House mice picked up poison resistance gene by having sex with related species

By Ed Yong | July 21, 2011 12:00 pm

Since 1948, people have been poisoning unwanted rats and mice with warfarin, a chemical that causes lethal internal bleeding. It’s still used, but to a lesser extent, for rodents have become increasingly resistant to warfarin ever since the 1960s. This is a common theme – humans create a fatal chemical – a pesticide or an antibiotic – and our targets evolve resistance. But this story has a twist. Ying Song from Rice University, Houston, has found that some house mice picked up the gene for warfarin resistance from a different species.

Warfarin works by acting against vitamin K. This vitamin activates a number of genes that create clots in blood, but it itself has to be activated by a protein called VKORC1. Warfarin stops VKORC1 from doing its job, thereby suppressing vitamin K. The clotting process fails, and bleeds continue to bleed.

Rodents can evolve to shrug off warfarin by tweaking their vkorc1 gene, which encodes the protein of the same name. In European house mice, scientists have found at least 10 different genetic changes (mutations) in vkorc1 that change how susceptible they are to warfarin. But only six of these changes were the house mouse’s own innovations. The other four came from a close relative – the Algerian mouse, which is found throughout northern Africa, Spain, Portugal, and southern France.

The two species separated from each other between 1.5 and 3 million years ago. They rarely meet, but when they do, they can breed with one another. The two species have identifiably different versions of vkorc1. But Song found that virtually all Spanish house mice carry a copy of vkorc1 that partially or totally matches the Algerian mouse version. Even in Germany, where the two species don’t mingle, a third of house mice carried copies of vkorc1 that descended from Algerian peers.

What does the Algerian version of the gene do? Song found out after getting a tip from a pest control officer who she works with. He told her that he was having trouble getting rid of house mice in a German bakery, even after trying a powerful second-generation rodenticide called bromadiolone, or “super-warfarin”.

The officer sent over some of these resistant mice and when Song looked at their genes, she found a surprise. Both copies of their vkorc1 genes were perfect matches for the version carried by Algerian mice, but the rest of their genes showed them to be house mice. This tiny out-of-place gene made all the difference – it made the house mice nigh-invulnerable to warfarin and its chemical relatives. Super-warfarin kills around 85% of normal house mice, but it only worked against 9% of the German ones with the Algerian gene.

By the time humans developed warfarin, Algerian mice already had a head-start in resisting it. These rodents live in open, scrubby habitats and they feed mostly on seeds. They don’t get a lot of food that’s rich in vitamin K, such as leafy green vegetables and Song thinks that their vkorc1 genes have adapted to help them cope with this vitamin deficiency – indeed, it’s one of the fastest-evolving genes in its entire genome.

It just so happens that the same adaptations also allow the mice to resist pesticides like warfarin that target vitamin K. It’s probably no coincidence that other rodents which specialise on grains – such as the golden hamster and Egyptian spiny mouse – also tend to tolerate warfarin-based chemicals.

The Algerian mice transferred their resistance to house mice by breeding with them, somewhere between 5 and 32 years ago. Hybrids between the two species would normally suffer from physical problems that limit their survival in the wild, and around half of them are sterile.

But these mice were buoyed by their warfarin-resistant copies of vkorc1. At a time when humans were using warfarin and related poisons, these hybrid mice had suddenly gained a valuable defence, one powerful enough to compensate for their other disadvantages. They survived and mated with other house mice, spreading the resistance gene to their own pups.

In this way, the mice are rather reminiscent of bacteria. Individual bacteria can develop genetic tweaks that render them invulnerable to antibiotics, but they can also pick up such mutations from one another. They do so via their equivalent of sex – a process called conjugation where genetic material passes across physical bridges, established across two bacteria. The house mice have done something similar, picking up a warfarin-resistant version of vkorc1 by having sex with Algerian mice.

Humans were probably responsible for these lucky liaisons. The two species used to live in completely different parts of the world. They would never have met, had humans not brought house mice with them as they expanded into Western Europe. Once the two species showed up in the same place, they started mating. Later, humans were again responsible for giving the hybrids an edge over their pure-bred house mouse relatives. Our attempts to kill them merely unveiled a strength that had been hiding for centuries.

Reference: Song, Endepols, Klemann, Richter, Matushcka, Shih, Nachman & Kohn. 2011. Adaptive Introgression of Anticoagulant Rodent Poison Resistance by Hybridization between Old World Mice. Current Biology

Comments (10)

  1. I think I’m missing something here…or having trouble following along.

    The two species used to live in completely different parts of the world. They would never have met, had humans not brought house mice with them as they expanded into Western Europe. Once the two species showed up in the same place, they started mating.

    The problem is with how I understand evolution. If these two species were able to mate, this would mean they had to have had a common ancestor in the recent past. And they haven’t quite diversified genetically yet to the point where all of their offspring would be infertile…in which case, I’m not sure you can call them separate species. They might be separate sub-species belonging to the same species? Either way, how then, if they had a common ancestor, does it make sense that they would have never met if humans hadn’t brought them together? It seems to me that humans may have reunited the two groups…because if they had a recent common ancestor, that would mean they were recently in the same place! (Granted, they may not have reunited without human intervention. And I do understand that if the groups moved away in opposite dirrections, that makes a reunion less likely, which just leaves me with the question of where was the ancestrial species located when it split?) They way you have it written, it sounds more like crocko’duck theory than evolution.
    To make matters more confusing, earlier in the post, you had said, “The two species separated from each other between 1.5 and 3 million years ago.” So, they did have a recent common ancestor! In which case, maybe this isn’t a recently inherited gene, but maybe a less dominate gene that has actually been carried around in the house mice since that split. Especially considering if this hypothetical transference happened “somewhere between 5 and 32 years ago,” but “rodents have become increasingly resistant to warfarin ever since the 1960s.” The 1960′s are longer than 32 years ago, or by “rodents,” does that not include house mice?

  2. It’s a misconception that different species can never mate and have fertile offspring. Some of them can but either they never do because they don’t overlap, or the offspring are unfit in some way. Song’s arguing that this would normally be the case for a house/Algerian hybrid, but the warfarin-resistance gene provided enough of an advantage to compensate for any deficits.

    Warfarin resistance has been around since the 1960s, in a variety of different rodents. House mice have developed a number of mutations that confer this ability, and only some of them have been picked up from the Algerian ones.

  3. Dave

    Interesting. So, given that warfarin is a popular drug, as well as a popular rodenticide, how long before humans develop resistance to it?


  4. Dave – rodents developed resistance to warfarin because it kills them. Resistance is adaptive; there’s strong selection pressure for it. Humans use warfarin to *not* die. Different scenario – why would we develop resistance?

  5. @Leo and Ed …. isn’t this somewhat of an argument for the idea that the segregation of “species” is a wall that’s permeable, or even an argument that maybe “species” needs to be rethought in some way?

    These aren’t the only two different “species” that can interbreed, after all.

    (And, no, I’m not a creationist, IDer or troll.)

  6. Peter Ellis

    They’ve separated enough that they almost never mate when they meet in the wild – they don’t recognise each other as being appropriate breeding partners. Very rarely, they’ll mate – more so if you deliberately put them together in a laboratory environment. When they do mate, the F1 hybrid offspring have fertility problems, kinda like mules. However, only the male hybrids are sterile – the female hybrids are fertile and can themselves produce further fertile offspring when mated with either of the parental strains.

  7. Paul

    #5: the definition of species is quite tricky, and has been thought and rethought many times. Darwin spent a good deal of space talking about the issue in Origins.

  8. Steve Morrison

    Carl Zimmer wrote a whole article for Scientific American a few years ago about the problem of defining “species”. Also, this Evolving Thoughts post lists a slew of possible working definitions of “species”.

  9. If this is giving the mice an advantage, how long will it take to spread across Europe? We’ve looked at the story at

  10. Matt B.

    Okay, technically no individual mouse got warfarin resistance by having sex with a member of another species; it got it by being the offspring of mice that had sex with a member of another species.

    And related to a weird conversation I had with a friend, does this interspecies mouse mating count as bestiality? (My friend was discussing humans and Klingons.)


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