Sea anemone Membrane Attack Complex/Perforin Superfamily demonstrates an evolutionary transitional state between venomous and developmental functions.

Gene duplication is a major force driving evolutionary innovation. A classic example is generating new animal toxins via duplication of physiological protein-encoding genes and recruitment into venom. While this process drives the innovation of many animal venoms, reverse-recruitment of toxins into non-venomous cells remains unresolved. Using comparative genomics, we find members of the Membrane Attack Complex and Perforin Family (MAC) have been recruited into venom-injecting cells (cnidocytes), in soft and stony corals and sea anemones, suggesting that the ancestral MAC was a cnidocyte expressed toxin. Further investigation into the model sea anemone Nematostella vectensis, reveals that three members have undergone Nematostella-specific duplications leading to their reverse-recruitment into endomesodermal cells. Furthermore, simultaneous knock-down of all three endomesodermally-expressed MACs leads to mis-development, supporting that these paralogs have non-venomous function. By resolving the evolutionary history and function of MACs in Nematostella, we provide the first proof for reverse-recruitment from venom to organismal development.