Study: Tandem duplication of SERPIN genes yields functional variation and snake venom inhibitors (DOI: 10.1093/molbev/msaf290)
Woodrats weigh less than half a pound but can survive venomous rattlesnake bites that would hospitalize, or even kill, a full-grown human.
New research from the University of Michigan has uncovered a clue explaining how these tiny rodents, also known as packrats, have evolved such potent immunity: by stockpiling extra copies of genes.
The research, described in the journal Molecular Biology and Evolution, focused on a group of genes called SERPINs, which encode a protein that blocks a common ingredient in snake venom. Previous research demonstrated that SERPINA1 inhibits European rattlesnake venom, but much less is known about a related gene called SERPINA3.
"We wanted to see if we could determine a genetic basis underlying this venom resistance," said Matthew Holding, an evolutionary biologist in the lab of David Ginsburg at the U-M Life Sciences Institute. "We noticed that, whereas humans have only one SERPINA3 gene, these rats have 12 copies. They each encode a slightly different protein, and we have no idea what any of them do."
This research was supported by the National Institutes of Health and the University of Michigan's Honors Summer Fellowship.
The dozen SERPINA3 genes in woodrats arose through a process called tandem duplication, whereby an extra copy of one gene is inserted into the genome during development. Because the original gene remains intact, performing its original functions, the new copy may evolve to encode a different protein with another function.
Tandem duplications are frequently found in snake venom. As snakes' prey become resistant to the venom, new proteins evolve to make the venom toxic in other ways. The research team wondered if genetic changes in snake venom could be driving SERPINA3 to duplicate and diversify in response.
Meilyn Ward, a former undergraduate student in the Ginsburg lab who co-led the study with Holding, tested the proteins made by each of the 12 woodrat SERPINA3 genes against venom samples gathered from the rattlesnakes that hunt these rodents. They found that many of the SERPINA3 proteins bound directly to components of the venom that make it toxic, blocking their ability to cause damage.
The research team also observed substantial variation in the different proteins' activities. Some of the proteins did not show any interaction with the venom, indicating that they have an entirely different role in the mammals' survival, whereas another protein simultaneously inhibited two different components that form the basis of the venom's toxicity.
"Our findings brought SERPINA3 proteins into the conversation about venom resistance," said Ward, who is now a medical student at Duke University. "Previous work in this area had focused mainly on SERPINA1, and we now know that these duplicate SERPINA3 genes are an important factor in the coevolution between woodrats and their predators.
Holding says this gives us an idea of how gene duplication can play a role in the evolution of venom resistance, as one of potentially many factors.
"And it uncovers one more tool in the rodents' toolbox and that can be studied across other animals as part of this larger question of how to survive venomous snakebites," he said.
In addition to Holding and Ward, study authors were Laura Haynes and David Ginsburg of the University of Michigan, Mark Margres of the University of South Florida,and Marjorie Matocq of the University of Nevada Reno.
