Eivind Andreas Baste Undheim

• Maurstad, Marius Filomeno; Kusy, Dominik; Undheim, Eivind Andreas Baste; Jakobsen, Kjetill Sigurd; Böhne, Astrid & Monteiro, Rita [Vis alle 20 forfattere av denne artikkelen] (2026). ERGA-BGE chromosome-level genome assembly of the giant stream lacewing  Osmylus fulvicephalus (Scopoli, 1763). Open Research Europe. 6. doi: 10.12688/openreseurope.23457.3. Fulltekst i vitenarkiv Vis sammendrag

  The giant stream lacewing, Osmylus fulvicephalus (Scopoli, 1763), is a widespread European species belonging to the insect order Neuroptera. Its cryptic larvae are predators found at the banks of streams and smaller rivers where they use their piercing, lance-shaped stylets to inject venom into their arthropod prey. Here, we present the reference genome of the giant stream lacewing as a crucial resource for uncovering the genetic basis of venom evolution in Neuroptera. The chromosome-level genome encompasses 674.7 Mb and is composed of 60 contigs and 24 scaffolds where 99.2% of the assembly is distributed among the 6 contiguous chromosomal pseudomolecules and two sex chromosomes (X and Y). Contig and scaffold N50 have a value of 51.5 Mb and 116.2 Mb, respectively. This reference genome is the first genomic resource from the family of lance lacewings, providing valuable data for clarifying the phylogenetic placement of the family Osmylidae within Neuroptera.

• Denes, Christopher E.; D'Araujo, Tian Y.; Chung, Felicity; Lau, Man Tat; Cole, Adam & Casewell, Nicholas R. [Vis alle 8 forfattere av denne artikkelen] (2026). Sea nettle jellyfish venom targets proteoglycans to cause cell death and pain. Science Advances. 12(36), s. 1–12. doi: 10.1126/sciadv.aec7585.
• Koch, Thomas Lund; Ferrari, Giada; Sumanam, Sunita B; Salcedo, Paula Flórez; Watkins, Maren & Chase, Kevin [Vis alle 13 forfattere av denne artikkelen] (2026). From neuropeptides to toxins: illuminating the origins of venom complexity in cone snails. Molecular Biology and Evolution (MBE). ISSN 0737-4038. 43, s. 1–20. doi: 10.1093/molbev/msag206. Fulltekst i vitenarkiv Vis sammendrag

  New genes and gene functions are key drivers of evolutionary innovation. Venomous animals, such as cone snails, provide striking examples of gene innovation, yet the mechanisms by which toxins arise remain poorly understood. Using the Conus textile genome, we uncover how neuropeptide genes were recruited into the venom and neofunctionalized as doppelgänger toxins. We identify over 20 independent recruitment events that evolved dynamically across the Conus lineage. Rather than arising from ohnologs of a whole-genome duplication event ∼200 mya, these toxins evolved through diverse mechanisms, including exon shuffling, alternative splicing, and ectopic recombination, often facilitated by lineage-specific transposable elements. Our findings reveal a dynamic interplay between genome architecture and molecular innovation, offering broad insight into the evolution of complex gene repertoires in venoms and beyond.

• Araya, Robin Aasegg; Maurstad, Marius Filomeno; Wilson, David T; Rash, Lachlan D; Mobli, Mehdi & Jakobsen, Kjetill Sigurd [Vis alle 7 forfattere av denne artikkelen] (2026). Ancient origin and dynamic evolution of bivalent spider toxins. Molecular Biology and Evolution (MBE). ISSN 0737-4038. 43(5). doi: 10.1093/molbev/msag076. Fulltekst i vitenarkiv Vis sammendrag

  Bivalent peptide toxins comprising 2 cysteine-rich domains have evolved from single-domain precursors on multiple occasions in animal venoms, resulting in enhanced molecular target selectivity and avidity. Although bivalent toxins are emerging as prevalent in animal venoms, the genomic and evolutionary processes driving the transitions between single- and multi-domain architectures remain poorly understood. Here, we investigated the evolution of bivalent inhibitor cystine knot (ICK) toxins in spider venom. We first generated a genome assembly of the tree-dwelling funnel-web spider Hadronyche cerberea, revealing a massive expansion of ICK toxin-encoding genes, including the bivalent π-hexatoxin-Hc1a. All ICK toxin genes share a conserved 3-exon structure, flanked by transposable elements (TEs) that may have facilitated gene expansion. This gene structure is shared by the Hc1a subfamily, where the entire mature bivalent toxin is encoded by the third exon. Leveraging de novo transcriptome assemblies from 86 spider species along with venom proteomic data, we show that bivalency in the Hc1a subfamily is of ancient origin and evolved via intra-exonic duplication not involving introns. This was followed by domain expansion and recurrent domain losses mediated by point mutations, deletions, and unequal crossing-over facilitated by high interdomain sequence similarity. In contrast, the bivalent toxin DkTx from Cyriopagopus schmidti is confined to a small group of tarantulas, where it appears to have evolved once, with subsequent domain losses potentially linked to TE activity. Our findings reveal that singular events of domain duplication can give rise to complex, asymmetrical evolutionary trajectories shaped by gene instability and selective retention of functional domains.

• Mendel, Helen C; Hopping, Gene; Undheim, Eivind Andreas Baste; Zuegg, Johannes; Lewis, Richard J & Forbes, Briony E [Vis alle 8 forfattere av denne artikkelen] (2025). PeptideMiner—neuropeptide discovery across the animal kingdom. GigaScience. 14. doi: 10.1093/gigascience/giaf078. Fulltekst i vitenarkiv Vis sammendrag

  Neuropeptides represent the largest and most diverse class of cell-to-cell signaling molecules, holding important roles in animal physiology and behavior. They are evolutionarily ancient and widely distributed across the animal kingdom. Although over 200 neuropeptides have been identified, only a small fraction has been functionally characterized. A recognized bottleneck is the lack of effective tools to study their biological roles and therapeutic potential. Interestingly, neuropeptide-like peptides are also found in animal venoms, where they contribute to prey capture or defensive strategies. Mapping neuropeptide families across the animal kingdom is challenging due to their high sequence divergence and short mature peptide sequences. To address this, we developed PeptideMiner, a search tool that employs profile-hidden Markov models (profile-HMMs) for family-specific peptide discovery. PeptideMiner was systematically validated and benchmarked against existing methods, demonstrating its superior performance. By applying PeptideMiner to several venom transcriptomes—including 24 previously unpublished datasets—we identified 10 novel natriuretic peptides from distantly related species and 57 novel insulin-like sequences from marine predatory cone snails. Chemical synthesis and structure–activity relationship studies of newly identified conoinsulins at human insulin receptors emphasized the value of our approach in elucidating ligand–receptor interactions and discovering new pharmacological probes and therapeutic leads. PeptideMiner offers a powerful platform for discovering new bioactive peptides and family-specific analogues, accelerating both natural product discovery and evolutionary research.

• Jenner, Ronald A.; Casewell, Nicholas R. & Undheim, Eivind Andreas Baste (2025). What is animal venom? Rethinking a manipulative weapon. Trends in Ecology & Evolution. ISSN 0169-5347. 40(9), s. 852–861. doi: 10.1016/j.tree.2025.05.009. Fulltekst i vitenarkiv Vis sammendrag

  The scientific study of animal venoms covers a broad phylogenetic domain. We argue that the true extent of this domain has been obscured by researchers having overlooked the biological essence of venom. Venoms manipulate the physiological functioning of recipients to produce extended phenotypes that are beneficial to the venom producer and detrimental to its victim. The ability to produce extended phenotypes in living victims, such as prey paralysis, distinguishes venom from saliva. Understanding venom from this perspective substantially broadens the phylogenetic domain of venom to include taxa that use toxic secretions to feed on plants and manipulate sexual partners, and it paves the way for unifying the field of venomics with the fields that study invertebrate–plant interactions and sexual conflict.

• Sharma, Gagan; Deuis, Jennifer R.; Jia, Xinying; Crawford, Theo; Rahnama, Sassan & Undheim, Eivind Andreas Baste [Vis alle 9 forfattere av denne artikkelen] (2025). Refining the NaV1.7 pharmacophore of a class of venom-derived peptide inhibitors via a combination of in silico screening and rational engineering. FEBS Letters. ISSN 0014-5793. 599(12), s. 1717–1732. doi: 10.1002/1873-3468.70036. Fulltekst i vitenarkiv Vis sammendrag

  Ion channels are among the main targets of venom peptides. Extensive functional screening has identified a number of these peptides as modulators of the voltage‐gated sodium channel subtype Na V 1.7, a potential target for the treatment of chronic pain. In this study, we used a bioinformatic approach that can automatically identify Na V 1.7 gating modifier toxins from sequence information alone. The method further enables the incorporation of evolutionarily accessible sequence space in structure–activity relationship studies. The in silico method identified a putative Na V 1.7 inhibitor, μ‐theraphotoxin Cg4a, which we produced recombinantly and confirmed as a Na V 1.7 inhibitor. Using structural and mutagenesis studies, we propose an improved definition of the pharmacophore of this class of Na V 1.7 inhibitors, aiding future in silico screening and classification of Na V 1.7 inhibitors.

• Isaksen, Anders; Nachtigall, Pedro Gabriel; Araya, Robin Aasegg; Beh, Jia Hao; Robinson, Samuel D. & Hansen, Thomas Fredrik [Vis alle 7 forfattere av denne artikkelen] (2025). Genome of the green-head ant, Rhytidoponera metallica, reveals mechanisms of toxin evolution in a genetically hyper-diverse eusocial species. Genome Biology. ISSN 1474-7596. 26(1). doi: 10.1186/s13059-025-03777-2. Fulltekst i vitenarkiv Vis sammendrag

  Background While ants are textbook examples of eusocial animals in which altruistic behavior is maintained through kin selection, several ants form genetically diverse colonies that challenge this concept. One example is the Australian green-head ant (Rhytidoponera metallica) whose colonies harbor such extreme genetic variation that they have been speculated to represent an unstable form of eusociality. Yet, R. metallica is among the most successful ants on the Australian subcontinent. This success has been hypothesized to be partly due to the diverse venoms harbored within each colony. However, the genomic basis and evolutionary scenarios that maintain this toxin diversity remain unknown. Results To examine toxin genomic architecture, quantify individual-level genetic variation, and identify both proximate and ultimate mechanisms that have facilitated the toxin diversity in R. metallica, we generate a high-quality draft genome from a single worker. Most ectatotoxin genes are in clusters that contain evidence of multiple, complex gene-family expansions, some of which are likely explained by the presence of transposable elements. We also show that toxin regions of the genome exhibit elevated genetic variation despite being under strong selection and that this variation can translate to phenotypic diversity through toxin alleles with different functional properties. Conclusions Taken together, our results point to classical gene duplication and diversification as the main evolutionary mechanism by which the main toxin family in ant venoms evolves, suggest toxin-gene functional diversification under frequency-dependent selection maintains colony-level venom hypervariability in R. metallica, and provide new insight into the role of multi-level selection in eusocial animals.

• Pélabon, Christophe; Agudelo-Cantero, Gustavo Adolfo; Ajoy, Yimen Gerardo Araya; Bolstad, Geir Hysing; Cheng, Changde & Galis, Frietson [Vis alle 26 forfattere av denne artikkelen] (2025). Evolvability: progress and key questions. BioScience. ISSN 0006-3568. 75(12), s. 1057–1057. doi: 10.1093/biosci/biaf111. Fulltekst i vitenarkiv Vis sammendrag

  Since the 1990s, evolutionary biologists have recognized the importance of explaining the ability of biological systems to evolve and how this ability itself evolves. This recognition of the need to explain evolvability emerged from an awareness that the kind and the amount of heritable variation available for natural selection require explanation. The concept of evolvability is now the focus of many research programs in diverse subdisciplines within evolutionary biology. In the present article, we first review and synthesise progress made in evolvability research. We then present key questions to set an agenda for future research on evolvability, identify challenges to answer these questions, and discuss opportunities to apply results from the evolvability research to conservation biology.

• Maurstad, Marius Filomeno; Ramiro, Iris Bea; Øyen, Jan Philip; Sombke, Andy; Büsse, Sebastian & Nachtigall, Pedro Gabriel [Vis alle 8 forfattere av denne artikkelen] (2025). The green lacewing venom system and the complex mechanisms underlying its evolution. Molecular Biology and Evolution (MBE). ISSN 0737-4038. 43. doi: 10.1093/molbev/msaf326. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Venom has independently evolved across many lineages, yet relatively few have been studied in detail, particularly among insects. Of these, Neuroptera (lacewings, antlions and relatives) remain largely unexplored, despite being widespread with agriculturally important groups such as green lacewings. While adults are non-venomous, neuropteran larvae are ferocious predators that use pincer-like mouthparts to inject paralysing and liquefying venom to subdue and consume their prey. Here, we provide a comprehensive investigation of the venom system in Neuroptera by integrating a high-quality genome, long-read transcriptomes spanning all life stages, microCT-reconstruction of venom glands, tissue-specific expression analyses, venom proteomics, and functional assays of the common green lacewing Chrysoperla carnea. We provide a re-description of the neuropteran venom system, demonstrate the venom’s insecticidal and cytotoxic activity, and show the venom comprises diverse toxin gene families and is richer and more similar to the venom of antlions than previously proposed. We show that this toxin arsenal is the result of a multitude of evolutionary events that include co-option, recruitment following gene duplication, diversification of toxin-paralogs by gene duplication, and functional innovation of new paralogs through both small structural and large architectural changes. In addition, we find that alternative splicing of toxin genes is an important contributor to the biochemical arsenal, which is a mechanism rarely documented among venomous animals. Our results demonstrate how multiple genomic and evolutionary mechanisms together contribute to the emergence and evolution of a complex molecular trait, and provide new insights into the evolution of venom in insects.

• Nachtigall, Pedro Gabriel; Hamilton, Brett R.; Kazandjian, Taline D.; Stincone, Paolo; Petras, Daniel & Casewell, Nicholas R. [Vis alle 7 forfattere av denne artikkelen] (2025). The gene regulatory mechanisms shaping the heterogeneity of venom production in the Cape coral snake. Genome Biology. ISSN 1474-7596. 26(1). doi: 10.1186/s13059-025-03602-w. Fulltekst i vitenarkiv Vis sammendrag

  Background Venoms and their associated glands and delivery structures have evolved numerous times among animals. Within these venom systems, the molecular, cellular, and morphological components interact and co-evolve to generate distinct, venom phenotypes that are increasingly recognized as models for studying adaptive evolution. However, toxins are often unevenly distributed across venom-producing tissues in patterns that are not necessarily adaptive but instead likely result from constraints associated with protein secretion. Results We generate a high-quality draft genome of the Cape coral snake (Aspidelaps lubricus) and combine analyses of venom gland single-cell RNA-seq data with spatial venom gland in situ toxin distributions. Our results reveal that while different toxin families are produced by distinct populations of cells, toxin expression is fine-tuned by regulatory modules that result in further specialization of toxin production within each cell population. We also find that the evolution of regulatory elements closely mirrors the evolution of their associated toxin genes, resulting in spatial association of closely related and functionally similar toxins in the venom gland. While this compartmentalization is non-adaptive, the modularity of the underlying regulatory network likely facilitated the repeated evolution of defensive venom in spitting cobras. Conclusions Our results provide new insight into the variability of toxin regulation across snakes, reveal the molecular mechanisms underlying the heterogeneous toxin production in snake venom glands, and provide an example of how constraints can result in non-adaptive character states that appear to be adaptive, which may nevertheless facilitate evolutionary innovation and novelty.

• Schendel, Vanessa; Hamilton, Brett R.; Robinson, Samuel D.; Green, Kathryn; Sayre, Marcel E. & Brown, Darren [Vis alle 13 forfattere av denne artikkelen] (2025). Exaptation of an evolutionary constraint enables behavioural control over the composition of secreted venom in a giant centipede. Nature Ecology and Evolution. 383. doi: 10.1038/s41559-024-02556-9. Fulltekst i vitenarkiv Vis sammendrag

  https://rdcu.be/dY48T

• Seldeslachts, Andrea; Maurstad, Marius Filomeno; Øyen, Jan Philip; Undheim, Eivind Andreas Baste; Peigneur, Steve & Tytgat, Jan (2024). Exploring oak processionary caterpillar induced lepidopterism (Part 1): unveiling molecular insights through transcriptomics and proteomics. Cellular and Molecular Life Sciences (CMLS). ISSN 1420-682X. 81. doi: 10.1007/s00018-024-05330-z. Fulltekst i vitenarkiv Vis sammendrag

  Lepidopterism, a skin inflammation condition caused by direct or airborne exposure to irritating hairs (setae) from processionary caterpillars, is becoming a significant public health concern. Recent outbreaks of the oak processionary caterpillar (Thaumetopoea processionea) have caused noteworthy health and economic consequences, with a rising frequency expected in the future, exacerbated by global warming promoting the survival of the caterpillar. Current medical treatments focus on symptom relief due to the lack of an effective therapy. While the source is known, understanding the precise causes of symptoms remain incomplete understood. In this study, we employed an advanced method to extract venom from the setae and identify the venom components through high-quality de novo transcriptomics, venom proteomics, and bioinformatic analysis. A total of 171 venom components were identified, including allergens, odorant binding proteins, small peptides, enzymes, enzyme inhibitors, and chitin biosynthesis products, potentially responsible for inflammatory and allergic reactions. This work presents the first comprehensive proteotranscriptomic database of T. processionea, contributing to understanding the complexity of lepidopterism. Furthermore, these findings hold promise for advancing therapeutic approaches to mitigate the global health impact of T. processionea and related caterpillars.

• Schendel, Vanessa; Müller, Carsten H. G.; Kenning, Matthes; Maxwell, Michael; Jenner, Ronald A. & Undheim, Eivind Andreas Baste [Vis alle 7 forfattere av denne artikkelen] (2024). The venom and telopodal defence systems of the centipede Lithobius forficatus are functionally convergent serial homologues. BMC Biology. 22(1). doi: 10.1186/s12915-024-01925-x. Fulltekst i vitenarkiv Vis sammendrag

  Background Evolution of novelty is a central theme in evolutionary biology, yet studying the origins of traits with an apparently discontinuous origin remains a major challenge. Venom systems are a well-suited model for the study of this phenomenon because they capture several aspects of novelty across multiple levels of biological complexity. However, while there is some knowledge on the evolution of individual toxins, not much is known about the evolution of venom systems as a whole. One way of shedding light on the evolution of new traits is to investigate less specialised serial homologues, i.e. repeated traits in an organism that share a developmental origin. This approach can be particularly informative in animals with repetitive body segments, such as centipedes. Results Here, we investigate morphological and biochemical aspects of the defensive telopodal glandular organs borne on the posterior legs of venomous stone centipedes (Lithobiomorpha), using a multimethod approach, including behavioural observations, comparative morphology, proteomics, comparative transcriptomics and molecular phylogenetics. We show that the anterior venom system and posterior telopodal defence system are functionally convergent serial homologues, where one (telopodal defence) represents a model for the putative early evolutionary state of the other (venom). Venom glands and telopodal glandular organs appear to have evolved from the same type of epidermal gland (four-cell recto-canal type) and while the telopodal defensive secretion shares a great degree of compositional overlap with centipede venoms in general, these similarities arose predominantly through convergent recruitment of distantly related toxin-like components. Both systems are composed of elements predisposed to functional innovation across levels of biological complexity that range from proteins to glands, demonstrating clear parallels between molecular and morphological traits in the properties that facilitate the evolution of novelty. Conclusions The evolution of the lithobiomorph telopodal defence system provides indirect empirical support for the plausibility of the hypothesised evolutionary origin of the centipede venom system, which occurred through functional innovation and gradual specialisation of existing epidermal glands. Our results thus exemplify how continuous transformation and functional innovation can drive the apparent discontinuous emergence of novelties on higher levels of biological complexity.

• Seldeslachts, Andrea; Undheim, Eivind Andreas Baste; Vriens, Joris; Tytgat, Jan & Peigneur, Steve (2024). Exploring oak processionary caterpillar induced lepidopterism (part 2): ex vivo bio-assays unmask the role of TRPV1. Cellular and Molecular Life Sciences (CMLS). ISSN 1420-682X. 81. doi: 10.1007/s00018-024-05318-9. Fulltekst i vitenarkiv Vis sammendrag

  As human skin comes into contact with the tiny hairs or setae of the oak processionary caterpillar, Thaumetopoea processionea, a silent yet intense chemical confrontation occurs. The result is a mix of issues: skin rashes and an intense itching that typically lasts days and weeks after the contact. This discomfort poses a significant health threat not only to humans but also to animals. In Western Europe, the alarming increase in outbreaks extends beyond areas near infested trees due to the dispersion of the setae. Predictions indicate a sustained rise in outbreaks, fueled by global changes favoring the caterpillar’s survival and distribution. Currently, the absence of an efficient treatment persists due to significant gaps in our comprehension of the pathophysiology associated with this envenomation. Here, we explored the interaction between the venom extract derived from the setae of T. processionea and voltage- and ligand-gated ion channels and receptors. By conducting electrophysiological analyses, we discovered ex vivo evidence highlighting the significant role of TPTX1-Tp1, a peptide toxin from T. processionea, in modulating TRPV1. TPTX1-Tp1 is a secapin-like peptide and demonstrates a unique ability to modulate TRPV1 channels in the presence of capsaicin, leading to cell depolarization, itch and inflammatory responses. This discovery opens new avenues for developing a topical medication, suggesting the incorporation of a TRPV1 blocker as a potential solution for the local effects caused by T. processionea.

• Ashwood, Lauren M.; Elnahriry, Khaled A.; Stewart, Zachary K.; Shafee, Thomas; Naseem, Muhammad Umair & Szanto, Tibor G. [Vis alle 23 forfattere av denne artikkelen] (2023). Genomic, functional and structural analyses elucidate evolutionary innovation within the sea anemone 8 toxin family. BMC Biology. 21, s. 1–25. doi: 10.1186/s12915-023-01617-y. Fulltekst i vitenarkiv Vis sammendrag

  Background The ShK toxin from Stichodactyla helianthus has established the therapeutic potential of sea anemone venom peptides, but many lineage-specific toxin families in Actiniarians remain uncharacterised. One such peptide family, sea anemone 8 (SA8), is present in all five sea anemone superfamilies. We explored the genomic arrangement and evolution of the SA8 gene family in Actinia tenebrosa and Telmatactis stephensoni, characterised the expression patterns of SA8 sequences, and examined the structure and function of SA8 from the venom of T. stephensoni. Results We identified ten SA8-family genes in two clusters and six SA8-family genes in five clusters for T. stephensoni and A. tenebrosa, respectively. Nine SA8 T. stephensoni genes were found in a single cluster, and an SA8 peptide encoded by an inverted SA8 gene from this cluster was recruited to venom. We show that SA8 genes in both species are expressed in a tissue-specific manner and the inverted SA8 gene has a unique tissue distribution. While the functional activity of the SA8 putative toxin encoded by the inverted gene was inconclusive, its tissue localisation is similar to toxins used for predator deterrence. We demonstrate that, although mature SA8 putative toxins have similar cysteine spacing to ShK, SA8 peptides are distinct from ShK peptides based on structure and disulfide connectivity. Conclusions Our results provide the first demonstration that SA8 is a unique gene family in Actiniarians, evolving through a variety of structural changes including tandem and proximal gene duplication and an inversion event that together allowed SA8 to be recruited into the venom of T. stephensoni.

• Robinson, Samuel D.; Deuis, Jennifer R.; Touchard, Axel; Keramidas, Angelo; Mueller, Alexander & Schroeder, Christina I. [Vis alle 16 forfattere av denne artikkelen] (2023). Ant venoms contain vertebrate-selective pain-causing sodium channel toxins. Nature Communications. 14, s. 1–11. doi: 10.1038/s41467-023-38839-1. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Stings of certain ant species (Hymenoptera: Formicidae) can cause intense, long-lasting nociception. Here we show that the major contributors to these symptoms are venom peptides that modulate the activity of voltage-gated sodium (Na V ) channels, reducing their voltage threshold for activation and inhibiting channel inactivation. These peptide toxins are likely vertebrate-selective, consistent with a primarily defensive function. They emerged early in the Formicidae lineage and may have been a pivotal factor in the expansion of ants.

• Silva, Daiane Laise da; Valladão, Rodrigo; Beraldo-Neto, Emidio; Coelho, Guilherme Rabelo; Neto, Oscar Bento da Silva & Vigerelli, Hugo [Vis alle 11 forfattere av denne artikkelen] (2023). Spatial Distribution and Biochemical Characterization of Serine Peptidase Inhibitors in the Venom of the Brazilian Sea Anemone Anthopleura cascaia Using Mass Spectrometry Imaging. Marine Drugs. 21(9), s. 1–20. doi: 10.3390/md21090481. Fulltekst i vitenarkiv Vis sammendrag

  Sea anemones are known to produce a diverse array of toxins with different cysteine-rich peptide scaffolds in their venoms. The serine peptidase inhibitors, specifically Kunitz inhibitors, are an important toxin family that is believed to function as defensive peptides, as well as prevent proteolysis of other secreted anemone toxins. In this study, we isolated three serine peptidase inhibitors named Anthopleura cascaia peptide inhibitors I, II, and III (ACPI-I, ACPI-II, and ACPI-III) from the venom of the endemic Brazilian sea anemone A. cascaia. The venom was fractionated using RP-HPLC, and the inhibitory activity of these fractions against trypsin was determined and found to range from 59% to 93%. The spatial distribution of the anemone peptides throughout A. cascaia was observed using mass spectrometry imaging. The inhibitory peptides were found to be present in the tentacles, pedal disc, and mesenterial filaments. We suggest that the three inhibitors observed during this study belong to the venom Kunitz toxin family on the basis of their similarity to PI-actitoxin-aeq3a-like and the identification of amino acid residues that correspond to a serine peptidase binding site. Our findings expand our understanding of the diversity of toxins present in sea anemone venom and shed light on their potential role in protecting other venom components from proteolysis.

• Robinson, Samuel D.; Schendel, Vanessa; Schroeder, Christina I.; Moen, Sarah; Mueller, Alexander & Walker, Andrew A. [Vis alle 11 forfattere av denne artikkelen] (2023). Intra-colony venom diversity contributes to maintaining eusociality in a cooperatively breeding ant. BMC Biology. 21(5), s. 1–19. doi: 10.1186/s12915-022-01507-9. Fulltekst i vitenarkiv Vis sammendrag

  Background Eusociality is widely considered to evolve through kin selection, where the reproductive success of an individual’s close relative is favored at the expense of its own. High genetic relatedness is thus considered a prerequisite for eusociality. While ants are textbook examples of eusocial animals, not all ants form colonies of closely related individuals. One such example is the ectatommine ant Rhytidoponera metallica, which predominantly forms queen-less colonies that have such a low intra-colony relatedness that they have been proposed to represent a transient, unstable form of eusociality. However, R. metallica is among the most abundant and widespread ants on the Australian continent. This apparent contradiction provides an example of how inclusive fitness may not by itself explain the maintenance of eusociality and raises the question of what other selective advantages maintain the eusocial lifestyle of this species. Results We provide a comprehensive portrait of the venom of R. metallica and show that the colony-wide venom consists of an exceptionally high diversity of functionally distinct toxins for an ant. These toxins have evolved under strong positive selection, which is normally expected to reduce genetic variance. Yet, R. metallica exhibits remarkable intra-colony variation, with workers sharing only a relatively small proportion of toxins in their venoms. This variation is not due to the presence of chemical castes, but has a genetic foundation that is at least in part explained by toxin allelic diversity. Conclusions Taken together, our results suggest that the toxin diversity contained in R. metallica colonies may be maintained by a form of group selection that selects for colonies that can exploit more resources and defend against a wider range of predators. We propose that increased intra-colony genetic variance resulting from low kinship may itself provide a selective advantage in the form of an expanded pharmacological venom repertoire. These findings provide an example of how group selection on adaptive phenotypes may contribute to maintaining eusociality where a prerequisite for kin selection is diminished.

• Maxwell, Michael J.; Thekkedam, Chris; Lamboley, Cedric; Chin, Yanni K.-Y.; Crawford, Theo & Smith, Jennifer J. [Vis alle 14 forfattere av denne artikkelen] (2023). A bivalent remipede toxin promotes calcium release via ryanodine receptor activation. Nature Communications. 14(1), s. 1–13. doi: 10.1038/s41467-023-36579-w. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Multivalent ligands of ion channels have proven to be both very rare and highly valuable in yielding unique insights into channel structure and pharmacology. Here, we describe a bivalent peptide from the venom of Xibalbanus tulumensis , a troglobitic arthropod from the enigmatic class Remipedia, that causes persistent calcium release by activation of ion channels involved in muscle contraction. The high-resolution solution structure of φ-Xibalbin3-Xt3a reveals a tandem repeat arrangement of inhibitor-cysteine knot (ICK) domains previously only found in spider venoms. The individual repeats of Xt3a share sequence similarity with a family of scorpion toxins that target ryanodine receptors (RyR). Single-channel electrophysiology and quantification of released Ca 2+ stores within skinned muscle fibers confirm Xt3a as a bivalent RyR modulator. Our results reveal convergent evolution of RyR targeting toxins in remipede and scorpion venoms, while the tandem-ICK repeat architecture is an evolutionary innovation that is convergent with toxins from spider venoms.

• Liu, Junyu; Maxwell, Michael; Cuddihy, Thom; Crawford, Theo; Bassetti, Madeline & Hyde, Cameron [Vis alle 10 forfattere av denne artikkelen] (2023). ScrepYard: An online resource for disulfide-stabilized tandem repeat peptides. Protein Science. ISSN 0961-8368. 32(2), s. 1–12. doi: 10.1002/pro.4566. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Receptor avidity through multivalency is a highly sought‐after property of ligands. While readily available in nature in the form of bivalent antibodies, this property remains challenging to engineer in synthetic molecules. The discovery of several bivalent venom peptides containing two homologous and independently folded domains (in a tandem repeat arrangement) has provided a unique opportunity to better understand the underpinning design of multivalency in multimeric biomolecules, as well as how naturally occurring multivalent ligands can be identified. In previous work, we classified these molecules as a larger class termed secreted cysteine‐rich repeat‐proteins (SCREPs). Here, we present an online resource; ScrepYard, designed to assist researchers in identification of SCREP sequences of interest and to aid in characterizing this emerging class of biomolecules. Analysis of sequences within the ScrepYard reveals that two‐domain tandem repeats constitute the most abundant SCREP domain architecture, while the interdomain “linker” regions connecting the functional domains are found to be abundant in amino acids with short or polar sidechains and contain an unusually high abundance of proline residues. Finally, we demonstrate the utility of ScrepYard as a virtual screening tool for discovery of putatively multivalent peptides, by using it as a resource to identify a previously uncharacterized serine protease inhibitor and confirm its predicted activity using an enzyme assay.

• Dashevsky, Daniel; Baumann, Kate; Undheim, Eivind Andreas Baste; Nouwens, Amanda; Ikonomopoulou, Maria P. & Schmidt, Justin O. [Vis alle 10 forfattere av denne artikkelen] (2023). Functional and Proteomic Insights into Aculeata Venoms. Toxins. 15(3), s. 1–25. doi: 10.3390/toxins15030224. Fulltekst i vitenarkiv Vis sammendrag

  Aculeate hymenopterans use their venom for a variety of different purposes. The venom of solitary aculeates paralyze and preserve prey without killing it, whereas social aculeates utilize their venom in defence of their colony. These distinct applications of venom suggest that its components and their functions are also likely to differ. This study investigates a range of solitary and social species across Aculeata. We combined electrophoretic, mass spectrometric, and transcriptomic techniques to characterize the compositions of venoms from an incredibly diverse taxon. In addition, in vitro assays shed light on their biological activities. Although there were many common components identified in the venoms of species with different social behavior, there were also significant variations in the presence and activity of enzymes such as phospholipase A2s and serine proteases and the cytotoxicity of the venoms. Social aculeate venom showed higher presence of peptides that cause damage and pain in victims. The venom-gland transcriptome from the European honeybee (Apis mellifera) contained highly conserved toxins which match those identified by previous investigations. In contrast, venoms from less-studied taxa returned limited results from our proteomic databases, suggesting that they contain unique toxins.

• Kazandjian, Taline D.; Hamilton, Brett R.; Robinson, Samuel D.; Hall, Steven R.; Bartlett, Keirah E. & Rowley, Paul [Vis alle 9 forfattere av denne artikkelen] (2022). Physiological constraints dictate toxin spatial heterogeneity in snake venom glands. BMC Biology. 20(1). doi: 10.1186/s12915-022-01350-y. Fulltekst i vitenarkiv Vis sammendrag

  Background Venoms are ecological innovations that have evolved numerous times, on each occasion accompanied by the co-evolution of specialised morphological and behavioural characters for venom production and delivery. The close evolutionary interdependence between these characters is exemplified by animals that control the composition of their secreted venom. This ability depends in part on the production of different toxins in different locations of the venom gland, which was recently documented in venomous snakes. Here, we test the hypothesis that the distinct spatial distributions of toxins in snake venom glands are an adaptation that enables the secretion of venoms with distinct ecological functions. Results We show that the main defensive and predatory peptide toxins are produced in distinct regions of the venom glands of the black-necked spitting cobra (Naja nigricollis), but these distributions likely reflect developmental effects. Indeed, we detected no significant differences in venom collected via defensive ‘spitting’ or predatory ‘biting’ events from the same specimens representing multiple lineages of spitting cobra. We also found the same spatial distribution of toxins in a non-spitting cobra and show that heterogeneous toxin distribution is a feature shared with a viper with primarily predatory venom. Conclusions Our findings suggest that heterogeneous distributions of toxins are not an adaptation to controlling venom composition in snakes. Instead, it likely reflects physiological constraints on toxin production by the venom glands, opening avenues for future research on the mechanisms of functional differentiation of populations of protein-secreting cells within adaptive contexts.

• An, Dongchen; Pinheiro-Junior, Ernesto Lopes; Béress, László; Gladkikh, Irina; Leychenko, Elena & Undheim, Eivind Andreas Baste [Vis alle 8 forfattere av denne artikkelen] (2022). AsKC11, a Kunitz Peptide from Anemonia sulcata, Is a Novel Activator of G Protein-Coupled Inward-Rectifier Potassium Channels. Marine Drugs. 20(2). doi: 10.3390/md20020140. Fulltekst i vitenarkiv Vis sammendrag

  (1) Background: G protein-coupled inward-rectifier potassium (GIRK) channels, especially neuronal GIRK1/2 channels, have been the focus of intense research interest for developing drugs against brain diseases. In this context, venom peptides that selectively activate GIRK channels can be seen as a new source for drug development. Here, we report on the identification and electrophysiological characterization of a novel activator of GIRK1/2 channels, AsKC11, found in the venom of the sea anemone Anemonia sulcata. (2) Methods: AsKC11 was purified from the sea anemone venom by reverse-phase chromatography and the sequence was identified by mass spectrometry. Using the two-electrode voltage-clamp technique, the activity of AsKC11 on GIRK1/2 channels was studied and its selectivity for other potassium channels was investigated. (3) Results: AsKC11, a Kunitz peptide found in the venom of A. sulcata, is the first peptide shown to directly activate neuronal GIRK1/2 channels independent from Gi/o protein activity, without affecting the inward-rectifier potassium channel (IRK1) and with only a minor effect on KV1.6 channels. Thus, AsKC11 is a novel activator of GIRK channels resulting in larger K+ currents because of an increased chord conductance. (4) Conclusions: These discoveries provide new insights into a novel class of GIRK activators.

• Reumont, Bjoern M. von; Anderluh, Gregor; Antunes, Agostinho; Ayvazyan, Naira; Beis, Dimitris & Caliskan, Figen [Vis alle 35 forfattere av denne artikkelen] (2022). Modern venomics-Current insights, novel methods, and future perspectives in biological and applied animal venom research. GigaScience. 11. doi: 10.1093/gigascience/giac048. Fulltekst i vitenarkiv Vis sammendrag

  Venoms have evolved >100 times in all major animal groups, and their components, known as toxins, have been fine-tuned over millions of years into highly effective biochemical weapons. There are many outstanding questions on the evolution of toxin arsenals, such as how venom genes originate, how venom contributes to the fitness of venomous species, and which modifications at the genomic, transcriptomic, and protein level drive their evolution. These questions have received particularly little attention outside of snakes, cone snails, spiders, and scorpions. Venom compounds have further become a source of inspiration for translational research using their diverse bioactivities for various applications. We highlight here recent advances and new strategies in modern venomics and discuss how recent technological innovations and multi-omic methods dramatically improve research on venomous animals. The study of genomes and their modifications through CRISPR and knockdown technologies will increase our understanding of how toxins evolve and which functions they have in the different ontogenetic stages during the development of venomous animals. Mass spectrometry imaging combined with spatial transcriptomics, in situ hybridization techniques, and modern computer tomography gives us further insights into the spatial distribution of toxins in the venom system and the function of the venom apparatus. All these evolutionary and biological insights contribute to more efficiently identify venom compounds, which can then be synthesized or produced in adapted expression systems to test their bioactivity. Finally, we critically discuss recent agrochemical, pharmaceutical, therapeutic, and diagnostic (so-called translational) aspects of venoms from which humans benefit.

• Finol-Urdaneta, Rocio K.; Ziegman, Rebekah; Dekan, Zoltan; McArthur, Jeffrey R.; Heitmann, Stewart & Luna-Ramirez, Karen [Vis alle 20 forfattere av denne artikkelen] (2022). Multitarget nociceptor sensitization by a promiscuous peptide from the venom of the King Baboon spider. Proceedings of the National Academy of Sciences of the United States of America (PNAS). ISSN 0027-8424. 119(5). doi: 10.1073/pnas.2110932119. Fulltekst i vitenarkiv Vis sammendrag

  Significance Pain development and discomfort are universal features of spider envenomation, yet severe pain arising from bites by Old World spiders is poorly understood. Molecular analyses of the venom of the King Baboon spider revealed abundant expression of the inhibitory cystine knot peptide Pm1a. Synthetic Pm1a induces pain in mice while simultaneously enhancing proexcitatory sodium currents and decreasing inhibitory potassium currents. These concomitant effects promote hyperexcitability in pain-sensing neurons that can be reversed by pharmacological inhibition of voltage-gated sodium channels. The coordinated modulation of excitatory and inhibitory ion channels involved in pain propagation may represent an economical and effective defense strategy in pain-inducing defensive venoms.

• Verdes, Aida; Taboada, Sergi; Hamilton, Brett R.; Undheim, Eivind Andreas Baste; Sonoda, Gabriel G. & Andrade, Sonia C.S. [Vis alle 10 forfattere av denne artikkelen] (2022). Evolution, Expression Patterns, and Distribution of Novel Ribbon Worm Predatory and Defensive Toxins. Molecular Biology and Evolution (MBE). ISSN 0737-4038. 39(5). doi: 10.1093/molbev/msac096. Fulltekst i vitenarkiv Vis sammendrag

  Ribbon worms are active predators that use an eversible proboscis to inject venom into their prey and defend themselves with toxic epidermal secretions. Previous work on nemertean venom has largely focused on just a few species and has not investigated the different predatory and defensive secretions in detail. Consequently, our understanding of the composition and evolution of ribbon worm venoms is still very limited. Here, we present a comparative study of nemertean venom combining RNA-seq differential gene expression analyses of venom-producing tissues, tandem mass spectrometry-based proteomics of toxic secretions, and mass spectrometry imaging of proboscis sections, to shed light onto the composition and evolution of predatory and defensive toxic secretions in Antarctonemertes valida. Our analyses reveal a wide diversity of putative defensive and predatory toxins with tissue-specific gene expression patterns and restricted distributions to the mucus and proboscis proteomes respectively, suggesting that ribbon worms produce distinct toxin cocktails for predation and defense. Our results also highlight the presence of numerous lineage-specific toxins, indicating that venom evolution is highly divergent across nemerteans, producing toxin cocktails that might be finely tuned to subdue different prey. Our data also suggest that the hoplonemertean proboscis is a highly specialized predatory organ that seems to be involved in a variety of biological functions besides predation, including secretion and sensory perception. Overall, our results advance our knowledge into the diversity and evolution of nemertean venoms and highlight the importance of combining different types of data to characterize toxin composition in understudied venomous organisms.

• Eagles, David A.; Saez, Natalie J.; Krishnarjuna, Bankala; Bradford, Julia J.; Chin, Yanni K.-Y. & Starobova, Hana [Vis alle 14 forfattere av denne artikkelen] (2022). A peptide toxin in ant venom mimics vertebrate EGF-like hormones to cause long-lasting hypersensitivity in mammals. Proceedings of the National Academy of Sciences of the United States of America (PNAS). ISSN 0027-8424. 119(7). doi: 10.1073/pnas.2112630119. Fulltekst i vitenarkiv Vis sammendrag

  Venoms are excellent model systems for studying evolutionary processes associated with predator–prey interactions. Here, we present the discovery of a peptide toxin, MIITX2-Mg1a, which is a major component of the venom of the Australian giant red bull ant Myrmecia gulosa and has evolved to mimic, both structurally and functionally, vertebrate epidermal growth factor (EGF) peptide hormones. We show that Mg1a is a potent agonist of the mammalian EGF receptor ErbB1, and that intraplantar injection in mice causes long-lasting hypersensitivity of the injected paw. These data reveal a previously undescribed venom mode of action, highlight a role for ErbB receptors in mammalian pain signaling, and provide an example of molecular mimicry driven by defensive selection pressure.

• Nixon, Samantha A.; Robinson, Samuel D.; Agwa, Akello J.; Walker, Andrew A.; Choudhary, Shivani & Touchard, Axel [Vis alle 13 forfattere av denne artikkelen] (2021). Multipurpose peptides: The venoms of Amazonian stinging ants contain anthelmintic ponericins with diverse predatory and defensive activities. Biochemical Pharmacology. ISSN 0006-2952. 192, s. 1–16. doi: 10.1016/j.bcp.2021.114693. Fulltekst i vitenarkiv Vis sammendrag

  In the face of increasing drug resistance, the development of new anthelmintics is critical for controlling nematodes that parasitise livestock. Although hymenopteran venom toxins have attracted attention for applications in agriculture and medicine, few studies have explored their potential as anthelmintics. Here we assessed hymenopteran venoms as a possible source of new anthelmintic compounds by screening a panel of ten hymenopteran venoms against Haemonchus contortus, a major pathogenic nematode of ruminants. Using bioassay-guided fractionation coupled with liquid chromatography-tandem mass spectrometry, we identified four novel anthelmintic peptides (ponericins) from the venom of the neotropical ant Neoponera commutata and the previously described ponericin M−PONTX−Na1b from Neoponera apicalis venom. These peptides inhibit H. contortus development with IC50 values of 2.8–5.6 μM. Circular dichroism spectropolarimetry indicated that the ponericins are unstructured in aqueous solution but adopt α-helical conformations in lipid mimetic environments. We show that the ponericins induce non-specific membrane perturbation, which confers broad-spectrum antimicrobial, insecticidal, cytotoxic, hemolytic, and algogenic activities, with activity across all assays typically correlated. We also show for the first time that ponericins induce spontaneous pain behaviour when injected in mice. We propose that the broad-spectrum activity of the ponericins enables them to play both a predatory and defensive role in neoponeran ants, consistent with their high abundance in venom. This study reveals a broader functionality for ponericins than previously assumed, and highlights both the opportunities and challenges in pursuing ant venom peptides as potential therapeutics.

• Robinson, Samuel D.; Kambanis, Lucas; Clayton, Daniel; Hinneburg, Hannes; Corcilius, Leo & Mueller, Alexander [Vis alle 15 forfattere av denne artikkelen] (2021). A pain-causing and paralytic ant venom glycopeptide. iScience. 24(10), s. 1–21. doi: 10.1016/j.isci.2021.103175. Fulltekst i vitenarkiv Vis sammendrag

  Ants (Hymenoptera: Formicidae) are familiar inhabitants of most terrestrial environments. Although we are aware of the ability of many species to sting, knowledge of ant venom chemistry remains limited. Herein, we describe the discovery and characterization of an O-linked glycopeptide (Mg7a) as a major component of the venom of the ant Myrmecia gulosa. Electron transfer dissociation and higher-energy collisional dissociation tandem mass spectrometry were used to localize three α-N-acetylgalactosaminyl residues (α-GalNAc) present on the 63-residue peptide. To allow for functional studies, we synthesized the full-length glycosylated peptide via solid-phase peptide synthesis, combined with diselenide–selenoester ligation-deselenization chemistry. We show that Mg7a is paralytic and lethal to insects, and triggers pain behavior and inflammation in mammals, which it achieves through a membrane-targeting mode of action. Deglycosylation of Mg7a renders it insoluble in aqueous solution, suggesting a key solubilizing role of the O-glycans.

• Ashwood, Lauren M.; Mitchell, Michaela; Madio, Bruno; Hurwood, David A.; King, Glenn F. & Undheim, Eivind Andreas Baste [Vis alle 8 forfattere av denne artikkelen] (2021). Tentacle Morphological Variation Coincides with Differential Expression of Toxins in Sea Anemones. Toxins. 13(452). doi: 10.3390/toxins13070452. Fulltekst i vitenarkiv Vis sammendrag

  Phylum Cnidaria is an ancient venomous group defined by the presence of cnidae, specialised organelles that serve as venom delivery systems. The distribution of cnidae across the body plan is linked to regionalisation of venom production, with tissue-specific venom composition observed in multiple actiniarian species. In this study, we assess whether morphological variants of tentacles are associated with distinct toxin expression profiles and investigate the functional significance of specialised tentacular structures. Using five sea anemone species, we analysed differential expression of toxin-like transcripts and found that expression levels differ significantly across tentacular structures when substantial morphological variation is present. Therefore, the differential expression of toxin genes is associated with morphological variation of tentacular structures in a tissue-specific manner. Furthermore, the unique toxin profile of spherical tentacular structures in families Aliciidae and Thalassianthidae indicate that vesicles and nematospheres may function to protect branched structures that host a large number of photosynthetic symbionts. Thus, hosting zooxanthellae may account for the tentacle-specific toxin expression profiles observed in the current study. Overall, specialised tentacular structures serve unique ecological roles and, in order to fulfil their functions, they possess distinct venom cocktails.

• Modica, Maria Vittoria; Ahmad, Rafi; Ainsworth, Stuart; Anderluh, Gregor; Antunes, Agostinho & Beis, Dimitris [Vis alle 23 forfattere av denne artikkelen] (2021). The new COST Action European Venom Network (EUVEN)—synergy and future perspectives of modern venomics. GigaScience. 10(3), s. 1–5. doi: 10.1093/gigascience/giab019. Fulltekst i vitenarkiv Vis sammendrag

  Venom research is a highly multidisciplinary field that involves multiple subfields of biology, informatics, pharmacology, medicine, and other areas. These different research facets are often technologically challenging and pursued by different teams lacking connection with each other. This lack of coordination hampers the full development of venom investigation and applications. The COST Action CA19144–European Venom Network was recently launched to promote synergistic interactions among different stakeholders and foster venom research at the European level.

• Calvete, Juan J.; Lomonte, Bruno; Saviola, Anthony J.; Bonilla, Fabián; Sasa, Mahmood & Williams, David J. [Vis alle 9 forfattere av denne artikkelen] (2021). Mutual enlightenment: A toolbox of concepts and methods for integrating evolutionary and clinical toxinology via snake venomics and the contextual stance. Toxicon: X. 9-10, s. 1–16. doi: 10.1016/j.toxcx.2021.100070. Fulltekst i vitenarkiv Vis sammendrag

  Snakebite envenoming is a neglected tropical disease that may claim over 100,000 human lives annually worldwide. Snakebite occurs as the result of an interaction between a human and a snake that elicits either a defensive response from the snake or, more rarely, a feeding response as the result of mistaken identity. Snakebite envenoming is therefore a biological and, more specifically, an ecological problem. Snake venom itself is often described as a “cocktail”, as it is a heterogenous mixture of molecules including the toxins (which are typically proteinaceous) responsible for the pathophysiological consequences of envenoming. The primary function of venom in snake ecology is pre-subjugation, with defensive deployment of the secretion typically considered a secondary function. The particular composition of any given venom cocktail is shaped by evolutionary forces that include phylogenetic constraints associated with the snake's lineage and adaptive responses to the snake's ecological context, including the taxa it preys upon and by which it is predated upon. In the present article, we describe how conceptual frameworks from ecology and evolutionary biology can enter into a mutually enlightening relationship with clinical toxinology by enabling the consideration of snakebite envenoming from an “ecological stance”. We detail the insights that may emerge from such a perspective and highlight the ways in which the high-fidelity descriptive knowledge emerging from applications of -omics era technologies – “venomics” and “antivenomics” – can combine with evolutionary explanations to deliver a detailed understanding of this multifactorial health crisis.

• Ashwood, Lauren M.; Undheim, Eivind Andreas Baste; Madio, Bruno; Hamilton, Brett R.; Daly, Marymegan & Hurwood, David A. [Vis alle 8 forfattere av denne artikkelen] (2021). Venoms for all occasions: The functional toxin profiles of different anatomical regions in sea anemones are related to their ecological function. Molecular Ecology. ISSN 0962-1083. s. 1–18. doi: 10.1111/mec.16286. Fulltekst i vitenarkiv
• Undheim, Eivind Andreas Baste & Jenner, Ronald A. (2021). Phylogenetic analyses suggest centipede venom arsenals were repeatedly stocked by horizontal gene transfer. Nature Communications. 12(1), s. 1–14. doi: 10.1038/s41467-021-21093-8. Fulltekst i vitenarkiv Vis sammendrag

  Venoms have evolved over a hundred times in animals. Venom toxins are thought to evolve mostly by recruitment of endogenous proteins with physiological functions. Here we report phylogenetic analyses of venom proteome-annotated venom gland transcriptome data, assisted by genomic analyses, to show that centipede venoms have recruited at least five gene families from bacterial and fungal donors, involving at least eight horizontal gene transfer events. These results establish centipedes as currently the only known animals with venoms used in predation and defence that contain multiple gene families derived from horizontal gene transfer. The results also provide the first evidence for the implication of horizontal gene transfer in the evolutionary origin of venom in an animal lineage. Three of the bacterial gene families encode virulence factors, suggesting that horizontal gene transfer can provide a fast track channel for the evolution of novelty by the exaptation of bacterial weapons into animal venoms.

• Kazandjian, Taline D.; Petras, Daniel; Robinson, Samuel D.; Thiel, Jory van; Greene, Harry W. & Arbuckle, Kevin [Vis alle 29 forfattere av denne artikkelen] (2021). Convergent evolution of pain-inducing defensive venom components in spitting cobras. Science. ISSN 0036-8075. 371(6527), s. 386–390. doi: 10.1126/science.abb9303. Fulltekst i vitenarkiv Vis sammendrag

  Convergent evolution provides insights into the selective drivers underlying evolutionary change. Snake venoms, with a direct genetic basis and clearly defined functional phenotype, provide a model system for exploring the repeated evolution of adaptations. While snakes use venom primarily for predation, and venom composition often reflects diet specificity, three lineages of cobras have independently evolved the ability to spit venom at adversaries. Using gene, protein, and functional analyses, we show that the three spitting lineages possess venoms characterized by an up-regulation of phospholipase A2 (PLA2) toxins, which potentiate the action of preexisting venom cytotoxins to activate mammalian sensory neurons and cause enhanced pain. These repeated independent changes provide a fascinating example of convergent evolution across multiple phenotypic levels driven by selection for defense.

• Walker, Andrew A.; Robinson, Samuel D.; Hamilton, Brett F.; Undheim, Eivind Andreas Baste & King, Glenn F. (2020). Deadly Proteomes: A Practical Guide to Proteotranscriptomics of Animal Venoms. Proteomics. ISSN 1615-9853. 20(1900324). doi: 10.1002/pmic.201900324. Fulltekst i vitenarkiv
• Chow, Chun Yuen; Chin, Yanni K. Y.; Ma, Linlin; Undheim, Eivind Andreas Baste & Herzig, Volker (2020). A selective NaV1.1 activator with potential for treatment of Dravet syndrome epilepsy. Biochemical Pharmacology. ISSN 0006-2952. 181, s. 1–15. doi: 10.1016/j.bcp.2020.113991. Fulltekst i vitenarkiv
• Pineda, Sandy S.; Chin, Yanni K. Y.; Undheim, Eivind Andreas Baste; Senff, Sebastian; Mobli, Mehdi & Dauly, C. [Vis alle 13 forfattere av denne artikkelen] (2020). Structural venomics reveals evolution of a complex venom by duplication and diversification of an ancient peptide-encoding gene. Proceedings of the National Academy of Sciences of the United States of America (PNAS). ISSN 0027-8424. 117(21), s. 11399–11408. doi: 10.1073/pnas.1914536117. Fulltekst i vitenarkiv
• Aili, Samira R.; Touchard, Axel; Hayward, Regan; Robinson, Samuel D.; Pineda, Sandy S. & Lalagüe, Hadrien [Vis alle 14 forfattere av denne artikkelen] (2020). An integrated proteomic and transcriptomic analysis reveals the venom complexity of the bullet ant Paraponera clavata. Toxins. 12(5), s. 1–30. doi: 10.3390/toxins12050324. Fulltekst i vitenarkiv Vis sammendrag

  A critical hurdle in ant venom proteomic investigations is the lack of databases to comprehensively and specifically identify the sequence and function of venom proteins and peptides. To resolve this, we used venom gland transcriptomics to generate a sequence database that was used to assign the tandem mass spectrometry (MS) fragmentation spectra of venom peptides and proteins to specific transcripts. This was performed alongside a shotgun liquid chromatography–mass spectrometry (LC-MS/MS) analysis of the venom to confirm that these assigned transcripts were expressed as proteins. Through the combined transcriptomic and proteomic investigation of Paraponera clavata venom, we identified four times the number of proteins previously identified using 2D-PAGE alone. In addition to this, by mining the transcriptomic data, we identified several novel peptide sequences for future pharmacological investigations, some of which conform with inhibitor cysteine knot motifs. These types of peptides have the potential to be developed into pharmaceutical or bioinsecticide peptides.

• Ashwood, Lauren M.; Norton, Raymond S.; Undheim, Eivind Andreas Baste; Hurwood, David A. & Prentis, Peter J. (2020). Characterising functional venom profiles of anthozoans and medusozoans within their ecological context. Marine Drugs. 18(202), s. 1–19. doi: 10.3390/md18040202. Fulltekst i vitenarkiv Vis sammendrag

  This review examines the current state of knowledge regarding toxins from anthozoans (sea anemones, coral, zoanthids, corallimorphs, sea pens and tube anemones). We provide an overview of venom from phylum Cnidaria and review the diversity of venom composition between the two major clades (Medusozoa and Anthozoa). We highlight that the functional and ecological context of venom has implications for the temporal and spatial expression of protein and peptide toxins within class Anthozoa. Understanding the nuances in the regulation of venom arsenals has been made possible by recent advances in analytical technologies that allow characterisation of the spatial distributions of toxins. Furthermore, anthozoans are unique in that ecological roles can be assigned using tissue expression data, thereby circumventing some of the challenges related to pharmacological screening.

• Herzig, Volker; Sunagar, Kartik; Wilson, David T. R.; Pineda, Sandy S.; Israel, Mathilde R. & Dutertre, Sebastien [Vis alle 15 forfattere av denne artikkelen] (2020). Australian funnel-web spiders evolved human-lethal δ-hexatoxins for defense against vertebrate predators. Proceedings of the National Academy of Sciences of the United States of America (PNAS). ISSN 0027-8424. 117(40), s. 24920–24928. doi: 10.1073/pnas.2004516117. Fulltekst i vitenarkiv Vis sammendrag

  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, by profiling venom-gland transcriptomes of 10 funnel-web species, we report 22 δ-HXTXs. Phylogenetic and evolutionary assessments reveal a remarkable sequence conservation of δ-HXTXs despite their deep evolutionary origin within funnel-web spiders, consistent with a defensive role. We demonstrate that δ-HXTX-Ar1a, the lethal toxin from the Sydney funnel-web spider Atrax robustus , induces pain in mice by inhibiting inactivation of voltage-gated sodium (Na V ) channels involved in nociceptive signaling. δ-HXTX-Ar1a also inhibited inactivation of cockroach Na V channels and was insecticidal to sheep blowflies. Considering their algogenic effects in mice, potent insecticidal effects, and high levels of sequence conservation, we propose that the δ-HXTXs were repurposed from an initial insecticidal predatory function to a role in defending against nonhuman vertebrate predators by male spiders, with their lethal effects on humans being an unfortunate evolutionary coincidence.

• Schendel, Vanessa; Rash, Lachlan D.; Jenner, Ronald A. & Undheim, Eivind Andreas Baste (2019). The diversity of venom: The importance of behavior and venom system morphology in understanding its ecology and evolution. Toxins. 11(11), s. 1–22. doi: 10.3390/toxins11110666. Fulltekst i vitenarkiv Vis sammendrag

  Venoms are one of the most convergent of animal traits known, and encompass a much greater taxonomic and functional diversity than is commonly appreciated. This knowledge gap limits the potential of venom as a model trait in evolutionary biology. Here, we summarize the taxonomic and functional diversity of animal venoms and relate this to what is known about venom system morphology, venom modulation, and venom pharmacology, with the aim of drawing attention to the importance of these largely neglected aspects of venom research. We find that animals have evolved venoms at least 101 independent times and that venoms play at least 11 distinct ecological roles in addition to predation, defense, and feeding. Comparisons of different venom systems suggest that morphology strongly influences how venoms achieve these functions, and hence is an important consideration for understanding the molecular evolution of venoms and their toxins. Our findings also highlight the need for more holistic studies of venom systems and the toxins they contain. Greater knowledge of behavior, morphology, and ecologically relevant toxin pharmacology will improve our understanding of the evolution of venoms and their toxins, and likely facilitate exploration of their potential as sources of molecular tools and therapeutic and agrochemical lead compounds.

• Jenner, Ronald A.; Reumont, Bjoern M. von; Campbell, Lahcen I. & Undheim, Eivind Andreas Baste (2019). Parallel Evolution of Complex Centipede Venoms Revealed by Comparative Proteotranscriptomic Analyses. Molecular Biology and Evolution (MBE). ISSN 0737-4038. 36(12), s. 2748–2763. doi: 10.1093/molbev/msz181. Fulltekst i vitenarkiv Vis sammendrag

  Centipedes are among the most ancient groups of venomous predatory arthropods. Extant species belong to five orders, but our understanding of the composition and evolution of centipede venoms is based almost exclusively on one order, Scolopendromorpha. To gain a broader and less biased understanding we performed a comparative proteotranscriptomic analysis of centipede venoms from all five orders, including the first venom profiles for the orders Lithobiomorpha, Craterostigmomorpha, and Geophilomorpha. Our results reveal an astonishing structural diversity of venom components, with 93 phylogenetically distinct protein and peptide families. Proteomically-annotated gene trees of these putative toxin families show that centipede venom composition is highly dynamic across macroevolutionary timescales, with numerous gene duplications as well as functional recruitments and losses of toxin gene families. Strikingly, not a single family is found in the venoms of representatives of all five orders, with 67 families being unique for single orders. Ancestral state reconstructions reveal that centipede venom originated as a simple cocktail comprising just four toxin families, with very little compositional evolution happening during the approximately 50 My before the living orders had diverged. Venom complexity then increased in parallel within the orders, with scolopendromorphs evolving particularly complex venoms. Our results show that even venoms composed of toxins evolving under the strong constraint of negative selection can have striking evolutionary plasticity on the compositional level. We show that the functional recruitments and losses of toxin families that shape centipede venom arsenals are not concentrated early in their evolutionary history, but happen frequently throughout.

• Drukewitz, Stephan H.; Bokelmann, Lukas; Undheim, Eivind Andreas Baste & Reumont, Bjorn M von (2019). Toxins from scratch? Diverse, multimodal gene origins in the predatory robber fly Dasypogon diadema indicate a dynamic venom evolution in dipteran insects. GigaScience. 8(7), s. 1–13. doi: 10.1093/gigascience/giz081. Fulltekst i vitenarkiv Vis sammendrag

  Venoms and the toxins they contain represent molecular adaptations that have evolved on numerous occasions throughout the animal kingdom. However, the processes that shape venom protein evolution are poorly understood because of the scarcity of whole-genome data available for comparative analyses of venomous species. We performed a broad comparative toxicogenomic analysis to gain insight into the genomic mechanisms of venom evolution in robber flies (Asilidae). We first sequenced a high-quality draft genome of the hymenopteran hunting robber fly Dasypogon diadema, analysed its venom by a combined proteotranscriptomic approach, and compared our results with recently described robber fly venoms to assess the general composition and major components of asilid venom. We then applied a comparative genomics approach, based on 1 additional asilid genome, 10 high-quality dipteran genomes, and 2 lepidopteran outgroup genomes, to reveal the evolutionary mechanisms and origins of identified venom proteins in robber flies. While homologues were identified for 15 of 30 predominant venom protein in the non-asilid genomes, the remaining 15 highly expressed venom proteins appear to be unique to robber flies. Our results reveal that the venom of D. diadema likely evolves in a multimodal fashion comprising (i) neofunctionalization after gene duplication, (ii) expression-dependent co-option of proteins, and (iii) asilid lineage-specific orphan genes with enigmatic origin. The role of such orphan genes is currently being disputed in evolutionary genomics but has not been discussed in the context of toxin evolution. Our results display an unexpected dynamic venom evolution in asilid insects, which contrasts the findings of the only other insect toxicogenomic evolutionary analysis, in parasitoid wasps (Hymenoptera), where toxin evolution is dominated by single gene co-option. These findings underpin the significance of further genomic studies to cover more neglected lineages of venomous taxa and to understand the importance of orphan genes as possible drivers for venom evolution.

• Casewell, Nicholas R; Petras, Daniel; Card, Daren C; Suranse, Vivek; Mychajliw, Alexis M. & Richards, David [Vis alle 33 forfattere av denne artikkelen] (2019). Solenodon genome reveals convergent evolution of venom in eulipotyphlan mammals. Proceedings of the National Academy of Sciences of the United States of America (PNAS). ISSN 0027-8424. 116(51), s. 25745–25755. doi: 10.1073/pnas.1906117116. Fulltekst i vitenarkiv Vis sammendrag

  Venom systems are key adaptations that have evolved throughout the tree of life and typically facilitate predation or defense. Despite venoms being model systems for studying a variety of evolutionary and physiological processes, many taxonomic groups remain understudied, including venomous mammals. Within the order Eulipotyphla, multiple shrew species and solenodons have oral venom systems. Despite morphological variation of their delivery systems, it remains unclear whether venom represents the ancestral state in this group or is the result of multiple independent origins. We investigated the origin and evolution of venom in eulipotyphlans by characterizing the venom system of the endangered Hispaniolan solenodon (Solenodon paradoxus). We constructed a genome to underpin proteomic identifications of solenodon venom toxins, before undertaking evolutionary analyses of those constituents, and functional assessments of the secreted venom. Our findings show that solenodon venom consists of multiple paralogous kallikrein 1 (KLK1) serine proteases, which cause hypotensive effects in vivo, and seem likely to have evolved to facilitate vertebrate prey capture. Comparative analyses provide convincing evidence that the oral venom systems of solenodons and shrews have evolved convergently, with the 4 independent origins of venom in eulipotyphlans outnumbering all other venom origins in mammals. We find thatKLK1s have been independently coopted into the venom of shrews and solenodons following their divergence during the late Cretaceous, suggesting that evolutionary constraints may be acting on these genes. Consequently, our findings represent a striking example of convergent molecular evolution and demonstrate that distinct structural backgrounds can yield equivalent functions.

• Walker, Andrew A.; Robinson, Samuel D.; Undheim, Eivind Andreas Baste; Jin, Jiayi; Han, Xiao & Fry, Bryan G. [Vis alle 8 forfattere av denne artikkelen] (2019). Missiles of mass disruption: Composition and glandular origin of venom used as a projectile defensive weapon by the assassin bug Platymeris rhadamanthus. Toxins. 11(11), s. 1–21. doi: 10.3390/toxins11110673. Fulltekst i vitenarkiv Vis sammendrag

  Assassin bugs (Reduviidae) produce venoms that are insecticidal, and which induce pain in predators, but the composition and function of their individual venom components is poorly understood. We report findings on the venom system of the red-spotted assassin bug Platymeris rhadamanthus, a large species of African origin that is unique in propelling venom as a projectile weapon when threatened. We performed RNA sequencing experiments on venom glands (separate transcriptomes of the posterior main gland, PMG, and the anterior main gland, AMG), and proteomic experiments on venom that was either defensively propelled or collected from the proboscis in response to electrostimulation. We resolved a venom proteome comprising 166 polypeptides. Both defensively propelled venom and most venom samples collected in response to electrostimulation show a protein profile similar to the predicted secretory products of the PMG, with a smaller contribution from the AMG. Pooled venom samples induce calcium influx via membrane lysis when applied to mammalian neuronal cells, consistent with their ability to cause pain when propelled into the eyes or mucus membranes of potential predators. The same venom induces rapid paralysis and death when injected into fruit flies. These data suggest that the cytolytic, insecticidal venom used by reduviids to capture prey is also a highly effective defensive weapon when propelled at predators.

• Chen, Xingchen; Leahy, Darren; Haeften, Jessica Van; Hartfield, Perry; Prentis, Peter J. & Burg, Chloé van der [Vis alle 14 forfattere av denne artikkelen] (2019). A Versatile and Robust Serine Protease Inhibitor Scaffold from Actinia tenebrosa. Marine Drugs. 17(701), s. 1–21. doi: 10.3390/md17120701. Fulltekst i vitenarkiv Vis sammendrag

  Serine proteases play pivotal roles in normal physiology and a spectrum of patho-physiological processes. Accordingly, there is considerable interest in the discovery and design of potent serine protease inhibitors for therapeutic applications. This led to concerted efforts to discover versatile and robust molecular scaffolds for inhibitor design. This investigation is a bioprospecting study that aims to isolate and identify protease inhibitors from the cnidarian Actinia tenebrosa. The study isolated two Kunitz-type protease inhibitors with very similar sequences but quite divergent inhibitory potencies when assayed against bovine trypsin, chymostrypsin, and a selection of human sequence-related peptidases. Homology modeling and molecular dynamics simulations of these inhibitors in complex with their targets were carried out and, collectively, these methodologies enabled the definition of a versatile scaffold for inhibitor design. Thermal denaturation studies showed that the inhibitors were remarkably robust. To gain a fine-grained map of the residues responsible for this stability, we conducted in silico alanine scanning and quantified individual residue contributions to the inhibitor’s stability. Sequences of these inhibitors were then used to search for Kunitz homologs in an A. tenebrosa transcriptome library, resulting in the discovery of a further 14 related sequences. Consensus analysis of these variants identified a rich molecular diversity of Kunitz domains and expanded the palette of potential residue substitutions for rational inhibitor design using this domain.

• Hamilton, Brett R.; Marshall, David L.; Casewell, Nicholas R.; Harrison, Robert A.; Blanksby, Stephen J. & Undheim, Eivind Andreas Baste (2019). Mapping enzyme activity on tissue by functional mass spectrometry imaging. Angewandte Chemie International Edition. ISSN 1433-7851. 59, s. 3855–3858. doi: 10.1002/anie.201911390. Fulltekst i vitenarkiv Vis sammendrag

  Enzymes are central components of most physiological processes, and are consequently implicated in various pathologies. High‐resolution maps of enzyme activity within tissues therefore represent powerful tools for elucidating enzymatic functions in health and disease. Here, we present a novel mass spectrometry imaging (MSI) method for assaying the spatial distribution of enzymatic activity directly from tissue. MSI analysis of tissue sections exposed to phospholipid substrates produced high‐resolution maps of phospholipase activity and specificity, which could subsequently be compared to histological images of the same section. Functional MSI thus represents a new and generalisable method for imaging biological activity in situ.

• Madio, Bruno; King, Glenn F. & Undheim, Eivind Andreas Baste (2019). Sea anemone toxins: A structural overview. Marine Drugs. 17(6), s. 1–26. doi: 10.3390/md17060325. Fulltekst i vitenarkiv Vis sammendrag

  Sea anemones produce venoms of exceptional molecular diversity, with at least 17 different molecular scaffolds reported to date. These venom components have traditionally been classified according to pharmacological activity and amino acid sequence. However, this classification system suffers from vulnerabilities due to functional convergence and functional promiscuity. Furthermore, for most known sea anemone toxins, the exact receptors they target are either unknown, or at best incomplete. In this review, we first provide an overview of the sea anemone venom system and then focus on the venom components. We have organised the venom components by distinguishing firstly between proteins and non-proteinaceous compounds, secondly between enzymes and other proteins without enzymatic activity, then according to the structural scaffold, and finally according to molecular target.

• Richter, Sandy; Helm, Conrad; Meunier, Frederic A.; Hering, Lars; Campbell, Lahcen I. & Drukewitz, Stephan H. [Vis alle 10 forfattere av denne artikkelen] (2017). Comparative analyses of glycerotoxin expression unveil a novel structural organization of the bloodworm venom system. BMC Evolutionary Biology. 17:64, s. 1–19. doi: 10.1186/s12862-017-0904-4. Fulltekst i vitenarkiv
• Undheim, Eivind Andreas Baste; Georgieva, DN; Thoen, Hanne Halkinrud; Norman, JA; Mork, Jarle & Betzel, C [Vis alle 7 forfattere av denne artikkelen] (2010). Venom on ice: First insights into Antarctic octopus venoms. Toxicon. ISSN 0041-0101. 56(6), s. 897–913. doi: 10.1016/j.toxicon.2010.06.013. Fulltekst i vitenarkiv
• Undheim, Eivind Andreas Baste; Norman, JA; Thoen, Hanne Halkinrud & Fry, BG (2010). Genetic identification of Southern Ocean octopod samples using mtCOI. Comptes rendus. Biologies. ISSN 1631-0691. 333(5), s. 395–404. doi: 10.1016/j.crvi.2010.02.002. Fulltekst i vitenarkiv
• Trembath, Dane F; Fearn, Simon & Undheim, Eivind Andreas Baste (2009). Natural history of the slaty grey snake (Stegonotus cucullatus) (Serpentes : Colubridae) from tropical north Queensland, Australia. Australian journal of zoology (Print). ISSN 0004-959X. 57(2), s. 119–124. doi: 10.1071/ZO08091. Fulltekst i vitenarkiv

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• Jenner, Ronald A.; Casewell, Nicholas R. & Undheim, Eivind Andreas Baste (2025). Venom versus poison: delivery mode matters. Trends in Ecology & Evolution. ISSN 0169-5347. 40(11), s. 1047–1047. doi: 10.1016/j.tree.2025.09.019. Fulltekst i vitenarkiv
• Gruber, Christian W.; Beets, Isabel; Boudreault, Pierre‐Luc; Bolzani, Vanderlan da S.; Carlsson, Jens & Fernandes, Pedro A. [Vis alle 17 forfattere av denne artikkelen] (2025). Biodiversity2Drugs—Renaissance of exploring nature‐derived peptides for GPCR ligand discovery. British Journal of Pharmacology. ISSN 0007-1188. 182(16), s. 3694–3694. doi: 10.1111/bph.70072. Fulltekst i vitenarkiv
• Modica, Maria Vittoria; Ahmad, Rafi; Ainsworth, Stuart; Anderluh, Gregor; Antunes, Agostinho & Beis, Dimitris [Vis alle 23 forfattere av denne artikkelen] (2021). Corrigendum to: The new COST Action European Venom Network (EUVEN)-synergy and future perspectives of modern venomics. GigaScience. 10(12). doi: 10.1093/gigascience/giab102. Fulltekst i vitenarkiv
• Hamilton, Brett R.; Schendel, Vanessa; Undheim, Eivind Andreas Baste; Oetjen, Janina; Ly, Alice & Wepf, Roger A. (2020). Imaging venom peptides and proteins at high mass resolution, high lateral resolution and high speed using the timsTOF fleX. bruker.com. s. 1–6. Fulltekst i vitenarkiv
• Utkin, Yuri; Vassilevski, Alexander; Kudryavtsev, Denis & Undheim, Eivind Andreas Baste (2019). Editorial: Animal toxins as comprehensive pharmacological tools to identify diverse ion channels. Frontiers in Pharmacology. 10. doi: 10.3389/fphar.2019.00423. Fulltekst i vitenarkiv

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