Different animals converge on similar toxin resistance

Toads, bugs, snakes, and more all resist similar toxins. And it turns out they use the same genetic trick...
14 September 2020

Interview with 

Anurag Agrawal, Cornell University


DNA helix


In the previous section, Anurag described how there are only a few tiny mutations behind monarch butterflies' resistance to cardiac glycosides. These toxins are ones that a lot of very different animals have independently learned to tolerate - from toads, to bugs, to snakes. And according to Shab Mohammadi from the University of Nebraska, they’ve all stumbled on the same trick...

Shab - The way that all of these animals that are resistant to these compounds known as cardiac glycosides achieve this resistance is a really perfect example of convergent evolution where wildly different unrelated species have all somehow achieved this same adaptive solution. The solution in this case involves mutations in the sodium potassium pump gene. These mutations alter the biochemistry of that region of the protein, so that instead of binding to the toxins, they repel them. They're different mutations, they're different specific changes in the code, but the end product, the end effect is the same and the region in which the mutations occur is the same.

Phil - Is it surprising that all these different, like very different in some cases, animals should have come up with the same solution?

Shab - Yeah, it is. It is very surprising. And it's remarkable when we see cases like this of extreme convergence, where you have this very specific solution to this shared problem.

Phil - But why then are the mutations that each animal uses, why are they slightly different?

Shab - That comes down to the dependence of mutations on the genetic background. We all have the same genes, but each gene has slight differences accumulated over millions of years of evolution. Your gene for the sodium potassium pump protein is slightly different than that of a, for example, hognose snake. And if you make a change to one region that interacts with another region, then they might work together to produce, for example, resistance to a toxin. If one change is there but, then you won't be able to produce the same resistance.

Phil - So how then do you test a mutation in a whole different context, AKA, a whole different animal?

Shab - We genetically engineer a virus to contain instructions to produce a protein with a mutation. And then we infect cells with this virus and the virus infects the cell and instructs the cell to produce this mutated version of the protein.

Phil - In that case, all you're basically getting is this sodium pump protein as if it's from one animal, but it's got the mutation from another?

Shab - Exactly. That's the end product.

Phil - So what do you find?

Shab - Well, we found that these mutations do indeed have highly context dependent effects. Moving the rat mutation onto a snake did not give snake resistance, and moving the mutation from a snake onto an ostrich ended up disabling the function of the protein.

Phil - And, and there was no situation where you could do one better on evolution and make the pump work better?

Shab - Yes, there was actually!

Phil - Oh my God!

Shab - The chinchilla is not a resistant animal, but when you move the rat mutation onto a chinchilla, it suddenly becomes the most resistant sodium potassium pump that I believe has ever been documented.

Phil - What, why?

Shab - We don't really know, but it all boils down to context dependence.

Phil - Now we've also been talking before about the cost of changing such an important protein like this. Is that something that you find in your studies as well?

Shab - There have been a few specific cases where we found other mutations throughout the gene compensating for negative effects caused by the resistance conferring mutations. Then it becomes a question of, well, in what order did these mutations have to happen? And you can imagine that these additional mutations must have been there in place before the resistance conferring mutations could have arisen.


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