Why mice have the potential to become as venomous as a viper

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Researchers have investigated the origins of one of the most highly specialized straits in the animal kingdom: oral venom. Unexpectedly, the researchers found that the basic genetic machinery is present in both mammals and reptiles. Specifically, there’s a molecular link between a venomous snake’s venom glands and a mammal’s salivary glands. In theory, if there’s pressure from natural selection, mice could potentially become venomous as well.

“This represents an ancient molecular framework that was likely already established in the ancestors of snakes and mammals. Mammals took a less complicated route and developed simple salivary glands while snakes diversified this system extensively to form the oral venom system. This allowed us to propose a unified model of venom evolution, namely that venoms across lizards and snakes evolved by taking advantage of existing genes in the salivary glands of their ancestors,” Agneesh Barua, a Ph.D. student at the Okinawa Institute of Science and Technology Graduate University (OIST) and lead author of the new study, told ZME Science.

Venom can be defined as a mixture of toxic molecules (“toxins”, which are mostly proteins) that one organism delivers to another (e.g. by a bite or a sting) for the purpose of defending itself, securing a meal, or deterring a competitor. Many different types of creatures — jellyfish, spiders, scorpions, snakes, and even some mammals — seem to have independently evolved venom. This had some scientists wondering whether venom actually evolved from non-venomous but related biological components inherited from a common ancestor. This couldn’t be proved — until now.

Researchers at the Okinawa Institute of Science and Technology Graduate University (OIST) in Japan and the Australian National University carefully assessed thousands of genes related to venom. Previously, scientists had focused on genes that express the toxic proteins found in venom. But Barua and colleagues took it a step further and cast a wider net so they could identify genes that were likely present before the venom system evolved.

To this aim, they used venom glands harvested from the Taiwan habu snake (Protobothrops mucrosquamatus), a pit viper that’s indigenous to Okinawa.

“We have been trying to understand how non-venomous animals evolved venom for a long time. But, this was difficult to do because venoms evolve rapidly and the ancestral state gets difficult to reconstruct with great accuracy. We worked around that by focusing not on the toxins themselves, but on the machinery that makes them, which turned out to be highly conserved,” the researcher said.

More than 3,000 “cooperating” genes were identified that interact in some way or form with venom genes. Some protected the host cells from stress caused by producing lots of toxic proteins, while others regulated protein modification and folding. This is actually extremely important because misfolded proteins can accumulate and damage cells.

“This makes perfect sense because venoms are a cocktail of toxin proteins. It is vital that the protein structure of these toxins is maintained, otherwise, the venom won’t work, and the animal would not be able to catch its prey,” Barua said.

The surprising part was when the researchers looked at the genomes of other animals, including those you’d never think to connect with a venomous creature, such as dogs, chimpanzees, or humans, and found that they contained their own versions of these genes. When they realized that venom genes were actually co-expressed together and with a relatively small number of other genes, this was a “striking moment” for the researchers.

“This suggests that there is a common molecular framework between venom glands in snakes and salivary tissue in non-venomous mammals. This represents an ancient molecular framework that was likely already established in the ancestors of snakes and mammals. Mammals took a less complicated route and developed simple salivary glands while snakes diversified this system extensively to form the oral venom system. This allowed us to propose a unified model of venom evolution, namely that venoms across lizards and snakes evolved by taking advantage of existing genes in the salivary glands of their ancestors,” Barua added.

The study suggests that salivary gland tissues within mammals were expressed by genes that had a similar pattern of activity to that seen in venomous snakes, so genes for salivary glands and venom glands must share an ancient functional core. After the two lineages split hundreds of millions of years ago, the venomous species evolved biological systems that produced toxins, the authors note.

Bearing all of this in mind, it’s not all that surprising that over a dozen species of mammals are actually venomous. These include Eulipotyphla (solenodons and some shrews), Monotremata (platypus), Chiroptera (vampire bats), and Primates (slow and pygmy slow lorises).

Theoretically, this means that virtually any species of mammal could potentially become venomous with enough prodding from natural selection.

“Humans will never develop venom. But there is a distinct possibility in other mammals. For example, suppose there is a genetic mutation in a few individuals of some species of wild mice that allows them to catch more insects. These individuals will be able to procure more food and thus have ‘higher fitness’. This could lead them to out-compete their peers in terms of mating (or just general well-being) and thereby produce more offsprings that will carry the beneficial mutation. Now imagine this happening for several generations. There will come a time when populations of these newly formed venomous mice could drive the non-venomous ones extinct, thereby firmly establishing the venom character in the gene pool,” Barua wrote in an e-mail.

“We would like to try evolving venomous mice in the laboratory. It would be a practical test of the mechanisms we hypothesise in the paper, and potentially provide clues about why venom doesn’t evolve more often.”

In the future, the team of researchers plans on further exploring the genetic regulatory network that underlies venom gland evolution.

“One question is — how does venom evolution modify this network? We’re planning a couple of different studies on this front. One is to look across species that have evolved venom, including other reptiles and mammals. Are there commonalities in these two lineages?”

“One of the main scepticisms regarding the idea of evolution is that of ‘intelligent design.’ Proponents of this idea validate it by citing examples where scientists have not been able to completely decipher the origin of highly specialised traits. Scientists have quite a good idea of how traits originate, but direct mechanistic explanations are rare owing to the incredible genetic complexity of traits. We provide a mechanistic explanation of one of the most specialised traits in nature, oral venoms. Our study, therefore, provides a firm argument for evolution and can provide people will the proof they need to denounce pseudoscientific claims like intelligent design,” Barua said.

The findings appeared in the Proceedings of the National Academy of Sciences.

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