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Phenotypes mediating species interactions manifest as the combined products of the genomes of interacting species; understanding the evolutionary processes acting in one lineage therefore cannot be attained without bridging the genomes of interacting species. Venoms have arisen independently more than 100 times in animals and serve diverse roles in species interactions, including predation and defense. Each venom is evolutionarily entwined with reciprocal phenotypes, such as venom resistance, in often diverse recipient species. Despite extensive work on venoms, the full genetic basis for resistance to whole venoms is largely unknown. Using the venom of the Florida blue centipede (Scolopendra viridis) comprised of 35 toxins and Drosophila melanogaster as model prey, we investigated the genetics of venom resistance for a naive prey through experimental evolution and genetic-mapping approaches. We identified 12 consensus genes across techniques associated with venom resistance, yet individual experiments suggested a genome-wide basis for resistance involving hundreds to thousands of genes, despite the relative simplicity of the venom of S. viridis. We found no evidence for fitness trade-offs associated with the evolution of resistance and revealed a stark contrast in the nature of venom resistance between prey sexes. The disparity in resistance genetics between prey sexes as well as the relative genetic complexity of venom versus resistance may ultimately give venomous predators a coevolutionary advantage over their prey.<\/jats:p>","DOI":"10.1093\/molbev\/msag048","type":"journal-article","created":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T18:37:49Z","timestamp":1772044669000},"source":"Crossref","is-referenced-by-count":0,"title":["The Genetic Architecture of Venom Resistance: A Novel Approach to Target Identification and Coevolutionary Discovery"],"prefix":"10.1093","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9474-8615","authenticated-orcid":false,"given":"Micaiah J","family":"Ward","sequence":"first","affiliation":[{"name":"Department of Biological Science, Florida State University , Tallahassee, FL 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