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Castoe lab leads breakthrough study of evolution of venom genes in snakes
New publication provides better understanding of how snake venom production functions at a genomic level
A new study from biologists at The University of Texas at Arlington and an international team of collaborators provides the first comprehensive explanation of how snake venom regulatory systems evolved — an important example that illuminates the evolution of new complex traits.
Todd Castoe, UTA professor of biology, is corresponding author of the paper, titled “Snake venom gene expression is coordinated by novel regulatory architecture and the integration of multiple co-opted vertebrate pathways.” It was published online June 1 by the journal Genome Research.
“We have relatively few detailed examples of how new regulatory systems evolve to drive novel complex traits,” Castoe said. “This study provides a valuable example that illustrates a surprising number of distinct ‘strategies’ for how evolution may re-wire regulatory networks, providing key expectations for how such re-wiring may occur in other species, including humans.”
Ever since Darwin introduced the theory of evolution by natural selection in the 19th century, understanding how new, complex traits evolve has been a difficult challenge in biology. This is because it must involve many coordinated changes, which can be hard to envision. Major changes in gene regulatory architecture are required, including the evolution of new regulatory sequences and “rewiring” of existing regulatory networks, Castoe said.
In order to learn more about this process, scientists strive to understand nature’s unique and creative solutions that underlie the evolution of particular complex traits. Snake venom and venom systems are an example of such a case. They have been studied extensively due to the medical relevance of snakebites and the possibility of using snake venom toxins to develop drugs and other therapeutics, including treatments for cancer. Despite this, little is known about the molecular mechanisms and genomic architecture underlying the regulation of snake venoms, and the evolutionary origins of this regulatory system, Castoe said.
“This work gives us a better understanding of how snake venom evolved and how venom production functions at a genomic level,” said Blair Perry, a postdoctoral researcher in the School of Biological Sciences at Washington State University and lead author of the new paper.
“In addition to studying specific venom genes, we can now investigate parts of the genome involved in the regulation of these genes as well,” said Perry, who received his Ph.D. from UTA in 2021, with Castoe as his faculty advisor. “This opens up new opportunities to understand how variation in snake venom, both within and between snake species, corresponds to variation in the genome.”
In 2019, the World Health Organization declared snakebite a neglected tropical disease. The primary challenge for treating snakebite is the extreme variation in venom composition across populations and species of snakes, Castoe noted.
“Our work provides the first description of the regulatory architecture that drives snake venom expression, providing critical context for understanding the molecular interactions that govern venom variation,” he said.
The evolution of snake venom required snakes to develop a highly specialized venom gland to produce and store a diverse and deadly protein cocktail for delivery to their victims, Castoe said. Venom glands are thought to be evolved from ancestral salivary glands, but Perry and colleagues show that this required the evolution of new regulatory sequences and the co-option (or repurposing) of existing regulatory systems to control the precise expression of these dangerous genes.
“Consider the challenges to understanding the origination and maintenance of this complex chemical weapons system,” said Stephen Mackessy, professor of biology at the University of Northern Colorado and a co-author of the study. “Venoms largely consist of repurposed regulatory proteins and peptides, overexpressed and stored in a specialized gland only millimeters from the snake‘s brain. These toxins must be stabilized yet ready to go at a moment’s notice, and they may be stored for long periods of time.
“Our earlier work has demonstrated that several mechanisms exist that promote this long-term storage, but the processes leading to the regulation, evolution and diversification of these systems have largely remained unknown. This study demonstrates that in addition to the toxin genes, regulatory pathways common to vertebrate animals were also co-opted to control this system.”
To create this novel system, snakes utilized a wide array of genomic possibilities, including tandem duplication of genes and regulatory sequences, cis-regulatory sequence seeding by transposable elements, and diverse transcriptional regulatory proteins controlled by a co-opted regulatory cascade, Castoe said. Some of this evolutionary novelty involved diversion of existing regulatory pathways, but often involved creating new gene regulatory sequences and genomic structural features.
Nicholas Casewell, professor and director of the Centre for Snakebite Research & Interventions at the Liverpool School of Tropical Medicine in Liverpool, UK, is an expert in the field that was not involved in the work. He said that snake venoms are valuable systems for understanding links between the genotype and phenotype of animals, and these biochemically active secretions also have major implications for humans with snakebites causing over 100,000 deaths a year. Despite its importance, he noted, scientists’ understanding of the regulation of venom by snakes remains almost poor.
“In this study the authors apply a diverse array of cutting-edge approaches to investigate this topic, and their ensuing collection of regulatory sequence, transcription factor, signaling cascade and chromatin accessibility data and associated analyses provide completely unparalleled insight into the regulatory architecture of the snake venom system,” Casewell said. “Their findings represent a major step forward in helping us to better understand how genes associated with internal physiological processes can be repurposed for external use in the form of venom.”
Giulia Pasquesi, a postdoctoral associate at the University of Colorado at Boulder who earned her Ph.D. from UTA in 2020 with Castoe as her faculty advisor, is a co-author of the paper. She examined the role of transposable elements (TE) — DNA sequences that move from one location on the genome to another — in the evolution of snake venom for this study.
“Whether snake-specific TEs contributed to the evolution of snake-specific traits, as has happened in mammals for key traits like placentation, had remained a fascinating open question until now,” Pasquesi said. “One of the findings of this study shows that the emergence of biological innovations follows recurring patterns, specifically that TEs can introduce novel regulatory sequences that ultimately facilitate the evolution of new complex traits.
“Of course, TEs are not the sole players, as complex polygenic traits require the fine-tuned coordination of not only gene expression, but also chromatin and local genomic re-organization. Still, it was really exciting for us to be able to demonstrate the contribution of TEs to the evolution of one of the most distinctive features of snakes, namely venom.”
Perry said that the study also demonstrates the value of considering many layers of biological complexity when seeking to understand how a trait of interest functions and how it evolved.
“By combining multiple types of genomic data, we were able to gain a more complete understanding of the diverse factors that play a role in the regulation and evolution of venom genes,” Perry said. “More broadly, this work provides a valuable example of the idiosyncrasies of evolution. One might expect that all venom genes followed the same evolutionary ‘strategies’ to become involved in venom. Our findings instead suggest that remarkably different genomic and evolutionary processes played critical roles in the evolution of specific venom genes.”
Other UTA co-authors of the study include Siddharth Gopalan and Aundrea Westfall, doctoral students in Castoe’s lab; Paul Chippindale, professor of biology; and Mark Pellegrino, assistant professor of biology.
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