What a selfish little piece of...

Posted 3 August 2011 by Steve Matheson

"The Selfish Gene." "Selfish DNA." Oh, how such phrases can get people bent out of shape. Stephen Jay Gould hated such talk (see a little book called The Panda's Thumb), and Richard Dawkins devoted more time to answering critics of his use of the term 'selfish' than should have been necessary. Dawkins' thesis was pretty straightforward, and he provided real examples of "selfish" behavior of genes in both The Selfish Gene and its superior sequel, The Extended Phenotype. But there have always been critics who can't abide the notion of a gene behaving badly. Leaving aside silly bickering about the attribution of selfishness or moral competence to little pieces of DNA, let's consider what we might mean if we tried to imagine a really selfish piece of DNA. I mean a completely self-centered, utterly narcissistic little piece of DNA, one that not only seeks its own interest but does so with rampant disregard for other pieces of DNA and even for the organism in which it travels. Can we imagine, for example, a piece of DNA that deliberately harms its host in order to propagate itself? Sure, we might picture genes acting in naked self-interest, perhaps colluding to create an organism that can fly and mate but can't eat. We can picture genes driving organisms to take outrageous risks in order to reproduce. And we can picture millions and millions of "jumping genes" that don't seem to care at all about the host's welfare while they hop about in bloated mammalian genomes. (If you are one who prefers to think of these transposable elements as beautifully-designed marvels of information transfer and storage, you can have a pass on that last one for now, because you won't like where we're going with this.) But can we picture a gene that actively harms its host in order to get ahead? At first, this might seem ridiculous. How can harming the host help a gene propagate

itself? We can talk about the examples above, and explain each through some reproductive benefit or trade-off. But I'm not talking about negligence here; I'm talking about harm. Well, okay. I'm talking about killing babies. I'm talking about a gene that kills the embryo in which it's expressed, unless the embryo promises to propagate the gene. The most famous example of such an outrageously selfish gene is the Medea element, found in certain beetles. ('Medea' is both an acronym and a deliciously evil description of the effect of the element.) Here's the basic idea: a female that carries the Medea element has some offspring. Some of those embryos will have the Medea element in their genomic endowment and others won't. But all of the embryos will be exposed to the Medea effect, because it comes into the embryo through the egg, which was created by the Medea-carrying mother. The Medea effect kills any embryo that doesn't carry its own copy of the Medea element. The survivors are the ones that carry the element. Pretty smart, huh? How this works, exactly, is not well understood. But Medea isn't the only selfish little piece of DNA that stoops to infanticide. Another example was described just a few years ago in the nematode C. elegans, that workhorse of developmental genetics. Called the peel-zeel element, it's just a little different from Medea: in the peel-zeel system, the embryo-killing curse comes from the dad. (Selfish elements like this are quite rare, and this paternally-acting system is the only known element of that kind.) But the sick story is otherwise the same: only those embryos that carry their own copy of the peel-zeel element can avoid sperm-carried destruction. Now some new results, published in this month's PLoS Biology, are revealing how this evil plan is carried out. The article, "A Novel Sperm-Delivered Toxin Causes Late-Stage Embryo Lethality and Transmission Ratio Distortion in C. elegans," was authored by Hannah Seidel and colleagues. The group had previously shown that the paternal genetic element would kill embryos that didn't have an "antidote," and had explained the peculiar genetic arrangement that keeps this element from being driven completely to fixation in the population. (An element that kills everyone but itself would be expected to quickly infest the entire population, but this doesn't occur in the case of the peel-zeel element.) Although the authors knew a bit about the antidote gene (called zeel-1), they knew nothing about the killer gene or how it worked; they knew only that it was probably very close to the antidote gene. They did have one particularly useful tool, especially valuable in the experimental wonderland of genetics that is C. elegans: they had some mutants with perfectly good antidote function but no killing ability. So they used those mutants to do some very nice genetic mapping experiments, and discovered the precise locations of the mutations that abolished the lethal effect. Interestingly, those mutations were in an "intergenic interval" in the fully-sequenced C. elegans genome, right next to zeel-1. In other words, the killing activity seemed to be right next to the antidote, in a part of the genome that contained no known genes. Or, more accurately, it contained no annotated genes. It turns out that we're still discovering new genes in fully-sequenced genomes. (It's actually not that easy to identify a bona fide gene in a gigantic DNA sequence.) And Seidel et al. had just discovered a new gene - the peel-1 gene. It makes a protein somewhat similar to zeel-1. Once they had the actual gene in hand, the authors could probe the protein's function.

They showed that it is packed into a particular type of delivery vehicle inside sperm, which are the only cells that express it. The delivery vehicles ensure that each embryo is provided with an adequate dose of the toxin. Oddly, the lethal protein acts somewhat late in development, in skin and muscle cells, and the embryo dies a grisly death unless it carries the antidote. The image on the right (from the cover of the July 2011 issue of PLoS Biology) shows two affected embryos (the blobs on the left and right) and one happily normal worm. In another cool experiment, the authors turned on the death gene artificially in adult animals, and it killed them just fine. They could save those otherwise-doomed worms by turning on the antidote artificially. The peel-zeel element, then, is a great example of a truly ruthless selfish genetic element. The toxin and the antidote are side-by-side in the genome, so that an animal with the antidote will almost certainly also receive the toxin. (Think about how different things would look if the antidote gene were separate from the toxin; the toxin could quickly lose its ability to propagate itself through the generations.) And the toxin is sperm-delivered to all embryos. This combination of traits allows the paternally-carried element to kill any embryo without a copy of the element. As far as we know, the peel-zeel system serves only its own interests. It offers no fitness advantage to its host, and is likely instead to exact a cost. Its presence in the nematode genome is easy to explain in a biosphere teeming with "selfish" DNA that admits no evident "purpose" beyond its own propagation. That's not to say it can't be useful; as an accompanying commentary notes, DNA-encoded toxin/antidote systems could be employed by well-meaning humans to seemingly benevolent ends. But whether or not one chooses to see the peel-zeel system as a product of "design," the pattern of "selfish" propagation is hard to miss. And, surely, hard to restrain. [Cross-posted at Quintessence of Dust.]
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Seidel, H., Ailion, M., Li, J., van Oudenaarden, A., Rockman, M., & Kruglyak, L. (2011). A Novel Sperm-Delivered Toxin Causes Late-Stage Embryo Lethality and Transmission Ratio Distortion in C. elegans. PLoS Biology, 9 (7) DOI: 10.1371/journal.pbio.1001115

17 Comments

Chris Lawson · 3 August 2011

Great post, Steve. I love these fascinating little genomic discoveries. (As for people who think of LINEs as "beautifully-designed marvels of information transfer and storage", they must not be aware that LINEs tend to copy themselves rather randomly, including into the middle of functional gene sequences or control sequences.)

DS · 3 August 2011

"But whether or not one chooses to see the peel-zeel system as a product of “design,” the pattern of “selfish” propagation is hard to miss. And, surely, hard to restrain."

And that's the point. In a complex system that has evolved over millions of years, we would expect to find all sorts of redundancies, inefficiencies, suboptimal characters, balanced lethals, selfish propagation, etc. This is not the kind of thing that one would expect from any kind of intelligent design. Assuming of course that the designer is not an incompetent boob, or that the nematodes were not punished because Eve ate an apple.

The more we learn about genomes the more we understand the basics of evolution. It certainly is exciting to live in the age of comparative genomics.

Matt Bright · 3 August 2011

Not sure it's worth assuming selfishness. As I mentioned at t'other blog, similar systems are used by bacteria to shut down cell division under starvation conditions. Might something similar be happening here - make it harder to produce too many offspring when a) they won't survive anyway and b) they'll eat all your stuff so that you starve to death before you get to spawn in times of plenty. Certainly it's a testable hypothesis.

Which, I think, is the problem with value judgments like 'selfish' when applied to genes. Internalise them too much, and you tend to see the 'selfish' answer. We're creatures burdened by a tendency to cognitive bias and the formation of bogus-but-temporarily-useful generalisations. Good science, surely, does everything it can to counteract such tendencies...

Vaughn · 3 August 2011

C elegans has a different system for dealing with starvation - the dauer stage. Young, developing worms enter a long-lived, non-feeding, non-reproducing stage called the "dauer" until food reappears. Then development continues to adulthood. If there is a function for the peel-zeel system, it is unlikely to be for surviving starvation.

The Jumbuck · 4 August 2011

The question is how did the toxin and the antidote come together. How could that happen by random chance? This is a problem for Darwinism and not intelligent design. Either they just came together by random chance or else the antidote was already there before the toxin which would mean foresight which blind evolution does not possess.

Midnight Rambler · 4 August 2011

Very, very cool. I'm not sure I buy any of their potential explanations for how the system arose though. The fact that antidote is closely related to two other genes while the toxin has no clear relation to any other gene makes me wonder if the latter might be an insert from a bacterial or viral pathogen. It's hard to see how this kind of system could have evolved with two genes in parallel, but not impossible, as they demonstrate the membrane domain of zeel alone can protect against low doses of peel (though I can't wait to hear Jumbuck's explanation of how this shows intelligence).

One other neat thing - it's not just the peel-zeel element that's missing in worms without it, they have a 19 kb deletion in the genome. Quite a big chunk! So much for "all mutations are deleterious"...

Rumraket · 4 August 2011

The Jumbuck said: The question is how did the toxin and the antidote come together. How could that happen by random chance? This is a problem for Darwinism and not intelligent design. Either they just came together by random chance or else the antidote was already there before the toxin which would mean foresight which blind evolution does not possess.

Do you have any evidence that the antidote existed before the toxin or are you just making shit up as creationists always do? Do you have any evidence for the existence of your intelligent designer or are you merely question begging? Do you understand the process of mutation? Do you understand that in any given population, there is variation? Do you understand that natural selection is acting on successful variants? Can you comprehend how this process is not "blind, random chance"? In short: Do you have even the slightest clue what you are talking about, or are you only propagandising for religious doctrine? That was a rethorical question.

The Jumbuck · 4 August 2011

Rumraket said:
The Jumbuck said: The question is how did the toxin and the antidote come together. How could that happen by random chance? This is a problem for Darwinism and not intelligent design. Either they just came together by random chance or else the antidote was already there before the toxin which would mean foresight which blind evolution does not possess.
Do you have any evidence that the antidote existed before the toxin or are you just making shit up as creationists always do?

Read for comprehension, moron! I said the only alternative is that they came together by random chance. If the toxin was there first, it would have been weeded out by NS right away!

Do you have any evidence for the existence of your intelligent designer or are you merely question begging? Do you understand the process of mutation? Do you understand that in any given population, there is variation? Do you understand that natural selection is acting on successful variants? Can you comprehend how this process is not "blind, random chance"?

I was talking about how the mutation came about in the first place, and not how it was prserved by NS.

In short: Do you have even the slightest clue what you are talking about, or are you only propagandising for religious doctrine? That was a rethorical question.

Dave Lovell · 4 August 2011

The Jumbuck said: If the toxin was there first, it would have been weeded out by NS right away!

Only if you make the mistake of assuming that calling something a "toxin" assigns to it the role of the Grim Reaper. Maybe both the "toxin" and "antidote" existed in part of the population as useful or benign genes before another mutation made the possession of one and not both a lethal combination. Regardless of the selfish gene implications, I have a question for the real developmental biologists here. My understanding from this article is that the "sperm carried destruction" is not the "toxin" it carries, but the ability to make it. But is the mechanism of death understood? How does the gene producing the "toxin" essentially differ from a developmental gene which signals something like "let the limb buds waste away" in a developing whale embryo, whilst the "antidote" says "but let half of them grow into flippers"? In the case of this gene, the "let it waste away" signal triggers a fatal development path for the worm. How is this essentially different from a mutant gene signaling "let the developing heart waste away" in a whale?

harold · 4 August 2011

I can't tell if Jumbuck is serious or a parody.

The question is how did the toxin and the antidote come together. How could that happen by random chance?

No-one has suggested that they necessarily appeared together spontaneously by random chance.

This is a problem for Darwinism and not intelligent design.

What is the design explanation? 1) Who is the designer? 2) What did the designer do, precisely? 3) When did the designer dot it? 4) How did the designer do it? 5) Why did the designer do it? 6) Is there any example of anything in the universe that you would agree was not designed?

Either they just came together by random chance or else the antidote was already there before the toxin which would mean foresight which blind evolution does not possess.

It would not imply conscious foresight if the zeel-1 gene existed first. Why do you think it would?

Steve Matheson · 4 August 2011

Dave Lovell said: Regardless of the selfish gene implications, I have a question for the real developmental biologists here. My understanding from this article is that the "sperm carried destruction" is not the "toxin" it carries, but the ability to make it. But is the mechanism of death understood? How does the gene producing the "toxin" essentially differ from a developmental gene which signals something like "let the limb buds waste away" in a developing whale embryo, whilst the "antidote" says "but let half of them grow into flippers"? In the case of this gene, the "let it waste away" signal triggers a fatal development path for the worm. How is this essentially different from a mutant gene signaling "let the developing heart waste away" in a whale?

Hi Dave. Actually, yes the sperm carries the actual toxin and not just the ability to make it. (Because of the way sexual reproduction works, that sperm cell might not carry the ability to make the toxin, i.e., the gene itself.) It has to be this way for the system to work, because the dad wants to kill all embryos except those that can make the antidote. If you look at Figure 3 of the paper, you can see the toxin (the PEEL-1 protein) in green, and it's packaged into sperm, ready for delivery to the embryos. Again, the green material is not genetic material – it's protein. As for how the toxin works, we still don't know. It's a membrane protein, and somewhat similar in structure to the antidote protein (they're both transmembrane proteins), but it offers no clues by way of similarity to known proteins. The authors provide some interesting and informed speculation in the discussion, where they also consider the means by which sperm avoid death themselves. This system is quite different from "let X waste away" pathways. Such pathways usually involve programmed cell death, in which the curse is created by the cell itself. In the zeel-peel system, the lethal activity is delivered to the embryo from outside. It is possible, however, that the death-inducing actions of the PEEL-1 protein are similar to the death-inducing actions that occur in programmed cell death.

harold · 4 August 2011

Steve Matheson -

Actually, yes the sperm carries the actual toxin and not just the ability to make it. (Because of the way sexual reproduction works, that sperm cell might not carry the ability to make the toxin, i.e., the gene itself.)

In other words, I assume, if the father is a heterozygote for for the peel-1 gene, all his sperm will be packed with the PEEL-1 protein, even though, on average, only half his sperm will carry the gene. Obviously, if he is a homozygote for the peel-1 gene, his sperm will all carry both the protein and the gene, and if he is a peel-1 negative homozygote, his sperm can never carry either. I assume, then, that a single-celled zygote is loaded up with the PEEL-1 protein, which is passed on to new cells as division proceeds, rather than expressed from the genome in cells. Eventually, at some stage of differentiation, the PEEL-1 protein becomes lethal to certain types of cells, which results in the death of the entire embryo. I skimmed the original reference (the whole thing is available, thanks), so feel free to correct and mis-statements of the details. A very interesting system.

harold · 4 August 2011

I assume, then, that a single-celled zygote is loaded up with the PEEL-1 protein, which is passed on to new cells as division proceeds, rather than expressed from the genome in cells.

Oops, of course in peel-1/zeel-1 heterozygote or homozygote cells, at least ZEEL-has to be expressed, duh, to prevent cell death. It's peel-1/zeel-1 negative homozygote embryoes that can never express either, and are killed by the PEEL-1 protein from the sperm. (*In all such cases, the father had to be a heterozygote*).

Steve Matheson · 4 August 2011

harold said:
I assume, then, that a single-celled zygote is loaded up with the PEEL-1 protein, which is passed on to new cells as division proceeds, rather than expressed from the genome in cells.
Oops, of course in peel-1/zeel-1 heterozygote or homozygote cells, at least ZEEL-has to be expressed, duh, to prevent cell death. It's peel-1/zeel-1 negative homozygote embryoes that can never express either, and are killed by the PEEL-1 protein from the sperm. (*In all such cases, the father had to be a heterozygote*).

Harold, you got it. Pretty wild, isn't it?

harold · 4 August 2011

Steve Matheson said:
harold said:
I assume, then, that a single-celled zygote is loaded up with the PEEL-1 protein, which is passed on to new cells as division proceeds, rather than expressed from the genome in cells.
Oops, of course in peel-1/zeel-1 heterozygote or homozygote cells, at least ZEEL-has to be expressed, duh, to prevent cell death. It's peel-1/zeel-1 negative homozygote embryoes that can never express either, and are killed by the PEEL-1 protein from the sperm. (*In all such cases, the father had to be a heterozygote*).
Harold, you got it. Pretty wild, isn't it?

Yes, it is. That's the amazing thing about actual science. There's always something unexpected. Interestingly, this system can only have an effect when the father is a heterozygote, and the mother is either a peel-1/zeel-1 negative homozygote or a heterozygote. To be killed, the embryo has to have a father whose sperm contain the protein, but not the gene, and also had to get a chromosome lacking the gene from the mother. Since it is a binary thing - 100% lethal in homozygote embryoes lacking the gene, of heterozygote fathers, otherwise no effect - it would be relatively straightforward to calculate the change in allele frequency per generation in terms of the frequency of the peel-1/zeel-1 allele. Isn't the Medea stuff a little unfair, though? Seems like Saturn would be more fair, since Dad is the issue (warning - link to disturbing Goya painting http://upload.wikimedia.org/wikipedia/commons/8/82/Francisco_de_Goya%2C_Saturno_devorando_a_su_hijo_%281819-1823%29.jpg)

Steve Matheson · 4 August 2011

harold said: Interestingly, this system can only have an effect when the father is a heterozygote, and the mother is either a peel-1/zeel-1 negative homozygote or a heterozygote. To be killed, the embryo has to have a father whose sperm contain the protein, but not the gene, and also had to get a chromosome lacking the gene from the mother. Since it is a binary thing - 100% lethal in homozygote embryoes lacking the gene, of heterozygote fathers, otherwise no effect - it would be relatively straightforward to calculate the change in allele frequency per generation in terms of the frequency of the peel-1/zeel-1 allele.

That's true, but it appears that there are at least two other influences on allele frequency in this system. First, there's the crazy mode of reproduction in C. elegans, namely self-fertilization by hermaphrodites. This means that the cassette isn't able to spread easily in the wild because there just aren't enough opportunities. The second issue is that the homozygotes are likely to have a fitness disadvantage, perhaps because there's not enough antidote to protect from the extra dose of toxin. These issues are nicely discussed in a primer published in the same issue of PLoS Biology.

Isn't the Medea stuff a little unfair, though? Seems like Saturn would be more fair, since Dad is the issue (warning - link to disturbing Goya painting http://upload.wikimedia.org/wikipedia/commons/8/82/Francisco_de_Goya%2C_Saturno_devorando_a_su_hijo_%281819-1823%29.jpg)

Cute, but you're a little confused. Medea is a different selfish element, in a different organism, and is a maternal-effect system. Hence the name there. You might consider contacting the C. elegans people to suggest a different name. Unfortunately, the worm community has long been committed to a boringly banal three- or four-letter-then-number nomenclature for genes. It's probably too late to save them.

harold · 4 August 2011

Medea is a different selfish element, in a different organism, and is a maternal-effect system.

As is expressed very clearly in the original post; I was just too eager to reference that Goya picture.