biostudies-literatureHerzig VRamaciotti FoundationsIndian Institute of ScienceDepartment of Health | National Health and Medical Research CouncilDepartment of Science and Technology, Ministry of Science and TechnologyAustralian Research Council24920-24928https://www.ebi.ac.uk/biostudies/studies/S-EPMC7547274biostudies-literatureUnknown117(40)Australian funnel-web spiders are infamous for causing human fatalities, which are induced by venom peptides known as δ-hexatoxins (δ-HXTXs). Humans and other primates did not feature in the prey or predator spectrum during evolution of these spiders, and consequently the primate lethality of δ-HXTXs remains enigmatic. Funnel-web envenomations are mostly inflicted by male spiders that wander from their burrow in search of females during the mating season, which suggests a role for δ-HXTXs in self-defense since male spiders rarely feed during this period. Although 35 species of Australian funnel-web spiders have been described, only nine δ-HXTXs from four species have been characterized, resulting in a lack of understanding of the ecological roles and molecular evolution of δ-HXTXs. Here, bProceedings of the National Academy of Sciences of the United States of AmericaAustralian funnel-web spiders evolved human-lethal δ-hexatoxins for defense against vertebrate predators.PMC7547274DP190100304APP1072113FT190100482APP1136889DST/INSPIRE/04/2017/000071ECR grantDBT-IISc Partnership ProgramAPP1162503SR/FST/LS-II/2018/233Wilson DTRPineda SSHerzig VSunagar KFry BGLewis RJDutertre SMcFarland BSHodgson WCKing GFUndheim EABAlewood PFBosmans FVetter IIsrael MRfalseAustralian funnel-web spiders evolved human-lethal δ-hexatoxins for defense against vertebrate predators.Australian funnel-web spiders are infamous for causing human fatalities, which are induced by venom peptides known as δ-hexatoxins (δ-HXTXs). Humans and other primates did not feature in the prey or predator spectrum during evolution of these spiders, and consequently the primate lethality of δ-HXTXs remains enigmatic. Funnel-web envenomations are mostly inflicted by male spiders that wander from their burrow in search of females during the mating season, which suggests a role for δ-HXTXs in self-defense since male spiders rarely feed during this period. Although 35 species of Australian funnel-web spiders have been described, only nine δ-HXTXs from four species have been characterized, resulting in a lack of understanding of the ecological roles and molecular evolution of δ-HXTXs. Here, b2020-01-01T00:00:00Z2020 Oct2026-05-01T17:26:11.765Z2025-04-06T13:14:13.392ZS-EPMC75472743295863610.1073/pnas.2004516117