Publications by authors named "Yehu Moran"

45 Publications

Transposons Increase Transcriptional Complexity: The Good Parasite?

Trends Genet 2021 Apr 12. Epub 2021 Apr 12.

Department of Ecology, Evolution and Behavior, Alexander Silberman Institute of Life Sciences, Faculty of Science, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel. Electronic address:

A recent study by Cosby et al. sheds light on the role of transposons in the adaptive evolution of their hosts. These genetic elements were thought to be largely deleterious. However, when coupled with alternative splicing, there appears to be an exponential increase in the diversity of proteins encoded, which display novel functions and are conserved by natural selection.
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http://dx.doi.org/10.1016/j.tig.2021.03.009DOI Listing
April 2021

The new COST Action European Venom Network (EUVEN)-synergy and future perspectives of modern venomics.

Gigascience 2021 Mar;10(3)

Department of Ecology and Evolution, University of Lausanne, UNIL Sorge Le Biophore, CH - 1015 Lausanne, Switzerland.

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.
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http://dx.doi.org/10.1093/gigascience/giab019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992391PMC
March 2021

Conservation and turnover of miRNAs and their highly complementary targets in early branching animals.

Proc Biol Sci 2021 Feb 24;288(1945):20203169. Epub 2021 Feb 24.

Department of Neurosciences and Developmental Biology; Faculty of Life Sciences, University of Vienna, Vienna, Austria.

MicroRNAs (miRNAs) are crucial post-transcriptional regulators that have been extensively studied in Bilateria, a group comprising the majority of extant animals, where more than 30 conserved miRNA families have been identified. By contrast, bilaterian miRNA targets are largely not conserved. Cnidaria is the sister group to Bilateria and thus provides a unique opportunity for comparative studies. Strikingly, like their plant counterparts, cnidarian miRNAs have been shown to predominantly have highly complementary targets leading to transcript cleavage by Argonaute proteins. Here, we assess the conservation of miRNAs and their targets by small RNA sequencing followed by miRNA target prediction in eight species of Anthozoa (sea anemones and corals), the earliest-branching cnidarian class. We uncover dozens of novel miRNAs but only a few conserved ones. Further, given their high complementarity, we were able to computationally identify miRNA targets in each species. Besides evidence for conservation of specific miRNA target sites, which are maintained between sea anemones and stony corals across 500 Myr of evolution, we also find indications for convergent evolution of target regulation by different miRNAs. Our data indicate that cnidarians have only few conserved miRNAs and corresponding targets, despite their high complementarity, suggesting a high evolutionary turnover.
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http://dx.doi.org/10.1098/rspb.2020.3169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935066PMC
February 2021

Insights into how development and life-history dynamics shape the evolution of venom.

Evodevo 2021 Jan 7;12(1). Epub 2021 Jan 7.

Department of Ecology, Evolution and Behavior, Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, 9190401, Jerusalem, Israel.

Venomous animals are a striking example of the convergent evolution of a complex trait. These animals have independently evolved an apparatus that synthesizes, stores, and secretes a mixture of toxic compounds to the target animal through the infliction of a wound. Among these distantly related animals, some can modulate and compartmentalize functionally distinct venoms related to predation and defense. A process to separate distinct venoms can occur within and across complex life cycles as well as more streamlined ontogenies, depending on their life-history requirements. Moreover, the morphological and cellular complexity of the venom apparatus likely facilitates the functional diversity of venom deployed within a given life stage. Intersexual variation of venoms has also evolved further contributing to the massive diversity of toxic compounds characterized in these animals. These changes in the biochemical phenotype of venom can directly affect the fitness of these animals, having important implications in their diet, behavior, and mating biology. In this review, we explore the current literature that is unraveling the temporal dynamics of the venom system that are required by these animals to meet their ecological functions. These recent findings have important consequences in understanding the evolution and development of a convergent complex trait and its organismal and ecological implications.
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http://dx.doi.org/10.1186/s13227-020-00171-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791878PMC
January 2021

Unravelling the developmental and functional significance of an ancient Argonaute duplication.

Nat Commun 2020 12 3;11(1):6187. Epub 2020 Dec 3.

Department of Ecology, Evolution and Behavior, Alexander Silberman Institute of Life Sciences, Faculty of Science, The Hebrew University of Jerusalem, 9190401, Jerusalem, Israel.

MicroRNAs (miRNAs) base-pair to messenger RNA targets and guide Argonaute proteins to mediate their silencing. This target regulation is considered crucial for animal physiology and development. However, this notion is based exclusively on studies in bilaterians, which comprise almost all lab model animals. To fill this phylogenetic gap, we characterize the functions of two Argonaute paralogs in the sea anemone Nematostella vectensis of the phylum Cnidaria, which is separated from bilaterians by ~600 million years. Using genetic manipulations, Argonaute-immunoprecipitations and high-throughput sequencing, we provide experimental evidence for the developmental importance of miRNAs in a non-bilaterian animal. Additionally, we uncover unexpected differential distribution of distinct miRNAs between the two Argonautes and the ability of one of them to load additional types of small RNAs. This enables us to postulate a novel model for evolution of miRNA precursors in sea anemones and their relatives, revealing alternative trajectories for metazoan miRNA evolution.
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http://dx.doi.org/10.1038/s41467-020-20003-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713132PMC
December 2020

Toxin-like neuropeptides in the sea anemone unravel recruitment from the nervous system to venom.

Proc Natl Acad Sci U S A 2020 11 15;117(44):27481-27492. Epub 2020 Oct 15.

Department of Ecology, Evolution, and Behavior, Alexander Silberman Institute of Life Sciences, Faculty of Science, Hebrew University of Jerusalem, 9190401 Jerusalem, Israel;

The sea anemone (Anthozoa, Cnidaria) is a powerful model for characterizing the evolution of genes functioning in venom and nervous systems. Although venom has evolved independently numerous times in animals, the evolutionary origin of many toxins remains unknown. In this work, we pinpoint an ancestral gene giving rise to a new toxin and functionally characterize both genes in the same species. Thus, we report a case of protein recruitment from the cnidarian nervous to venom system. The ShK-like1 peptide has a ShKT cysteine motif, is lethal for fish larvae and packaged into nematocysts, the cnidarian venom-producing stinging capsules. Thus, ShK-like1 is a toxic venom component. Its paralog, ShK-like2, is a neuropeptide localized to neurons and is involved in development. Both peptides exhibit similarities in their functional activities: They provoke contraction in polyps and are toxic to fish. Because ShK-like2 but not ShK-like1 is conserved throughout sea anemone phylogeny, we conclude that the two paralogs originated due to a -specific duplication of a ShK-like2 ancestor, a neuropeptide-encoding gene, followed by diversification and partial functional specialization. ShK-like2 is represented by two gene isoforms controlled by alternative promoters conferring regulatory flexibility throughout development. Additionally, we characterized the expression patterns of four other peptides with structural similarities to studied venom components and revealed their unexpected neuronal localization. Thus, we employed genomics, transcriptomics, and functional approaches to reveal one venom component, five neuropeptides with two different cysteine motifs, and an evolutionary pathway from nervous to venom system in Cnidaria.
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http://dx.doi.org/10.1073/pnas.2011120117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959521PMC
November 2020

TATA Binding Protein (TBP) Promoter Drives Ubiquitous Expression of Marker Transgene in the Adult Sea Anemone .

Genes (Basel) 2020 09 16;11(9). Epub 2020 Sep 16.

Department of Ecology, Evolution and Behavior, Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel.

has emerged as one as the most established models of the phylum Cnidaria (sea anemones, corals, hydroids and jellyfish) for studying animal evolution. The availability of a reference genome and the relative ease of culturing and genetically manipulating this organism make it an attractive model for addressing questions regarding the evolution of venom, development, regeneration and other interesting understudied questions. We and others have previously reported the use of tissue-specific promoters for investigating the function of a tissue or a cell type of interest in vivo. However, to our knowledge, genetic regulators at the whole organism level have not been reported yet. Here we report the identification and utilization of a ubiquitous promoter to drive a wide and robust expression of the fluorescent protein mCherry. We generated animals containing a TATA binding protein (TBP) promoter upstream of the mCherry gene. Flow cytometry and fluorescent microscopy revealed expression of mCherry in diverse cell types, accounting for more than 90% of adult animal cells. Furthermore, we detected a stable mCherry expression at different life stages and throughout generations. This tool will expand the existing experimental toolbox to facilitate genetic engineering and functional studies at the whole organism level.
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http://dx.doi.org/10.3390/genes11091081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565589PMC
September 2020

Some like it hot: population-specific adaptations in venom production to abiotic stressors in a widely distributed cnidarian.

BMC Biol 2020 09 9;18(1):121. Epub 2020 Sep 9.

Department of Ecology, Evolution and Behavior, Alexander Silberman Institute of Life Sciences, Faculty of Science, The Hebrew University of Jerusalem, Jerusalem, Israel.

Background: In cnidarians, antagonistic interactions with predators and prey are mediated by their venom, whose synthesis may be metabolically expensive. The potentially high cost of venom production has been hypothesized to drive population-specific variation in venom expression due to differences in abiotic conditions. However, the effects of environmental factors on venom production have been rarely demonstrated in animals. Here, we explore the impact of specific abiotic stresses on venom production of distinct populations of the sea anemone Nematostella vectensis (Actiniaria, Cnidaria) inhabiting estuaries over a broad geographic range where environmental conditions such as temperatures and salinity vary widely.

Results: We challenged Nematostella polyps with heat, salinity, UV light stressors, and a combination of all three factors to determine how abiotic stressors impact toxin expression for individuals collected across this species' range. Transcriptomics and proteomics revealed that the highly abundant toxin Nv1 was the most downregulated gene under heat stress conditions in multiple populations. Physiological measurements demonstrated that venom is metabolically costly to produce. Strikingly, under a range of abiotic stressors, individuals from different geographic locations along this latitudinal cline modulate differently their venom production levels.

Conclusions: We demonstrate that abiotic stress results in venom regulation in Nematostella. Together with anecdotal observations from other cnidarian species, our results suggest this might be a universal phenomenon in Cnidaria. The decrease in venom production under stress conditions across species coupled with the evidence for its high metabolic cost in Nematostella suggests downregulation of venom production under certain conditions may be highly advantageous and adaptive. Furthermore, our results point towards local adaptation of this mechanism in Nematostella populations along a latitudinal cline, possibly resulting from distinct genetics and significant environmental differences between their habitats.
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http://dx.doi.org/10.1186/s12915-020-00855-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488265PMC
September 2020

The emerging field of venom-microbiomics for exploring venom as a microenvironment, and the corresponding Initiative for Venom Associated Microbes and Parasites (iVAMP).

Toxicon X 2019 Oct 20;4:100016. Epub 2019 Sep 20.

Department of Biological Science, Florida State University, Tallahassee, FL 32306, USA.

Venom is a known source of novel antimicrobial natural products. The substantial, increasing number of these discoveries have unintentionally culminated in the misconception that venom and venom-producing glands are largely sterile environments. Culture-dependent and -independent studies on the microbial communities in venom microenvironments reveal the presence of archaea, algae, bacteria, fungi, protozoa, and viruses. Venom-centric microbiome studies are relatively sparse to date with the adaptive advantages that venom-associated microbes might offer to their hosts, or that hosts might provide to venom-associated microbes, remaining largely unknown. We highlight the potential for the discovery of venom microbiomes within the adaptive landscape of venom systems. The considerable number of convergently evolved venomous animals, juxtaposed with the comparatively few known studies to identify microbial communities in venom, provides new possibilities for both biodiversity and therapeutic discoveries. We present an evidence-based argument for integrating microbiology as part of venomics (i.e., venom-microbiomics) and introduce iVAMP, the Initiative for Venom Associated Microbes and Parasites (https://ivamp-consortium.github.io/), as a growing collaborative consortium. We express commitment to the diversity, inclusion and scientific collaboration among researchers interested in this emerging subdiscipline through expansion of the iVAMP consortium.
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http://dx.doi.org/10.1016/j.toxcx.2019.100016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286055PMC
October 2019

NvPOU4/Brain3 Functions as a Terminal Selector Gene in the Nervous System of the Cnidarian Nematostella vectensis.

Cell Rep 2020 03;30(13):4473-4489.e5

Sars International Centre for Marine Molecular Biology, University of Bergen, 5006 Bergen, Norway; Department for Biological Sciences, University of Bergen, 5006 Bergen, Norway. Electronic address:

Terminal selectors are transcription factors that control the morphological, physiological, and molecular features that characterize distinct cell types. Here, we show that, in the sea anemone Nematostella vectensis, NvPOU4 is expressed in post-mitotic cells that give rise to a diverse set of neural cell types, including cnidocytes and NvElav1-expressing neurons. Morphological analyses of NvPOU4 mutants crossed to transgenic reporter lines show that the loss of NvPOU4 does not affect the initial specification of neural cells. Transcriptomes derived from the mutants and from different neural cell populations reveal that NvPOU4 is required for the execution of the terminal differentiation program of these neural cells. These findings suggest that POU4 genes have ancient functions as terminal selectors for morphologically and functionally disparate types of neurons and they provide experimental support for the relevance of terminal selectors for understanding the evolution of cell types.
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http://dx.doi.org/10.1016/j.celrep.2020.03.031DOI Listing
March 2020

Initial Virome Characterization of the Common Cnidarian Lab Model .

Viruses 2020 02 15;12(2). Epub 2020 Feb 15.

Department of Ecology, Evolution and Behavior, Alexander Silberman Institute of Life Sciences, Faculty of Science, The Hebrew University of Jerusalem, Jerusalem 9190401, Israel.

The role of viruses in forming a stable holobiont has been the subject of extensive research in recent years. However, many emerging model organisms still lack any data on the composition of the associated viral communities. Here, we re-analyzed seven publicly available transcriptome datasets of the starlet sea anemone , the most commonly used anthozoan lab model, and searched for viral sequences. We applied a straightforward, yet powerful approach of de novo assembly followed by homology-based virus identification and a multi-step, thorough taxonomic validation. The comparison of different lab populations of revealed the existence of the core virome composed of 21 viral sequences, present in all adult datasets. Unexpectedly, we observed an almost complete lack of viruses in the samples from the early developmental stages, which together with the identification of the viruses shared with the major source of the food in the lab, the brine shrimp , shed new light on the course of viral species acquisition in . Our study provides an initial, yet comprehensive insight into virome and sets the first foundation for the functional studies of viruses and antiviral systems in this lab model cnidarian.
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http://dx.doi.org/10.3390/v12020218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7077227PMC
February 2020

The Birth and Death of Toxins with Distinct Functions: A Case Study in the Sea Anemone Nematostella.

Mol Biol Evol 2019 09;36(9):2001-2012

Department of Ecology, Evolution and Behavior, Alexander Silberman Institute of Life Sciences, Faculty of Science, The Hebrew University of Jerusalem, Jerusalem, Israel.

The cnidarian Nematostella vectensis has become an established lab model, providing unique opportunities for venom evolution research. The Nematostella venom system is multimodal: involving both nematocytes and ectodermal gland cells, which produce a toxin mixture whose composition changes throughout the life cycle. Additionally, their modes of interaction with predators and prey vary between eggs, larvae, and adults, which is likely shaped by the dynamics of the venom system. Nv1 is a major component of adult venom, with activity against arthropods (through specific inhibition of sodium channel inactivation) and fish. Nv1 is encoded by a cluster of at least 12 nearly identical genes that were proposed to be undergoing concerted evolution. Surprisingly, we found that Nematostella venom includes several Nv1 paralogs escaping a pattern of general concerted evolution, despite belonging to the Nv1-like family. Here, we show two of these new toxins, Nv4 and Nv5, are lethal for zebrafish larvae but harmless to arthropods, unlike Nv1. Furthermore, unlike Nv1, the newly identified toxins are expressed in early life stages. Using transgenesis and immunostaining, we demonstrate that Nv4 and Nv5 are localized to ectodermal gland cells in larvae. The evolution of Nv4 and Nv5 can be described either as neofunctionalization or as subfunctionalization. Additionally, the Nv1-like family includes several pseudogenes being an example of nonfunctionalization and venom evolution through birth-and-death mechanism. Our findings reveal the evolutionary history for a toxin radiation and point toward the ecological function of the novel toxins constituting a complex cnidarian venom.
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http://dx.doi.org/10.1093/molbev/msz132DOI Listing
September 2019

Too Many False Targets for MicroRNAs: Challenges and Pitfalls in Prediction of miRNA Targets and Their Gene Ontology in Model and Non-model Organisms.

Bioessays 2019 04;41(4):e1800169

Department of Ecology, Evolution and Behavior, Alexander Silberman Institute of Life Sciences, Faculty of Science, The Hebrew University of Jerusalem, 9190401, Jerusalem, Israel.

Short ("seed") or extended base pairing between microRNAs (miRNAs) and their target RNAs enables post-transcriptional silencing in many organisms. These interactions allow the computational prediction of potential targets. In model organisms, predicted targets are frequently validated experimentally; hence meaningful miRNA-regulated processes are reported. However, in non-models, these reports mostly rely on computational prediction alone. Many times, further bioinformatic analyses such as Gene Ontology (GO) enrichment are based on these in silico projections. Here such approaches are reviewed, their caveats are highlighted and the ease of picking false targets from predicted lists is demonstrated. Discoveries that shed new light on how miRNAs evolved to regulate targets in various phyletic groups are discussed, in addition to the pitfalls of target identification in non-model organisms. The goal is to prevent the misuse of bioinformatic tools, as they cannot bypass the biological understanding of miRNA-target regulation.
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http://dx.doi.org/10.1002/bies.201800169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6701991PMC
April 2019

Cell type-specific expression profiling unravels the development and evolution of stinging cells in sea anemone.

BMC Biol 2018 09 27;16(1):108. Epub 2018 Sep 27.

Department of Ecology, Evolution and Behavior, Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, 9190401, Jerusalem, Israel.

Background: Cnidocytes are specialized cells that define the phylum Cnidaria. They possess an "explosive" organelle called cnidocyst that is important for prey capture and anti-predator defense. An extraordinary morphological and functional complexity of the cnidocysts has inspired numerous studies to investigate their structure and development. However, the transcriptomes of the cells bearing these unique organelles are yet to be characterized, impeding our understanding of the genetic basis of their biogenesis.

Results: In this study, we generated a nematocyte reporter transgenic line of the sea anemone Nematostella vectensis using the CRISPR/Cas9 system. By using a fluorescence-activated cell sorter (FACS), we have characterized cell type-specific transcriptomic profiles of various stages of cnidocyte maturation and showed that nematogenesis (the formation of functional cnidocysts) is underpinned by dramatic shifts in the spatiotemporal gene expression. Among the genes identified as upregulated in cnidocytes were Cnido-Jun and Cnido-Fos1-cnidarian-specific paralogs of the highly conserved c-Jun and c-Fos proteins of the stress-induced AP-1 transcriptional complex. The knockdown of the cnidocyte-specific c-Jun homolog by microinjection of morpholino antisense oligomer results in disruption of normal nematogenesis.

Conclusions: Here, we show that the majority of upregulated genes and enriched biochemical pathways specific to cnidocytes are uncharacterized, emphasizing the need for further functional research on nematogenesis. The recruitment of the metazoan stress-related transcription factor c-Fos/c-Jun complex into nematogenesis highlights the evolutionary ingenuity and novelty associated with the formation of these highly complex, enigmatic, and phyletically unique organelles. Thus, we provide novel insights into the biology, development, and evolution of cnidocytes.
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http://dx.doi.org/10.1186/s12915-018-0578-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6161364PMC
September 2018

The methyltransferase HEN1 is required in Nematostella vectensis for microRNA and piRNA stability as well as larval metamorphosis.

PLoS Genet 2018 08 17;14(8):e1007590. Epub 2018 Aug 17.

Department of Ecology, Evolution and Behavior, Alexander Silberman Institute of Life Sciences, Faculty of Science, The Hebrew University of Jerusalem, Jerusalem, Israel.

Small non-coding RNAs (sRNAs) such as microRNAs (miRNAs), small interfering RNAs (siRNAs) and piwi-interacting RNAs (piRNAs) regulate the levels of endogenous, viral and transposable element RNA in plants (excluding piRNAs) and animals. These pathways are explored mainly in bilaterian animals, such as vertebrates, arthropods and nematodes, where siRNAs and piRNAs, but not miRNAs bind their targets with a perfect match and mediate the cleavage of the target RNA. Methylation of the 3' ends of piRNAs and siRNAs by the methyltransferase HEN1 protects these sRNAs from degradation. There is a noticeable selection in bilaterian animals against miRNA-mRNA perfect matching, as it leads to the degradation of miRNAs. Cnidarians (sea anemones, corals, hydroids and jellyfish), are separated from bilaterians by more than 600 million years. As opposed to bilaterians, cnidarian miRNAs frequently bind their targets with a nearly perfect match. Knowing that an ortholog of HEN1 is widely expressed in the sea anemone Nematostella vectensis, we tested in this work whether it mediates the stabilization of its sRNAs. We show that the knockdown of HEN1 in Nematostella results in a developmental arrest. Small RNA sequencing revealed that the levels of both miRNAs and piRNAs drop dramatically in the morphant animals. Moreover, knockdown experiments of Nematostella Dicer1 and PIWI2, homologs of major bilaterian biogenesis components of miRNAs and piRNAs, respectively, resulted in developmental arrest similar to HEN1 morphants. Our findings suggest that HEN1 mediated methylation of sRNAs reflects the ancestral state, where miRNAs were also methylated. Thus, we provide the first evidence of a methylation mechanism that stabilizes miRNAs in animals, and highlight the importance of post-transcriptional regulation in non-bilaterian animals.
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http://dx.doi.org/10.1371/journal.pgen.1007590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6114907PMC
August 2018

Dispersal and speciation: The cross Atlantic relationship of two parasitic cnidarians.

Mol Phylogenet Evol 2018 09 25;126:346-355. Epub 2018 Apr 25.

Department of Molecular Evolution and Development, University of Vienna, Austria. Electronic address:

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http://dx.doi.org/10.1016/j.ympev.2018.04.035DOI Listing
September 2018

Dynamics of venom composition across a complex life cycle.

Elife 2018 02 9;7. Epub 2018 Feb 9.

Department of Ecology, Evolution and Behavior, Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.

Little is known about venom in young developmental stages of animals. The appearance of toxins and stinging cells during early embryonic stages in the sea anemone suggests that venom is already expressed in eggs and larvae of this species. Here, we harness transcriptomic, biochemical and transgenic tools to study venom production dynamics in . We find that venom composition and arsenal of toxin-producing cells change dramatically between developmental stages of this species. These findings can be explained by the vastly different interspecific interactions of each life stage, as individuals develop from a miniature non-feeding mobile planula to a larger sessile polyp that predates on other animals and interact differently with predators. Indeed, behavioral assays involving prey, predators and are consistent with this hypothesis. Further, the results of this work suggest a much wider and dynamic venom landscape than initially appreciated in animals with a complex life cycle.
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http://dx.doi.org/10.7554/eLife.35014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5832418PMC
February 2018

Characterization of the piRNA pathway during development of the sea anemone Nematostella vectensis.

RNA Biol 2017 12 13;14(12):1727-1741. Epub 2017 Sep 13.

a Department of Molecular Evolution and Development; Centre of Organismal Systems Biology, Faculty of Life Sciences , University of Vienna ; Althanstrasse 14, Wien , Austria.

PIWI-interacting RNAs (piRNAs) and associated proteins comprise a conserved pathway for silencing transposons in metazoan germlines. piRNA pathway components are also expressed in multipotent somatic stem cells in various organisms. piRNA functions have been extensively explored in bilaterian model systems, however, comprehensive studies in non-bilaterian phyla remain limited. Here we investigate the piRNA pathway during the development of Nematostella vectensis, a well-established model system belonging to Cnidaria, the sister group to Bilateria. To date, no population of somatic stem cells has been identified in this organism, despite its long life-span and regenerative capacities that require a constant cell-renewal. We show that Nematostella piRNA pathway components are broadly expressed in early developmental stages, while piRNAs themselves show differential expression, suggesting specific developmental roles of distinct piRNA families. In adults, piRNA associated proteins are enriched in the germline but also expressed in somatic cells, indicating putative stem cell properties. Furthermore, we provide experimental evidence that Nematostella piRNAs cleave transposable elements as well as protein-coding genes. Our results demonstrate that somatic expression of piRNA associated proteins as well as the roles of piRNAs in transposon repression and gene regulation are likely ancestral features that evolved before the split between Cnidaria and Bilateria.
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http://dx.doi.org/10.1080/15476286.2017.1349048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731801PMC
December 2017

Evolution of miRNA Tailing by 3' Terminal Uridylyl Transferases in Metazoa.

Genome Biol Evol 2017 06;9(6):1547-1560

Department of Ecology, Evolution and Behavior, Alexander Silberman Institute of Life Sciences, Faculty of Science, The Hebrew University of Jerusalem, Jerusalem, Israel.

In bilaterian animals the 3' ends of microRNAs (miRNAs) are frequently modified by tailing and trimming. These modifications affect miRNA-mediated gene regulation by modulating miRNA stability. Here, we analyzed data from three nonbilaterian animals: two cnidarians (Nematostella vectensis and Hydra magnipapillata) and one poriferan (Amphimedon queenslandica). Our analysis revealed that nonbilaterian miRNAs frequently undergo modifications like the bilaterian counterparts: the majority are expressed as different length isoforms and frequent modifications of the 3' end by mono U or mono A tailing are observed. Moreover, as the factors regulating miRNA modifications are largely uncharacterized in nonbilaterian animal phyla, in present study, we investigated the evolution of 3' terminal uridylyl transferases (TUTases) that are known to involved in miRNA 3' nontemplated modifications in Bilateria. Phylogenetic analysis on TUTases showed that TUTase1 and TUTase6 are a result of duplication in bilaterians and that TUTase7 and TUTase4 are the result of a vertebrate-specific duplication. We also find an unexpected number of Drosophila-specific gene duplications and domain losses in most of the investigated gene families. Overall, our findings shed new light on the evolutionary history of TUTases in Metazoa, as they reveal that this core set of enzymes already existed in the last common ancestor of all animals and was probably involved in modifying small RNAs in a similar fashion to its present activity in bilaterians.
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http://dx.doi.org/10.1093/gbe/evx106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5509036PMC
June 2017

The evolutionary origin of plant and animal microRNAs.

Nat Ecol Evol 2017 02;1(3):27

Department of Molecular Evolution and Development, Centre of Organismal Systems Biology, University of Vienna, Althanstr. 14, 1090 Vienna, Austria.

microRNAs (miRNAs) are a unique class of short endogenous RNAs that became known in the last few decades as major players in gene regulation at the post-transcriptional level. Their regulatory roles make miRNAs crucial for normal development and physiology in several distinct groups of eukaryotes including plants and animals. The common notion in the field is that miRNAs have evolved independently in those distinct lineages, but recent evidence from non-bilaterian metazoans, plants, as well as various algae raise the possibility that already the last common ancestor of these lineages might have employed a miRNA pathway for post-transcriptional regulation. In this review we present the commonalities and differences of the miRNA pathways in various eukaryotes and discuss the contrasting scenarios of their possible evolutionary origin and their proposed link to organismal complexity and multicellularity.
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http://dx.doi.org/10.1038/s41559-016-0027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5435108PMC
February 2017

Conservation of miRNA-mediated silencing mechanisms across 600 million years of animal evolution.

Nucleic Acids Res 2017 01 6;45(2):938-950. Epub 2016 Sep 6.

Non-coding RNAs and mechanisms of cytoplasmic gene regulation, Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine, Berlin 13125, Germany

Our current knowledge about the mechanisms of miRNA silencing is restricted to few lineages such as vertebrates, arthropods, nematodes and land plants. miRNA-mediated silencing in bilaterian animals is dependent on the proteins of the GW182 family. Here, we dissect the function of GW182 protein in the cnidarian Nematostella, separated by 600 million years from other Metazoa. Using cultured human cells, we show that Nematostella GW182 recruits the CCR4-NOT deadenylation complexes via its tryptophan-containing motifs, thereby inhibiting translation and promoting mRNA decay. Further, similarly to bilaterians, GW182 in Nematostella is recruited to the miRNA repression complex via interaction with Argonaute proteins, and functions downstream to repress mRNA. Thus, our work suggests that this mechanism of miRNA-mediated silencing was already active in the last common ancestor of Cnidaria and Bilateria.
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http://dx.doi.org/10.1093/nar/gkw792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5314787PMC
January 2017

The Rise and Fall of an Evolutionary Innovation: Contrasting Strategies of Venom Evolution in Ancient and Young Animals.

PLoS Genet 2015 Oct 22;11(10):e1005596. Epub 2015 Oct 22.

Department of Ecology, Evolution and Behavior, The Alexander Silberman Institute for Life Sciences, Hebrew University of Jerusalem, Jerusalem, Israel.

Animal venoms are theorized to evolve under the significant influence of positive Darwinian selection in a chemical arms race scenario, where the evolution of venom resistance in prey and the invention of potent venom in the secreting animal exert reciprocal selection pressures. Venom research to date has mainly focused on evolutionarily younger lineages, such as snakes and cone snails, while mostly neglecting ancient clades (e.g., cnidarians, coleoids, spiders and centipedes). By examining genome, venom-gland transcriptome and sequences from the public repositories, we report the molecular evolutionary regimes of several centipede and spider toxin families, which surprisingly accumulated low-levels of sequence variations, despite their long evolutionary histories. Molecular evolutionary assessment of over 3500 nucleotide sequences from 85 toxin families spanning the breadth of the animal kingdom has unraveled a contrasting evolutionary strategy employed by ancient and evolutionarily young clades. We show that the venoms of ancient lineages remarkably evolve under the heavy constraints of negative selection, while toxin families in lineages that originated relatively recently rapidly diversify under the influence of positive selection. We propose that animal venoms mostly employ a 'two-speed' mode of evolution, where the major influence of diversifying selection accompanies the earlier stages of ecological specialization (e.g., diet and range expansion) in the evolutionary history of the species-the period of expansion, resulting in the rapid diversification of the venom arsenal, followed by longer periods of purifying selection that preserve the potent toxin pharmacopeia-the period of purification and fixation. However, species in the period of purification may re-enter the period of expansion upon experiencing a major shift in ecology or environment. Thus, we highlight for the first time the significant roles of purifying and episodic selections in shaping animal venoms.
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http://dx.doi.org/10.1371/journal.pgen.1005596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4619613PMC
October 2015

Ecological venomics: How genomics, transcriptomics and proteomics can shed new light on the ecology and evolution of venom.

J Proteomics 2016 Mar 15;135:62-72. Epub 2015 Sep 15.

Department of Ecology, Evolution and Behavior, Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem 91904, Israel. Electronic address:

Animal venom is a complex cocktail of bioactive chemicals that traditionally drew interest mostly from biochemists and pharmacologists. However, in recent years the evolutionary and ecological importance of venom is realized as this trait has direct and strong influence on interactions between species. Moreover, venom content can be modulated by environmental factors. Like many other fields of biology, venom research has been revolutionized in recent years by the introduction of systems biology approaches, i.e., genomics, transcriptomics and proteomics. The employment of these methods in venom research is known as 'venomics'. In this review we describe the history and recent advancements of venomics and discuss how they are employed in studying venom in general and in particular in the context of evolutionary ecology. We also discuss the pitfalls and challenges of venomics and what the future may hold for this emerging scientific field.
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http://dx.doi.org/10.1016/j.jprot.2015.09.015DOI Listing
March 2016

Evolution of an ancient venom: recognition of a novel family of cnidarian toxins and the common evolutionary origin of sodium and potassium neurotoxins in sea anemone.

Mol Biol Evol 2015 Jun 9;32(6):1598-610. Epub 2015 Mar 9.

Venom Evolution Laboratory, School of Biological Sciences, The University of Queensland, St. Lucia, Queensland, Australia Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland, Australia

Despite Cnidaria (sea anemones, corals, jellyfish, and hydroids) being the oldest venomous animal lineage, structure-function relationships, phyletic distributions, and the molecular evolutionary regimes of toxins encoded by these intriguing animals are poorly understood. Hence, we have comprehensively elucidated the phylogenetic and molecular evolutionary histories of pharmacologically characterized cnidarian toxin families, including peptide neurotoxins (voltage-gated Na(+) and K(+) channel-targeting toxins: NaTxs and KTxs, respectively), pore-forming toxins (actinoporins, aerolysin-related toxins, and jellyfish toxins), and the newly discovered small cysteine-rich peptides (SCRiPs). We show that despite long evolutionary histories, most cnidarian toxins remain conserved under the strong influence of negative selection-a finding that is in striking contrast to the rapid evolution of toxin families in evolutionarily younger lineages, such as cone snails and advanced snakes. In contrast to the previous suggestions that implicated SCRiPs in the biomineralization process in corals, we demonstrate that they are potent neurotoxins that are likely involved in the envenoming function, and thus represent the first family of neurotoxins from corals. We also demonstrate the common evolutionary origin of type III KTxs and NaTxs in sea anemones. We show that type III KTxs have evolved from NaTxs under the regime of positive selection, and likely represent a unique evolutionary innovation of the Actinioidea lineage. We report a correlation between the accumulation of episodically adaptive sites and the emergence of novel pharmacological activities in this rapidly evolving neurotoxic clade.
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http://dx.doi.org/10.1093/molbev/msv050DOI Listing
June 2015

Evolution of voltage-gated ion channels at the emergence of Metazoa.

J Exp Biol 2015 Feb;218(Pt 4):515-25

Department of Integrative Biology and Center for Computational Biology and Bioinformatics, University of Texas, Austin, TX 78712, USA Department of Neuroscience, University of Texas at Austin, TX 78712, USA Josephine Bay Paul Center for Molecular Biology and Evolution, Marine Biological Laboratory, Woods Hole, MA 02543, USA.

Voltage-gated ion channels are large transmembrane proteins that enable the passage of ions through their pore across the cell membrane. These channels belong to one superfamily and carry pivotal roles such as the propagation of neuronal and muscular action potentials and the promotion of neurotransmitter secretion in synapses. In this review, we describe in detail the current state of knowledge regarding the evolution of these channels with a special emphasis on the metazoan lineage. We highlight the contribution of the genomic revolution to the understanding of ion channel evolution and for revealing that these channels appeared long before the appearance of the first animal. We also explain how the elucidation of channel selectivity properties and function in non-bilaterian animals such as cnidarians (sea anemones, corals, jellyfish and hydroids) can contribute to the study of channel evolution. Finally, we point to open questions and future directions in this field of research.
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http://dx.doi.org/10.1242/jeb.110270DOI Listing
February 2015

The evolution of the four subunits of voltage-gated calcium channels: ancient roots, increasing complexity, and multiple losses.

Genome Biol Evol 2014 Aug 21;6(9):2210-7. Epub 2014 Aug 21.

Department of Integrative Biology and Center for Computational Biology and Bioinformatics, University of Texas, Austin Department of Neuroscience, University of Texas at Austin Josephine Bay Paul Center for Molecular Biology and Evolution, Marine Biological Laboratory, Woods Hole, Massachusetts

The alpha subunits of voltage-gated calcium channels (Ca(v)s) are large transmembrane proteins responsible for crucial physiological processes in excitable cells. They are assisted by three auxiliary subunits that can modulate their electrical behavior. Little is known about the evolution and roles of the various subunits of Ca(v)s in nonbilaterian animals and in nonanimal lineages. For this reason, we mapped the phyletic distribution of the four channel subunits and reconstructed their phylogeny. Although alpha subunits have deep evolutionary roots as ancient as the split between plants and opistokonths, beta subunits appeared in the last common ancestor of animals and their close-relatives choanoflagellates, gamma subunits are a bilaterian novelty and alpha2/delta subunits appeared in the lineage of Placozoa, Cnidaria, and Bilateria. We note that gene losses were extremely common in the evolution of Ca(v)s, with noticeable losses in multiple clades of subfamilies and also of whole Ca(v) families. As in vertebrates, but not protostomes, Ca(v) channel genes duplicated in Cnidaria. We characterized by in situ hybridization the tissue distribution of alpha subunits in the sea anemone Nematostella vectensis, a nonbilaterian animal possessing all three Ca(v) subfamilies common to Bilateria. We find that some of the alpha subunit subtypes exhibit distinct spatiotemporal expression patterns. Further, all six sea anemone alpha subunit subtypes are conserved in stony corals, which separated from anemones 500 MA. This unexpected conservation together with the expression patterns strongly supports the notion that these subtypes carry unique functional roles.
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http://dx.doi.org/10.1093/gbe/evu177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4202318PMC
August 2014

The specificity of Av3 sea anemone toxin for arthropods is determined at linker DI/SS2-S6 in the pore module of target sodium channels.

Biochem J 2014 Oct;463(2):271-7

*Department of Plant Molecular Biology & Ecology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel.

Av3 is a peptide neurotoxin from the sea anemone Anemonia viridis that shows specificity for arthropod voltage-gated sodium channels (Navs). Interestingly, Av3 competes with a scorpion α-toxin on binding to insect Navs and similarly inhibits the inactivation process, and thus has been classified as 'receptor site-3 toxin', although the two peptides are structurally unrelated. This raises questions as to commonalities and differences in the way both toxins interact with Navs. Recently, site-3 was partly resolved for scorpion α-toxins highlighting S1-S2 and S3-S4 external linkers at the DIV voltage-sensor module and the juxtaposed external linkers at the DI pore module. To uncover channel determinants involved in Av3 specificity for arthropods, the toxin was examined on channel chimaeras constructed with the external linkers of the mammalian brain Nav1.2a, which is insensitive to Av3, in the background of the Drosophila DmNav1. This approach highlighted the role of linker DI/SS2-S6, adjacent to the channel pore, in determining Av3 specificity. Point mutagenesis at DI/SS2-S6 accompanied by functional assays highlighted Trp404 and His405 as a putative point of Av3 interaction with DmNav1. His405 conservation in arthropod Navs compared with tyrosine in vertebrate Navs may represent an ancient substitution that explains the contemporary selectivity of Av3. Trp404 and His405 localization near the membrane surface and the hydrophobic bioactive surface of Av3 suggest that the toxin possibly binds at a cleft by DI/S6. A partial overlap in receptor site-3 of both toxins nearby DI/S6 may explain their binding competition capabilities.
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http://dx.doi.org/10.1042/BJ20140576DOI Listing
October 2014

Cnidarian microRNAs frequently regulate targets by cleavage.

Genome Res 2014 Apr 18;24(4):651-63. Epub 2014 Mar 18.

Department for Molecular Evolution and Development, Center for Organismal Systems Biology, Faculty of Life Sciences, University of Vienna, 1090 Vienna, Austria;

In bilaterians, which comprise most of extant animals, microRNAs (miRNAs) regulate the majority of messenger RNAs (mRNAs) via base-pairing of a short sequence (the miRNA "seed") to the target, subsequently promoting translational inhibition and transcript instability. In plants, many miRNAs guide endonucleolytic cleavage of highly complementary targets. Because little is known about miRNA function in nonbilaterian animals, we investigated the repertoire and biological activity of miRNAs in the sea anemone Nematostella vectensis, a representative of Cnidaria, the sister phylum of Bilateria. Our work uncovers scores of novel miRNAs in Nematostella, increasing the total miRNA gene count to 87. Yet only a handful are conserved in corals and hydras, suggesting that microRNA gene turnover in Cnidaria greatly exceeds that of other metazoan groups. We further show that Nematostella miRNAs frequently direct the cleavage of their mRNA targets via nearly perfect complementarity. This mode of action resembles that of small interfering RNAs (siRNAs) and plant miRNAs. It appears to be common in Cnidaria, as several of the miRNA target sites are conserved among distantly related anemone species, and we also detected miRNA-directed cleavage in Hydra. Unlike in bilaterians, Nematostella miRNAs are commonly coexpressed with their target transcripts. In light of these findings, we propose that post-transcriptional regulation by miRNAs functions differently in Cnidaria and Bilateria. The similar, siRNA-like mode of action of miRNAs in Cnidaria and plants suggests that this may be an ancestral state.
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http://dx.doi.org/10.1101/gr.162503.113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3975064PMC
April 2014

The evolution of microRNA pathway protein components in Cnidaria.

Mol Biol Evol 2013 Dec 11;30(12):2541-52. Epub 2013 Sep 11.

Department for Molecular Evolution and Development, Center for Organismal Systems Biology, Faculty of Life Sciences, University of Vienna, Vienna, Austria.

In the last decade, it became evident that posttranscriptional regulation of gene expression by microRNAs is a central biological process in both plants and animals. Yet, our knowledge about microRNA biogenesis and utilization in animals stems mostly from the study of Bilateria. In this study, we identified genes encoding the protein components of different parts of the microRNA pathway in Cnidaria, the likely sister phylum of Bilateria. These genes originated from three cnidarian lineages (sea anemones, stony corals, and hydras) that are separated by at least 500 My from one another. We studied the expression and phylogeny of the cnidarian homologs of Drosha and Pasha (DGCR8) that compose the microprocessor, the RNAse III enzyme Dicer and its partners, the HEN1 methyltransferase, the Argonaute protein effectors, as well as members of the GW182 protein family. We further reveal that whereas the bilaterian dicer partners Loquacious/TRBP and PACT are absent from Cnidaria, this phylum contains homologs of the double-stranded RNA-binding protein HYL1, the Dicer partner found in plants. We also identified HYL1 homologs in a sponge and a ctenophore. This finding raises questions regarding the independent evolution of the microRNA pathway in plants and animals, and together with the other results shed new light on the evolution of an important regulatory pathway.
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http://dx.doi.org/10.1093/molbev/mst159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3840309PMC
December 2013

BcsTx3 is a founder of a novel sea anemone toxin family of potassium channel blocker.

FEBS J 2013 Oct 23;280(19):4839-52. Epub 2013 Aug 23.

Department of Physiology, Institute of Biosciences, University of São Paulo, Brazil.

Sea anemone venoms have become a rich source of peptide toxins which are invaluable tools for studying the structure and functions of ion channels. In this work, BcsTx3, a toxin found in the venom of a Bunodosoma caissarum (population captured at the Saint Peter and Saint Paul Archipelago, Brazil) was purified and biochemically and pharmacologically characterized. The pharmacological effects were studied on 12 different subtypes of voltage-gated potassium channels (K(V)1.1-K(V)1.6; K(V)2.1; K(V)3.1; K(V)4.2; K(V)4.3; hERG and Shaker IR) and three cloned voltage-gated sodium channel isoforms (Na(V)1.2, Na(V)1.4 and BgNa(V)1.1) expressed in Xenopus laevis oocytes. BcsTx3 shows a high affinity for Drosophila Shaker IR channels over rKv1.2, hKv1.3 and rKv1.6, and is not active on NaV channels. Biochemical characterization reveals that BcsTx3 is a 50 amino acid peptide crosslinked by four disulfide bridges, and sequence comparison allowed BcsTx3 to be classified as a novel type of sea anemone toxin acting on K(V) channels. Moreover, putative toxins homologous to BcsTx3 from two additional actiniarian species suggest an ancient origin of this newly discovered toxin family.
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http://dx.doi.org/10.1111/febs.12456DOI Listing
October 2013