The Onychomys pangenome reveals the unique molecular adaptations that confer toxin resistance

Abstract Background Predatory grasshopper mice ( Onychomys sp.) have co-evolved resistance to painful and lethal neurotoxins produced by their scorpion prey. Previous studies have reported that structural and functional modifications of the sodium channel Nav1.8 block the effect of painful toxins in grasshopper mice. However, key questions about the molecular adaptations underlying toxin resistance remain. Results We generate high-quality reference genomes and annotations for Onychomys species and Peromyscus eremicus . Using a comprehensive pipeline, we detect signatures of positive selection and identify Onychomys -specific mutations in Nav1.3 ( Scn3a ), a sodium channel gene expressed in the central nervous system and the peripheral sensory system after nerve damage. We also detect an Onychomys -specific tandem gene duplication of the Cblif gene, which encodes a glycoprotein crucial for vitamin B12 absorption. This duplication may represent an adaptation likely to support the species' dietary specialisation and modified stomach morphology, characterized by an abundance of parietal cells that express Cblif . To better understand the molecular response to toxin exposure, we generate RNA sequencing data from the dorsal root ganglion and the trigeminal ganglion of the mice exposed to toxic sprays from pinacate beetles. We detect upregulation of genes associated with transportation processes in Onychomys torridus . Conclusions Our findings suggest that Onychomys -specific Scn3a mutations, together with the upregulation of transport-related genes following toxin exposure, may contribute to the evolution of toxin resistance in grasshopper mice.