HEX represents the first canonical toxin-antidote system in vertebrates, operating through maternally deposited SP100 toxin that induces genotoxic stress in all embryos and zygotically expressed SP110 antidote that selectively rescues HEX-carrying embryos, thereby violating Mendelian inheritance by killing wild-type offspring and biasing transmission through the female germline in mice.

Toxin-antidote (TA) systems are selfish genetic elements that bias their own inheritance by coupling a toxin that kills offspring with an antidote that specifically rescues carriers. Although widespread across bacteria, archaea, fungi, plants, and invertebrates, TA systems have not been described in vertebrates. Here we report the first vertebrate TA system, which sabotages mammalian embryogenesis. We define HEX (Homogenously staining region-mediated Embryo eXecution) as a selfish element that biases its transmission through the female mouse germline. Crosses between HEX heterozygous females and wild-type males result in selective lethality of wild-type embryos, yielding preferential survival of HEX-bearing progeny. Using mouse genetics, embryo transfer, and zygote micromanipulation, we show that HEX operates through a canonical TA mechanism: the maternally deposited toxin SP100 induces genotoxic stress in embryos, while the linked antidote SP110 selectively rescues HEX-positive embryos. Both components are core factors of the interferon signaling pathway, revealing that HEX co-opts innate immune machinery to drive transmission bias. These findings establish a vertebrate TA system and demonstrate that selfish elements can repurpose fundamental cellular pathways to violate Mendelian inheritance, with profound consequences for female fertility.