Tuesday, October 25, 2005

Vampire by proxy

It's heartwarming that when people see articles about bizarre feeding or sexual practices in invertebrates, they instantly think of me and send me a PDF (thanks, Kevin Bolding!) Here's a spider, Evarcha culicivora, with a happy appetite—it eats mosquitos. We Minnesotans would be pleased with that.

However, it prefers to snack on mosquitos that have already had a blood meal. It likes its prey to load up on our blood first, and then it catches the engorged mosquito and gets a tasty dollop of red-blooded chordate juice with the crunchy insect. We're like ketchup to these guys!

Spiders do not feed directly on vertebrate blood, but a small East African jumping spider (Salticidae), Evarcha culicivora, feeds indi- rectly on vertebrate blood by choosing as preferred prey female mosquitoes that have had recent blood meals. Experiments show that this spider can identify its preferred prey by sight alone and by odor alone. When presented with two types of size-matched motionless lures, E. culicivora consistently chose blood-fed female mosquitoes in preference to nonmosquito prey, male mosquitoes, and sugar-fed female mosquitoes (i.e., females that had not been feeding on blood). When the choice was between mosquitoes of different sizes (both blood- or both sugar-fed), small juveniles chose the smaller prey, whereas adults and larger juveniles chose the larger prey. However, preference for blood took precedence over preference for size (i.e., to get a blood meal, small individuals took prey that were larger than the preferred size, and larger individuals took prey that were smaller than the preferred size). When presented with odor from two prey types, E. culicivora approached the odor from blood-fed female mosquitoes signifi- cantly more often the odor of the prey that were not carrying blood.

More power to the clever arachnid, I guess, but I'm just not used to thinking of myself as a condiment.

---

Jackson RR, Nelson XJ, Sune GO (2005) A spider that feeds indirectly on vertebrate blood by choosing female mosquitoes as prey. Proc Natl Acad Sci U S A. 102(42):15155-60.

Monday, October 24, 2005

Flap those gills and fly!

I am going mildly nuts right now—somehow, I managed to arrange things so multiple deadlines hit me on one day: tomorrow. I've got a new lecture to polish up for our introductory biology course, a small grant proposal due, and of course, tomorrow evening is our second Café Scientifique. Let's not forget that I also have a neurobiology lecture to give this afternoon, and I owe them a stack of grading which is not finished yet. I'm really looking forward to Wednesday.

Anyway, so my new lecture for our introductory biology course is on…creationism, yuck. What I'm planning to do is to describe some of the most common creationist arguments and then give a biologist's rebuttal. Creationism is really a waste of our class time, but using it to explain some general concepts that any informed biologist should understand (and that the creationists, including Mike Behe, are astonishingly clueless about) will make it a little more productive, I hope. We'll find out tomorrow.

One of the common creationist claims I plan to shoot down is the whole idea of "irreducible complexity" as an obstacle to evolution. I was going to bring up two ideas that invalidate it: the principle of scaffolding (which I discussed here), and exaptation, in which features evolved for some other purpose than the one that they play in an organism we observe today. I was looking for a good example, and then John Wilkins fortuitously sent me a paper that filled the bill (we evilutionists, you know, are sneakily sending each other data behind the scenes to help in our assault on ignorance. We're devious that way.)

The question is how insect wings evolved. Wings are a classic issue in evolution, because they aren't going to function for flight at all until they've achieved a certain minimal size—half a wing isn't any good at all for getting an animal in the air, so any explanation for their selective evolution has to incorporate alternative functions: as stabilizers for cursorial animals, for instance, or traps for catching small prey on the run.

In insects, we have an interesting origin explanation for wings: they're modified gills. It makes sense. For gills, you want to have an increased surface area for gas exchange, and you want them exposed to the external environment. Most animals evolved sophisticated gills with convoluted surfaces and tucked them away in a protective chamber, with a mechanism to pump water over them, but others took a simpler path. Mayflies, for instance, have flat vanes on each segment in the larval stage as respiratory surfaces—they even look like wings. Arthropods evolved a recipe for flat, cuticular structures to serve as gills, and perhaps one explanation for the evolution of wings is that they simply re-evoked that recipe as adults, used it for gliding, and then expanded and elaborated on the formula incrementally to generate flapping, powered flight.

More evidence for this hypothesis comes from an analysis of non-flying arthropods, the crustaceans. The arthropod limb is primitively complex with multiple branches, shown below, while insects have stripped it down to a simpler jointed stalk. Many crustaceans have retained the tripartite branching structure of the limb, with an endopod (the foot), an exopod, and of most interest to us right now, a dorsal epipod.

The insect arrangement is illustrated at the top. They have wings and legs, diagrammed as simple discs (appropriately; they form from imaginal discs in the larva). We also have a lot of information about patterns of gene expression in these structures in insects. A gene called engrailed (en) is expressed in just the posterior half of each segment, and this gene has the same pattern in crustaceans. There is also a gene called Distal-less (Dll) that is expressed in all appendages; that one isn't quite as interesting for this study. The genes that are particularly provocative are pdm, which is expressed only in the insect wing and not in the leg, and apterous (ap), which is expressed only in the dorsal half of the wing and in a narrow ring on the leg. The question is whether a) crustaceans also have pdm and ap, and b) if they do, are they expressed in the epipod, which would suggest that wings and epipods are homologous structures.

And the answer is yes to both. Genes homologous to the Drosophila ap and pdm genes were identified in Artemia, and they are active in just the epipods of the crustacean limb. Pdm is similarly active in the epipods of the crayfish.

What it implies in the evolution of the arthropods is that the wings of pterygote insects are derived from epipod gills, or alternatively, have coopted a molecular pathway that first arose in epipods. While most of the terrestrial arthropods have been simplifying their limbs, the winged insects retained one element that gave them the power of flight.

It's this kind of history that invalidates Behe's notion of irreducible complexity. Sure, it's hard to imagine why an aquatic arthropod would begin the stepwise Darwinian process of assembling a set of wings for flight, but what this work shows is that there is an incremental pathway for expanding epipods as aqueous respiratory surfaces. The mistake creationists make, which seems intrinsic to their nature, is to assign functions erroneously to adaptations, when the simpler idea that structures have only local and immediate functions is far more productive over the long term. It's the same with Behe's favorite example, the flagellum: if it evolved as a secretory pump first, it wouldn't have required every feature of an "outboard motor" to function. His mistake is to assume that every step in its evolution was part of a drive to make a motor.

---

Averof M, Cohen SM (1997) Evolutionary origin of insect wings from ancestral gills. Nature 385:627-630.

Saturday, October 22, 2005

Cicadas

The winner of the AAAS Multimedia Science and Engineering Visualization Challenge is this very nifty movie of the 17 year cicadas. The whole above-ground part of their life cycle is right there to creep everyone out.

Just plain mean

Phil Plait alerted me to this abusive page where FARK is making fun of cephalopods. Look at this little fella—he's adorable!

Friday, October 21, 2005

Looking for Halloween costume ideas?

If you want something really terrifying, dress up as one of the viruses DarkSyde describes. They are truly creepy.

And if you believe certain people, every one of them was intelligently designed by the Great Cosmic Bastard.

Friday Ark #57

I've got to start pimpin' the Friday Ark more—they're slipping on the invertebrate category again. Here are a few organisms the Modulator needs to add: pycnogonids (invertebrates), plesiosaurs (didn't make it), and crinoids at this other site (more invertebrates). Send him more!

Thursday, October 20, 2005

Pycnogonid tagmosis and echoes of the Cambrian

I'm going to introduce you to either a fascinating question or a throbbing headache in evolution, depending on how interested you are in peculiar details of arthropod anatomy (Mrs Tilton may have just perked up, but the rest of you may resume napping). The issue is tagmosis.

The evolutionary foundation for the organization of many animal body plans is segmental—we are made of rings of similar stuff, repeated over and over again along our body length. That's sufficient to make a creature like a tapeworm or a leech (well, almost—leeches have sophisticated specializations), but there are further steps involved in making a fly or a spider or a human. There is an arrangement of positional information along the length of an animal, so one segment can recognize whether it is near the head or the tail, and the acquisition of new patterns of gene expression based on that positional information that cause the development of specialized structures in different segments. That process of specializing segments is called tagmosis. It's how a fly forms mouthparts in head segments, legs and wings in thoracic segments, and no limbs at all in abdominal segments.

The relationships between segments and how they are specialized are key features in identifying patterns of descent in the arthropod clade. An analysis of those elements in an obscure group, the pycnogonids, has uncovered a surprising relationship—they seem to be related to well known Cambrian organism. You'll have to read through to the end to discover what it is.

Tagmosis isn't such a difficult concept so far. Add to the specializations the idea that segments can be reduced and lost (maybe) and more commonly fused with adjacent segments, though, and it starts to get messy when you look at an organism and try to puzzle out what segment is what. You may look at an adult fly's head and see a smooth and relatively seamless dome, but that structure is assembled embryonically from six segments.

I think.

One other property of tagmosis is that analyzing it triggers the most passionate, heated, long-running arguments. I write "six segments", and could say more about the identity of each of those segments, and somewhere there is an arthropod taxonomist and embryologist who will wax wroth and prepare a lightning bolt with which to smite me low. Let me just say outright that I am not an expert in arthropod anatomy, and everything I write here about the details is provisional and subject to correction by real experts. I'm just going to recite the rough pattern as many of us understand it, and I'm sure that anyone with knowledge much deeper than mine will happily enlighten and correct me. Please don't kill me. I have to finish paying my childrens' tuition.

Anyway, the general pattern of segment organization in an insect's head is that the first segment forms something called the acron, the second has the antennae, the third the mouth, the fourth the mandibles, and the fifth the maxillae, and the sixth the labium. Look at the weird tangle of dangly bits in the bottom half of a grasshopper's face for instance, and what you see are highly modified limbs all scrunched together.

That's what insects are like. What about other arthropods? This is where it gets interesting. There are different specializations, different patterns of organization, in different arthropod groups. These differences would be useful cues to sort out their evolutionary histories, since modifications of the head and brain and feeding structures are rather fundamental to the organisms' life styles, if only we were confident of the homologies. Here, for instance, is a table of arthropod segment and appendage identities, taken from Raff's Shape of Life^{(amzn/b&n/abe/pwll)}.

---

That's Raff's consolidation of observations from several sources, so again, please don't kill me if you favor a different set of homologies. It's an example.

Resolving the homologies here would help us understand how these groups are related to one another. It's a tricky business (especially with all those ferocious taxonomists taking pot-shots at you), but the way to get at the answers is straightforward: hard work. Examining a wide array of organisms. And using new tools to see deeper into the tissues and molecules of these highly modified head segments.

So here's an example of exactly those strategies. It's a study of a rather obscure group of organisms, the pycnogonids or sea spiders. They're an ancient group of bizarre arthropods (here's a photo of a 425 million year old sea spider; it's very fun, a color stereopair. Cross your eyes and see it in 3 dimensions!) that have long been considered a sister group to the chelicerates, which includes spiders and horseshoe crabs and scorpions. They have a thin stalk of a body and long spindly limbs, and on their heads they have a prominent pair of appendages called chelifores. These appendages have long been thought to be homologous to the chelicerae, or "fangs", of spiders, but at the same time there have been enough doubts that no one was quite confident enough to call them chelicerae, so chelifores they are. If they are homologous to chelicerae, though, that would help confirm that the pycnogonids are closely related to spiders. If they aren't homologous, there's going to be a bit of a scramble as the arthropod family tree gets reorganized.

Here's a drawing of a larval (left) and adult (right) pycnogonid. As you might know, one way to probe the origins of a structure is to look embryonically and examine the relationships in a relatively simple, unelaborated form.

A couple of charming facts about pycnogonid child-rearing: It's the father who's in charge of tending to the embryos, and my favorite detail of all, the larvae consist of just the primitive head of the animal—no thorax, no abdomen, no legs. Just a head. The appendages in the drawing on the left are all the head appendages, and only later as it matures does the larva sprout a body. I think that is so cute.

The question is whether those big chelifores are homologous to spider chelicerae. How would we figure that out? In the table up above, you can see that spider chelicerae form on the second head segment…so we want to see to which segment the chelifores belong.

One way to work that out is to identify the neuromeres that innervate it. The insect brain is made up of lobes or ganglia called neuromeres associated with each segment, that extend nerves into the appendages also associated with that segment. In adults, these ganglia tend to run together and fuse, making their relationships harder to sort out, but their positions in the embryo are much clearer. The neuromere in segment 1 is called the protocerebrum, that in segment 2 is the deuterocerebrum, and the one in segment 3 is the tritocerebrum. If the pycnogonid chelifore is homologous to a spider chelicera, it should be innervated in the same way, by nerves from the deuterocerebrum in segment 2.

The answer is illustrated in the complicated figure below. The photograph is of immunostained neurons in the larval head, which are grouped into ganglia. The diagram in the top half labels the clumps of cells; in orange is PR, the protocerebrum, and two pairs of small nodes below, labeled A2G and A3G respectively, are the deutero- and tritocerebrum. Can you tell which ganglion has nerves (in red) running into the chelifores (LCH and RCH)?

Yep. The chelifores are not innervated by the deuterocerebrum, so this piece of evidence suggests that they are not homologous to chelicerae. They are innervated by the protocerebrum. They are something different. They seem to be homologous to certain other organs found in ancient stem-group arthropods known from the Cambrian, Kerygmachela and Leanchoilia and the best known of them all, Anomalocaris, all of which had a large structure on the front of their heads called the great appendage, which as near as can be distinguished in the fossil material, is part of segment 1 and was probably innervated by the protocerebrum.

I think it's really cool that a distant cousin and descendant of Anomalocaris is still doddering about in the ocean depths.

As I mentioned above, this observation does shake up the arthropod family tree a bit. Below are two different cladograms. The right side is the current view, with the Pycnogonida and Chelicerata as sister clades, more closely related to each other than to the Mandibulata, insects and crustaceans. This view assumes chelicerae and chelifores are homologous structures. On the left side is the cladogram if they are not homologous, and the chelifore is instead homologous to the great appendage of the stem arthropods. That would mean the Pycnogonida are linked to the base of the arthropod tree, and are the most primitive branch of that distinguished group.

With pycnogonids as the surviving member of the most basal arthropods, we can also infer something about the organization of the ancestral arthropod's head and brain.

…our results support previous models of head evolution that predict that the original arthropod bore an acronless four-segmented head, encapsulating a tripartite circumoral brain rotated in an axial position, reminiscent of that found in onychoporans, nematodes and other cycloneuralians.

That's one of the beautiful things about evolutionary biology. The data fit together so well, and every new observation brings us a clearer picture of our planet's evolutionary history. We can still see echoes of the ancient world in the molecules of life.

---

Maxmen A, Browne WE, Martindale MQ, Giribet G (2005) Neuroanatomy of sea spiders implies an appendicular origin of the protocerebral segment. Nature 437(7062):1144-8.

Wednesday, October 19, 2005

Tangled Bank #39

You'll find Tangled Bank #39 at The Questionable Authority right now. Go!

Tuesday, October 18, 2005

Plesiosaur poop!

As Chris Clarke told me, "They were big ducks!" Two newly discovered elasmosaurid plesiosaur specimens from the Cretaceous contained a surprise that told us a little more about their diet.

What was found were specimens with their stomach contents preserved, and what they contained were gastroliths, or gizzard stones (no surprise there; plesiosaur remains have long been associated with gastroliths) and gastropods and crinoids. The gastroliths in this case were identified to have come from a site over 300km away, so the plesiosaurs were certainly doing some traveling over their lifetimes.

Here's a new word for me, too: bromalite. You've probably heard of coprolites before, fossilized feces. A bromalite is basically fossilized colon contents, all the stuff that has worked its way through the gut but hasn't been excreted yet…so this poor beastie was killed before it could void its bowels one last time. Here's a picture of that terminal lump of intestinal blockage:

This changes our view of their feeding habits a bit—they were ducking their heads down under water to scoop up benthic (bottom dwelling organisms) like clams and gulping them down. I've always had this image of long-necked plesiosaurs darting after fish, but they may have used those necks more to reach down and snaffle up less mobile prey.

---

McHenry CR, Cook AG, Wroe S (2005) Bottom-feeding plesiosaurs. Science 310(5745):75.

Disquieting facts about evolution

Jody Wheeler finds a jewel of a quote from Barbara Forrest:

We have established scientifically some disquieting facts: (1) human beings have evolved from nonhuman life forms, meaning that (2) at one time we did not exist, and that (3) according to paleontological and astronomical evidence, at some time in the future we shall cease to exist.

Furthermore, from a scientific standpoint, there is no discernible reason that we had to evolve in the first place, and there is no guarantee that we shall continue to evolve successfully; more hominid species have become extinct than have survived. The price of such knowledge has been the gnawing question of whether human existence has genuine meaning if it was constructed with cranes rather than supported by skyhooks, as Daniel Dennett says.

The problem of meaning is easily resolved for those who embrace a preconstructed system of meaning such as religion. However, religion cannot help us find meaning in any honest sense unless it can assimilate the truth about where human beings have come from, and the only real knowledge we have about where we came from we have acquired through science.

I can see where many would find that first paragraph disturbing. You'd think the concept of personal mortality would make a similar idea about the species as a whole familiar, if uncomfortable to contemplate, but fundamentalist Christianity seems to be an exercise in the denial of death.

Now if only she hadn't cited the awful Dennett…

Monday, October 17, 2005

Science and non-science

Yesterday's San Francisco Chronicle had an interesting op-ed: Creation and the limits of science.

The requirement that science stick to material observation means that the scientist can state that the world acts as if it were created 14 billion years ago. It does not mean the scientist can legitimately claim that science shows that the world actually was created 14 billion years ago.

Indeed, it is not inconsistent with science to assert that the world was created 6,000 years ago or 10 minutes ago.

This point was elegantly articulated decades ago by the British Nobel Prize-winning philosopher and logician Bertrand Russell. Russell observed that it was entirely possible that the world was created 10 minutes ago and that he, Bertrand Russell, was created simultaneously, wrinkles and memory included.

Since this hypothesis could in no way be tested, it held little interest for Russell.

When I raise Russell's line of reasoning with scientists, they're surprised and dubious, but once they've thought it through, they agree with the logic.

I'm neither surprised nor dubious—I thought it was conventional wisdom. Creationists have a specific set of beliefs that are actually very easily justified. Just declare a miracle. They have this god-being who can do anything and everything, so why not use him? Poof, the universe exists. Poof, it's populated. Zap, he kills everyone with a magical flood. And of course, abracadabra, he conceals all the evidence for these amazing events beneath a mirage of old age. There aren't any arguments science can bring to bear against any of that. As Russel noted, the sin of Last Thursdayism is that it's simply uninteresting.

The Omphalos hypothesis is just the most extreme version of an uninteresting explanation. Unfortunately, as comic book fans know and mock, the omnipotent superhero who can do anything without any struggle also makes for an awfully boring narrative. The old gods at least engaged in a little carnal boinking or got drunk and brawled, but this new monotheism is awfully tedious and sterile that way. And it's increasingly hard to take credit for natural events like rain and grain sprouting with those scientists explaining everything. And when people are looking for real miracles, they turn away from the priests and look to the much more reliable doctors.

The 'scientific' creationists and Intelligent Design creationists know this, and they've been scrabbling to grab a piece of science's credibility for years. They've contrived feasibility studies of Noah's Ark, used computer models (poorly) to argue for vapor canopies, and fudged physics to claim the speed of light has been decreasing. This is where our beef with creationism lies—their desperate abuse and corruption of science to rationalize their beliefs. They do bad science. It's the same with the Intelligent Designers—it's not that that kind of intervention is declared impossible a priori, but that they don't have the evidence to support their contention. If they just said "God (or Designer) did it," we'd be done with the argument…although then, of course, they'd have abdicated any attempt to smuggle their religion into our public school science classrooms.

I do have a few gripes with Craig's article. This comment—"it is not inconsistent with science to assert that the world was created 6,000 years ago or 10 minutes ago"—is not correct. As I say over and over again, science is a process, not a body of conclusions, and any competing process that relies on assertion and revealed knowledge is inconsistent with science. When someone tries to replace the hard work of observation and testing and logic with clerical fiat, they are being anti-scientific in a very profound and fundamental way.

I also think he is splitting rhetorical hairs.

In the present contentious environment, the scientific community needs to cease making the indefensible claim that science shows the world was not created 6,000 years ago.

To say that science shows the world was not created 6000 years ago is a perfectly reasonable statement, unless one mistakenly treats science as an oracle and interprets it as meaning that science has uncovered an absolute truth about the world. When it is treated appropriately as a collection of evidence and tools and procedures, then it is clearly true: the scientific evidence is incompatible with a young earth. You have to use non-scientific ideas to show otherwise.

Creeping crinoids

They move. They look like immobile plants, squatting there on their stalks, but it turns out they can take off and scuttle slowly around.

How to euthanize a fish

Idyllopus asks a good question: how do you humanely euthanize a fish? As a fish biologist, I get this question fairly often.

Another question I get is, "Fish can't feel pain, right?" It's usually phrased exactly that way, too—they aren't looking for an accurate answer, they're looking for a reassurance that casual brutality towards cold and slimy creatures is acceptable. The actual answer, though, is "Of course they can feel pain, you clueless boob! Mind if I put this barbed hook through your lip?"^* The fish cutaneous sensory network is intricate and exquisite, and they react vigorously to noxious stimuli. We often don't recognize their responses because fish faces are rather expressionless, but if you're in the know you learn to notice the signs. Zebrafish, for instance, blanch noticeably when they're stressed or fearful or in pain.

So how should one kill a fish? People recommend some incredibly brutal methods. Throw them in a blender, they say, it's quick—yeah, and I imagine that throwing cats in a woodchipper would be quick, too, but no one suggests that humane societies should adopt it. There's also the 'club them over the head' method, or 'pick them up by the tail and whack them hard against a table edge'. Those work, if the executioner is swift and sure, which most people aren't. In most cases you end up with a fish frantically flopping on the table, or a bleeding mess of an animal that's feebly twitching, so you have to whack it a few times. (This is how my father and I used to kill salmon, though: we had a heavily weighted club, and we were also very quick and confident.) I think plucking an aquatic animal out of its environment and swinging it through a hostile atmosphere also counts as inhumane.

Less nasty techniques are the freezer and alcohol strategies. I don't think putting a fish in a freezer is humane: they don't seem to react strongly to slowly freezing to death, but then they can't—their metabolism is shutting down. Fish tend to be very sensitive to cold, though, and seek out optimal temperatures and avoid the cold, and can respond to changes of a few degrees with shock, so I have my doubts that this is a good way for them to go. Putting them in water with a few percent alcohol might be OK; they do get drunk, pass out, and die, just like people can.

Here's the way I euthanize fish, though, and since I've killed many thousands, I can say it's the cleanest, least painful way to do it, for both me and the fish. It's an anesthetic used for frogs and fish that goes by various names: ms222, MESAB, 3-aminobenzoic acid ethyl ester, tricaine methanesulfonate, or, as most of the pet and aquaculture supply houses call it, Finquel. For routine anesthesia, I use a 0.2% solution of the stuff—let a fish swim in it for a few minutes, they lose consciousness, you can do various surgeries on them, and then put them in clean fresh water, and a few minutes later, they're awake and swimming around again. If I need to euthanize them, I use a 0.4% solution (or more crudely, I use my 0.2% stock and sprinkle a few extra crystals of the ms222 powder in the beaker), put the fish in it, they fall asleep…and after 3-5 minutes, their heart stops. It will kill them at lower doses, but simply takes longer.

I get my stuff from Sigma, catalog number a-5040, for those of you who can purchase through academic suppliers. Otherwise, here are a few commercial places that will sell it to you: Doctors Foster & Smith, PondRX, and Argent Labs. It's about $15-20 for a 5 gram bottle, which sounds expensive, but a little goes a very long ways. I bought a 25 gram bottle 8 years ago, and I've still got lots left…and I euthanize fish far more often than your usual pet fish owner.

It's good to be prepared, too. Several years ago, my colony was suddenly struck with hemorrhagic septicemia, a bacterial infection that causes blood vessels to rupture and fish to die slowly and unpleasantly and messily, and after spending days trying to treat it with antibiotics and water changes and new tanks and hoses and so forth, I had to spend a sad afternoon putting about 400 fish out of their misery. Using an anesthetic in bulk was the only reasonable way to do it.

^*While I am fully aware that fish can feel pain, I still enjoy fishing and eating fish. I just don't delude myself into thinking the fish are enjoying themselves in a friendly tussle out there on the end of the line.

Saturday, October 15, 2005

Tourette's and SLITRK1

Our brains are complicated structures in a delicate balance, and there are many ways that their function can go wrong. Tourette's Syndrome, for instance, is a strange disorder where the afflicted have motor and vocal tics of varying severity—the most dramatic cases have socially debilitating outbursts of grunting, barking, or shouting, but most cases involve only minor twitches. They are driven by unusual behavioral compulsions beyond their control (I think many of our behaviors are driven by deep biological imperatives that we take for granted and don't notice because everyone else is doing the same thing…Tourette's is a situation where the drives generate behaviors that do stand out). A new paper in Science describes one gene that may play a role in Tourette's, and I thought the most interesting thing about it was the multiple, subtle ways the gene can be modified to affect the behavior.

The gene of interest is SLITRK1. This gene gets its name from its similarity to Slit, a well-known gene that is secreted and can repel growing neurons, and Trk, a family of tyrosine protein kinase receptors—it's a protein that can bind extracellular signaling molecules, and can also affect the growth of neuronal processes. SLITRK1 is also expressed in specific regions of the brain that are known to be affected in Tourette's Syndrome. That's a suggestive combination.

Just being suggestive isn't enough, though: you need to find evidence of a link. Here's an example of such evidence, a teenaged boy with an easily detected chromosomal change.

The pedigree shows that the affected individual (the dark square) has no family history of Tourette's Syndrome; he's a brand new case, likely the product of a novel mutation. Examining his chromosomes revealed a change in chromosome 13, with a region (q11 to q33) inverted, which was not shared with any of his other family members. There are 3 genes in this region that might be affected, but only SLITRK1 has the association with the brain to make it a likely candidate.

This boy has a perfectly normal SLITRK1 gene, though. It's within the inverted region, but has not been damaged in any way by the flip—it has only changed its position within the chromosome. The investigators suspect a position effect. Gene activity can be modulated by the location within a chromosome, by the level of activity of neighboring genes. For instance, cellular mechanisms to inactivate genes, such as methylation or the binding of proteins, are not perfectly precise, so a gene that is located near a region that is strongly inactivated is at risk that it will be 'accidentally' silenced with a high frequency. They suspect that this boy's SLITRK1 gene has been downregulated in its new location.

With SLITRK1 as a new suspect as one causal agent in Tourette's Syndrome, the investigators began screening known Tourette's sufferers for more anomalies in this particular gene. Most were negative. This is not a surprise; complex behavioral syndromes are not going to be easily pinned down to precisely one cause. However, they did find another individual with the pedigree to the right; he was affected with Tourette's, and his mother (the half-shaded circle) had a related syndrome, trichotillomania.

When their SLITRK1 genes were screened, mother and son were found to have something unique, that was not shared with other, unaffected members of the family. Their gene had a truncating frameshift mutation. This is not a subtle change at all, but an abrupt break in the gene product. One of their copies of the SLITRK1 gene is completely nonfunctional.

They found other cases of a changed SLITRK1 gene in individuals with Tourette's, but this one is the most subtle of them all. In this case, the coding sequence of the gene is unchanged, but one nucleotide of the untranslated region of the gene is changed from a G to an A. This a portion of the DNA that gets transcribed into the RNA string, but is clipped out of the sequence that will make the actual protein—you'd think it wasn't particularly significant. In this case, however, the change helps the SLITRK1 RNA bind better with a specific micro-RNA, miR-189. Micro RNAs are tiny pieces of RNA that bind to transcripts and modulate their translation into protein, in this case to reduce the production of SLITRK1 in the cells.

So, in a minority of Tourette's cases, they've discovered three kinds of changes to SLITRK1 that are correlated with the syndrome: a change in gene position within the chromosome, a truncation of the gene product, and an increased sensitivity to micro RNA binding. What exactly does SLITRK1 do to neurons?

You can't poke around in Tourette's brains, and you can't go around tweaking their genes to see what happens either, but you can do a cool experiment: introduce human SLITRK1 genes into mouse cells.

On the left are a quartet of mouse neurons in the control group at 6 days in vitro. They had a construct introduce that consisted of only GFP, green fluorescent protein, as a marker.

In the middle are a quartet of neurons containg GFP and human wildtype SLITRK1. These were significantly bushier than the controls.

On the right are mouse cells with the truncated mutant form of SLITRK1; they are significantly less branchy than the cells with wildtype SLITRK1. The presence of the gene is clearly associated with more complex arbors in these cells.

So changes in this gene are associated with changes in behavior, and gene expression affects growth and morphology of neurons. I'm comfortable with the case made that this gene affects processes that are responsible for some cases of Tourette's Syndrome. I want to emphasize, though, that this is not a Tourette's Syndrome gene—it is one among many genes that modulate complex interactions in brain development, and contributes to the molecular machinery that assembles the brain. We have to be very careful about statements that a particular gene is for something. We wouldn't say that cadmium red pigments are responsible for an artist's painting of a sunset, after all, even if they are helpful in generating brilliant color. A good artist can make a great painting with only ochre in his spectrum of reds, and all the cadmiums and chromiums in the world won't turn a duffer at the easel into a Matisse. It's the same with genes like this that affect the brain; a broken SLITRK1 does not make for a broken brain, just as an unmutated form doesn't guarantee a healthy one—it just means the individual is working with a different palette.

---

Abelson JF, Kwan KY, O'roak BJ, Baek DY, Stillman AA, Morgan TM, Mathews CA, Pauls DL, Rasin MR, Gunel M, Davis NR, Ercan-Sencicek AG, Guez DH, Spertus JA, Leckman JF, Dure LS 4th, Kurlan R, Singer HS, Gilbert DL, Farhi A, Louvi A, Lifton RP, Sestan N, State MW (2005) Sequence Variants in SLITRK1 Are Associated with Tourette's Syndrome. Science 310(5746):317-20.

Pedantry and dead-pan sarcasm

It's something those Brits do so well.

Affiliated sites:

Random Dozen