Edited by Günter P. Wagner, Yale University, New Haven, CT, and approved February 11, 2021 (received for review October 27, 2020)Although oral venom systems are ecologically important characters, how they originated is still unclear. In this study, we show that oral venom systems likely originated from a gene regulatory network conserved across amniotes. This network, which we term the “metavenom network,” comprises over 3,000 housekeeping genes coexpressed with venom and play a role in protein folding and modification. Comparative transcriptomics revealed that the network is conserved...…Edited by Günter P. Wagner, Yale University, New Haven, CT, and approved February 11, 2021 (received for review October 27, 2020)Although oral venom systems are ecologically important characters, how they originated is still unclear. In this study, we show that oral venom systems likely originated from a gene regulatory network conserved across amniotes. This network, which we term the “metavenom network,” comprises over 3,000 housekeeping genes coexpressed with venom and play a role in protein folding and modification. Comparative transcriptomics revealed that the network is conserved...WW…