Molecular Mechanisms of Toxin-Antidote (TA) Elements: The Cell as a Battlefield
Despite their significance, the molecular mechanisms of eukaryotic TA systems remain largely unknown, limiting our understanding of how these elements spread and persist. The first aim of the TOX-ANT ERC Starting Grant addressed this gap by investigating the sup-35/pha-1 TA system in Caenorhabditis elegans. Using single-particle cryo-electron microscopy (cryo-EM), we resolved—for the first time—the structure of an animal selfish toxin. Specifically, we determined the structures of SUP-35 in several oligomeric states, as well as the active toxic complex composed of SUP-35 and its cofactors SUP-36 and SUP-37 (Pühringer et al., in preparation). These findings, supported by extensive biochemical and genetic data, provide unprecedented insight into how TA toxins originate and why they are evolutionarily successful.
Exploring the Diversity of TA Elements in Nature
The second aim of TOX-ANT sought to uncover the prevalence and mechanistic diversity of TA elements across species. We extended our investigations to two additional nematode species, C. tropicalis and C. briggsae, identifying numerous novel TAs. Unlike previously known elements, many of these do not cause embryonic lethality but instead interfere with post-embryonic development. These discoveries demonstrate that TA systems are not rare anomalies but rather a widespread class of selfish elements with diverse modes of action. Our findings highlight novel gene drive strategies and underscore the broader evolutionary significance of TAs.
Key publication:
Ben-David, E, et al. “Ubiquitous selfish toxin-antidote elements in Caenorhabditis species.” Current Biology 31, 5990–6000 (2021).
Mavericks: Virus-like Transposons and Horizontal Gene Transfer in Animals
DNA is traditionally passed from parent to offspring, but it can also be transmitted horizontally—across unrelated individuals or even species—a process known as horizontal gene transfer (HGT). While HGT is well documented in prokaryotes, its mechanisms in animals remain poorly understood.
While studying a novel TA element in C. briggsae, we identified Maverick elements—virus-like transposons that likely serve as long-sought vectors of HGT in eukaryotes. Mavericks, or Polintons, combine features of both viruses and transposons: they are flanked by terminal inverted repeats and encode viral-like proteins, including capsid components, DNA polymerases, and integrases. We found that two novel nematode gene families—wosp proteases and krma kinases—are frequently captured by Mavericks and have undergone widespread horizontal transfer between distantly related nematode species. These results reveal that the interplay between viruses and transposons can shape genetic exchange and evolution across vast evolutionary timescales.
Key publication:
Widen, S.A. et al. “Virus-like transposons cross the species barrier and drive the evolution of genetic incompatibilities.” Science 380(6652): eade0705 (2023).
Evolution of Genomic Imprinting and Parent-of-Origin Effects
Genomic imprinting—a form of epigenetic regulation where gene expression depends on parental origin—is essential for development in many organisms, yet its molecular origins remain obscure. Nearly 30 years ago, Denise Barlow proposed that imprinting may have evolved from host defense systems targeting parasitic DNA. However, direct mechanistic evidence has been lacking.
Using the slow-1/grow-1 TA system in C. tropicalis, we demonstrated how parent-of-origin effects can arise through the co-option of the piRNA pathway. Our genetic and molecular analyses revealed that the piRNA pathway can silence selfish genes in a parent-specific manner, offering a powerful evolutionary advantage. These findings trace the origins of imprinting-like mechanisms to nematodes—organisms that lack canonical DNA methylation—and support the idea that host defense against selfish elements can give rise to complex regulatory phenomena.
Key publication:
Pliota, P. et al. “Selfish conflict underlies RNA-mediated parent-of-origin effects.” Nature 628, 122–129 (2024).
