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With secondhand gene, house mice resist poison

Cell Press

Since the 1950s, people have tried to limit the numbers of mice and rats using a poison known as warfarin. But, over the course of evolution, those pesky rodents have found a way to make a comeback, resisting that chemical via changes to a gene involved in vitamin K recycling and blood clotting. Now, researchers reporting online on July 21 in Current Biology, a Cell Press publication, show that European mice have in some cases acquired that resistance gene in a rather unorthodox way: they got it secondhand from an Algerian mouse.

"House mice not only have become resistant to rat poisons in the 'usual' way, but also in a very 'unusual' way, through interbreeding with a separate mouse species that is removed by 1.5 to 3 million years," said Michael Kohn of Rice University. "Our work is perhaps the first to catch this unusual process in the act."

The findings show that, as in microbes, there is more than one way for new traits to evolve in animals: via new mutations arising within a species, and via the transfer of genes between species, the researchers say. They also help to explain how rodents have foiled some of our best attempts to kill them so rapidly, and with such apparent ease.

The researchers made their discovery by tracing the evolution of vitamin K epoxide reductase enzyme complex (VKOR), and specifically the subcomponent of that enzyme responsible for warfarin sensitivity or resistance, in the genomes of house mice (Mus musculus domesticus) and Algerian mice (M. spretus). They also showed in laboratory experiments that the gene variant derived from Algerian mice does indeed lend house mice resistance to warfarin.

Kohn's team suspects that M. spretus is naturally resistant to warfarin because they inhabit arid steppe-like terrain and live mostly on dry plant matter and seeds, all poor sources for vitamin K. Once the M. spretus gene variant was introduced into house mice via hybridization between the two species, they too were "pre-adapted" for warfarin resistance.

Kohn said he belongs to the camp that thinks such breaches between species barriers shouldn't happen all that often. But, on an evolutionary time scale, even rare events can change the course of evolution in significant ways.

In this case, it's clear that humans had a heavy influence: we not only introduced a poison that temporarily increased the fitness of mouse hybrids over their parents to allow the eventual transfer of a warfarin resistance gene from one species to another, but we also brought the mice together in the first place with the spread of agriculture from the Fertile Crescent, Kohn said.

"Nature will respond to challenges in the most creative ways, even if challenges are human-made and presumably foolproof," Kohn said. On the other hand, he added, evolution might be more predictable in some ways than we had imagined. After all, the very same gene and gene pathway has evolved multiple times to confer resistance to warfarin in both mice and rats. "Understanding such constraints and the mechanisms by which evolution proceeds will be critical for our continued ability to stay one step ahead of evolved resistances in the animals, plants, and microbes that we wish to control," he said.


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