result in insufficient expression of <i>Cbr-xol-1</i>, an X-linked master switch responsible for intimately linked sex determination and dosage compensation pathways, consequently triggering aberrant X-chromosome repression in males, and ultimately leading to embryonic inviability. In contrast, male embryos from the reciprocal cross maintain normal expression level of <i>C. nigoni xol-1</i> genes, consistent with their viability. We further demonstrate that the cis-regulatory regions of <i>Cbr-xol-1</i> and <i>Cni-xol-1</i> have functionally diverged. Finally, X transcription is also aberrantly repressed in lethal hybrid male embryos from crosses between gonochoristic species <i>C. latens</i> and <i>C. remanei</i>. Our results suggest an evolutionary scenario in which incompatibility of the dosage compensation system leads to reproductive isolation.