Blister beetles (Coleoptera: Meloidae) are currently subdivided into three subfamilies: Eleticinae (a basal group), Nemognathinae, and Meloinae. These are all characterized by the endogenous production of the defensive terpene cantharidin (CA), whereas the two most derived subfamilies show a hypermetamorphic larval development. Here, we provide novel draft genome assemblies of five species sampled across the three blister beetle subfamilies (Iselma pallidipennis, Stenodera caucasica, Zonitis immaculata, Lydus trimaculatus, and Mylabris variabilis) and performed a comparative analysis with other available Meloidae genomes and the closely-related canthariphilous species (Pyrochroa serraticornis) to disclose adaptations at a molecular level. Our results highlighted the expansion and selection of genes potentially responsible for CA production and metabolism, as well as its mobilization and vesicular compartmentalization. Furthermore, we observed adaptive selection patterns and gain of genes devoted to epigenetic regulation, development, and morphogenesis, possibly related to hypermetamorphosis. We hypothesize that most genetic adaptations occurred to support both CA biosynthesis and hypermetamorphosis, two crucial aspects of Meloidae biology that likely contributed to their evolutionary success. Integrative Zoology© 2024 The Authors. Integrative Zoology published by International Society of Zoological Sciences, Institute of Zoology/Chinese Academy of Sciences and John Wiley & Sons Australia, Ltd.

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