Woodrats (Neotoma spp.) are one of the only animals that can tolerate large quantities of creosote, a shrub with leaves coated in a chemical cocktail of poisonous resin. The critter’s constitution has astounded biologists and represents a decades-long debate—over evolutionary time, how do animals adapt to a deadly diet? Do detoxification enzymes become more specialized or more abundant?

The study, led by University of Utah (U) biologists, is the first to pinpoint the specific genes and enzymes that allow woodrats to eat the near-lethal food without obvious harm. The scientists compared the detoxification pathways of two woodrat species that encountered creosote independently in their evolutionary histories to those who had never encountered creosote. Before creosote invaded parts of the Southwest, woodrat populations had a smaller number of genes that coded for enzymes that process creosote toxins. As creosote grew to dominate the landscape, natural selection drove a detox-gene duplication bonanza, resulting in massive increases in the numbers of genes that produce enzymes that eliminate creosote toxins. Curiously, these enzymes did not become more specialized to detoxify creosote—there was just much more of them.

The authors propose that gene duplication is an important mechanism by which animals initially adapt to new environmental pressures.

“These woodrats have only been exposed to creosote bush for about 15,000 years—in an evolutionary timescale, that’s very little time,” said Dylan Klure, postdoctoral researcher at the U and lead author of the study. “Some other changes may happen in the future, but right now, the duplication innovation is what’s allowed them to become so toxin-resistant so quickly.”

The study published on Jan. 10, 2025, in the journal Science.

There are two primary hypotheses for how animals evolve tolerance to toxic chemicals. The first is that new DNA mutations modify existing detoxification enzymes to metabolize toxins faster and more efficiently—a lower quantity, higher quality approach. The second is that detoxification genes and the enzymes they produce don’t change much, but duplicate in number over evolutionary time, allowing animals to produce more detoxification enzymes in response to toxin consumption—a greater quantity, lower quality approach. Previous research found that herbivorous insects process toxins using specialized enzymes that metabolize chemicals faster. Since the 1970s, biologists have favored this “enzyme quality over quantity” hypothesis. This study found the exact opposite.

“We discovered that creosote-feeding woodrats don’t have specialized enzymes to metabolize creosote toxins, just more—many more, and from a wide variety of existing detox enzymes,” said Denise Dearing, U biologist and senior author of the study. “These duplications of existing genes increase the quantity of detoxification enzymes produced, enabling more toxin to be eliminated.”

Digging deep into detox DNA

Dearing and collaborators have studied the resilient Neotoma rodents for decades. In 2022, the scientists published a study that uncovered a spectrum of creosote tolerance. They collected one species of woodrat, N. lepida, from across the contemporary range of creosote bush in the Southwest, as well as woodrats outside of creosote’s range. In laboratory diet trials, they observed that individual woodrats had different tolerance levels—some could even subsist on a diet equivalent to feeding on 100% creosote bush leaves. A more recent study from 2024 on the super-tolerants revealed a list of potential candidate genes underlying their superior detox ability.

This new study expanded their analysis to include numerous populations of both creosote-tolerant and creosote-sensitive N. lepida along with N. bryanti, a woodrat species that also independently evolved to feed on creosote. First, they fed all animals the same low dose of creosote toxins to compare gene activity in the livers of creosote-tolerant to creosote-sensitive woodrats. Next, they looked for differences between tolerant and sensitive woodrats at the DNA level and saw profound and remarkably consistent genomic changes in both species.

“From the first experiment, we got a list of genes that are differentially activated in the tolerant and sensitive woodrats. The separate genomic study told us which sequences of DNA are different in their genomes, including how many copies they have of each gene. The intersection of those two results led us to some very interesting detoxifications genes,” said Michael Shapiro, biologist at the U and coauthor of the study.

Some of the duplicated genes are part of the glucuronidation pathway, a crucial detox mechanism for human beings. The glucuronidation pathway has been the focus of countless medical studies because it’s responsible for metabolizing a fifth of all human medications. The most tolerant woodrats had nearly 40 copies of one specific glucuronidation gene. In contrast, humans only have two copies of our closest gene counterpart.

Ice age provides a natural experiment

Woodrats are ideal for studying the roots of rapid evolution due to their unique natural history. About 26,000 years ago during the Last Glacial Maximum, Earth was significantly colder and drier. An exception was southwestern North America, where the jet stream funneled heavy rains to a lush landscape with abundant water, including Utah’s Lake Bonneville. Around 20,000 years ago, a massive global warming event dried out the region and the low elevation, temperate terrain was overtaken by the drought-tolerant creosote bush creeping up from the south.

Fossilized woodrat nests reveal that their diets shifted in step with the expanding desert habitat. While still favoring less hostile fare, over generations, the woodrats ate even-more creosote as the bush outcompeted their previous staple, juniper.

It’s unusual for populations of the same species, from similar geographic regions, to exhibit such a variance in gene copy number. For the woodrats, the increase in gene copy number is likely due an adaptation to creosote toxins—the rodents with the highest numbers of gene copies came from areas where creosote has existed the longest.

“When creosote invades, it just takes over. It’s kind of an adapt-or-die situation,” said Klure. “A likely scenario is that initially some animals just happened to have more copies of detox genes than others and were tolerant enough to feed on the plant. They lived, had offspring and their offspring carried those additional copies. Over time, natural selection favored these individuals, resulting in the expansion of these detox genes to incredibly high levels.”

The research reveals the mammalian genome’s flexibility in adapting to novel diets and toxic environmental compounds. The woodrats could even serve as a model to understand why individual humans metabolize drugs differently. Humans exhibit variation in detoxification gene numbers, which is thought to have been driven by the consumption of toxic plant-based diets. Woodrats offer the opportunity to test this hypothesis in a controlled system.

Other authors include Robert Greenhalgh of the University of Utah and Teri Orr of the U and New Mexico State University. The study was funded by the National Science Foundation, the National Institutes of Health, University of Utah Global Change and Sustainability Center and the U’s Graduate School Research Fellowship.

The study, Parallel gene expansions drive rapid dietary adaptation in herbivorous woodrats, published in Science on Jan. 10, 2025.

• Lisa Potter Research communications specialist, University of Utah Communications
  949-533-7899 lisa.potter@utah.edu