I’ve known for years that this was going to happen: Mario Capecchi, Oliver Smithies and Briton Martin Evans have won the Nobel Prize in Medicine for their work on targeted gene mutations. If you’re interested in what kinds of work they’ve done, I described one paper on Hox regulatory evolution, and this work on the evolution of the Hox code wouldn’t have been possible without their knockout techniques.
I’ve written a long introduction to the work I’m about to describe, but here’s the short summary: the parts of organisms are interlinked by what has historically been called laws of correlation, which are basically sets of rules that define the relationship between different characters. An individual attribute is not independent of all others: vary one feature, and as Darwin said, “other modifications, often of the most unexpected nature, will ensue”.
Now here’s a beautiful example: the regulation of the growth of mammalian molars. Teeth have long been a useful tool in systematics—especially in mammals, they are diverse, they have important functional roles, and they preserve well. They also show distinct morphological patterns, with incisors, canines, premolars, and molars arranged along the jaw, and species-specific variations within each of those tooth types. Here, for example, is the lower jaw of a fox. Look at the different kinds of teeth, and in particular, look at the differences within just the molars.
Note that in this animal, there are three molars (the usual number for most mammals, although there are exceptions), and that the frontmost molar, M1, is the largest, M2 is the second largest, and M3, the backmost molar, is the smallest. This won’t always be the case! Some mammals have a larger M3, and others may have three molars of roughly equal size. What rules regulate the relative size of the various molars, and are there any consistent rules that operate across different species?
To answer those questions, we need to look at how the molars develop, which is exactly what Kavanagh et al. have done.
Cuvier, and his British counterpart, Richard Owen, had an argument against evolution that you don’t hear very often anymore. Cuvier called it the laws of correlation, and it was the idea that organisms were fixed and integrated wholes in which every character had a predetermined value set by all the other characters present.
In a word, the form of the tooth involves that of the condyle; that of the shoulder-blade; that of the claws: just as the equation of a curve involves all its properties. And just as by taking each property separately, and making it the base of a separate equation, we should obtain both the ordinary equation and all other properties whatsoever which it possesses; so, in the same way, the claw, the scapula, the condyle, the femur, and all the other bones taken separately, will give the tooth, or one another; and by commencing with any one, he who had a rational conception of the laws of the organic economy, could reconstruct the whole animal.
Cuvier famously (and incorrectly) argued that he could derive the whole of the form of an animal from a single part, and that this unity of form meant that species were necessarily fixed. An organism was like a complex, multi-part equation that used only a single variable: you plugged a parameter like ‘ocelot’ into the Great Formula, and all the parts and pieces emerged without fail; plug in a different parameter, say ‘elephant’, and all the attributes of an elephant would be expressed. By looking at one element, such as the foot, you could determine whether you were looking at an elephant or an ocelot, and thereby derive the rest of the animal.
All of us mammals have pretty much the same set of genes, yet obviously there have to be some significant differences to differentiate a man from a mouse. What we currently think is a major source of morphological diversity is in the cis regulatory regions; that is, stretches of DNA outside the actual coding region of the gene that are responsible for switching the gene on and off. We might all have hair, but where we differ is when and where mice and men grow it on their bodies, and that is under the control of these regulatory elements.
A new paper by Fondon and Garner suggests that there is another source of variation between individuals: tandem repeats. Tandem repeats are short lengths of DNA that are repeated multiple times within a gene, anywhere from a handful of copies to more than a hundred. They are also called VNTRs, or variable number tandem repeats, because different individuals within a population may have different numbers of repeats. These VNTRs are relatively easy to detect with molecular tools, and we know that populations (humans included) may carry a large reservoir of different numbers of repeats, but what exactly the differences do has never been clear. One person might carry 3 tandem repeats in a particular gene, while her neighbor might bear 15, with no obvious differences between them that can be traced to that particular gene. So the question is what, if anything, does having a different number of tandem repeats do to an organism?
One concept that is sometimes used in developmental biology is the idea of the “master control gene” or “master switch” — a single gene whose expression is both necessary and sufficient to trigger activation of many other genes in a coordinated fashion, leading to the development of a specific tissue or organ. It’s a handy concept on which to hang a discussion of transcription factors, but it may actually be of rather limited utility in the real world of molecular genetics: there don’t seem to be a lot of examples of master control genes out there! Pax-6 is the obvious one, a gene that initiates development of the eye, and other genes may be mentioned in certain stem cell pathways, but even in the eyes of vertebrates, for example, eye development is more complicated than a single switch, and similarly, many other developmental processes seem to use multiple or redundant regulatory controls — the cases where we have a single gene bottleneck are either rare or poorly represented in the literature.
They’re still at least pedagogically useful, though — it’s a simple case of imposition of a specific developmental pathway on a patch of tissue.
The Hox genes are a set of transcription factors that exhibit an unusual property: they provide a glimpse of one way that gene expression is translated into metazoan morphology. For the most part, the genome seems to be a welter of various genes scattered about almost randomly, with no order present in their arrangement on a chromosome — the order only becomes apparent in their expression through the process of development. The Hox genes, on the other hand, seem like an island of comprehensible structure. These are all genes that specify segment identity — whether a segment of the embryo should form part of the head, thorax, or abdomen, for instance — and they’re all clustered together in one (usually) tidy spot.
Within that cluster, we see further evidence of order. Look at just the Drosophila part of the diagram below: there are 8 Hox genes in a row, and their order within that row reflects the order of expression in the fly body. On the left or 3′ end of the DNA strand, lab (labial) is expressed in the head, while Abd-B (Abdominal-B) is expressed at the end of the abdomen.
Knocking out individual Hox genes in the fly causes homeotic transformations — one body part develops into another. These genes are early actors in the cascade of interactions that enable the development of morphologically distinct regions in a segmented animal — the activation of a Hox gene from the 3′ end is one of the earliest triggers that leads the segment to develop into part of the head.
Now look at the mouse part of the diagram above. We vertebrates have Hox genes that are homologous to the fly Hox genes, and they’re also clustered in discrete locations with 3’→5′ order reflecting anterior→posterior order of expression. There are differences — the two most obvious that we have more Hox genes on the 5′ side (these correspond to expression in the tail—flies do not have anything homologous to the chordate tail), and vertebrates also have four banks of Hox genes, HoxA, HoxB, HoxC, and HoxD. This complicates matters. Vertebrates have these parallel, overlapping sets of Hox genes, which suggests that morphology could be a product of a combinatorial expression of the genes in the four Hox clusters: there could be a Hox code, where identity can be defined with more gradations by mixing up the bounds of expression of each of the genes.
I got some email today with lots of constructive suggestions (See? Not all my email is evil!) for how we ought to change the education of biology students — such as by giving them a foundation in the history and philosophy of our science, using creationist arguments as bad examples so the students can see the errors for themselves, etc. — and it was absolutely brilliant, even the parts where he disagreed with some things I’d written before. Best email ever!
Of course, what helped is that I spent my summer “vacation” putting together a new freshman first semester course for biology majors that I’m teaching for the first time right now, and it’s exactly the course he described. It was eerie, like one of my future students had invented a time machine and come back into the past to tell me what to do. A lot of the course content is locked up behind a password-protected firewall, I’m afraid, but just to show you what I’m talking about, I’ll put the course schedule below the fold.
When we look at the face of another person, we can recognize specific features that have familial resemblances. In my family, for instance, I can recognize a “Myers nose” that my grandmother and my father and some of my siblings and kids have, and it’s different than my wife’s or my mother’s nose. These are subtle differences in shape—a bit of a curve, a knob, a seam—and their inheritance suggests that these differences are specified somehow in the DNA. If you think about it, though…how can whether the profile of a nose is straight or curved be encoded in a linear stretch of nucleotides? The complicated answer is that it isn’t—morphology is a consequence of epigenetic interactions during development—but we know that the alleles present in the genome do contribute in some significant way to three-dimensional form. How?
We don’t know all the details. This is one of those huge research problems that has gaping holes, full of promise and interest, where we don’t understand exactly how all the pieces fit together. However, here’s an important point that is relevant to other, larger issues in evolution: even where we lack full information about mechanisms, we can roughly perceive the shape of the answer, and that helps us rule out many alternative explanations and guides us in the general direction of a more complete understanding.
People’s noses are a difficult subject for research; we don’t get to define human crosses, people tend to be a little snippy about telling them who to breed with and taking their genes apart, and humans are awfully slow to breed. Fish are better experimental animals, much more pliable and faster and more prolific in their breeding. Some fish, such as the African cichlids, also have highly diverse populations and species with easily recognized and often quite dramatic morphological differences—and we can explore how those differences are generated by genetic and molecular differences in development. In particular, we can start to figure out how fish jaws are shaped by developmental processes.
Some of you may have never seen an arthropod embryo (or any embryo, for that matter). You’re missing something: embryos are gorgeous and dynamic and just all around wonderful, so let’s correct that lack. Here are two photographs of an insect and a spider embryo. The one on the left is a grasshopper, Schistocerca nitens at about a third of the way through development; the one on the right is Achaearanea tepidariorum. Both are lying on their backs, or dorsal side, with their legs wiggling up towards you.
There are differences in the photographic technique — one is an SEM, the other is a DAPI-stained fluorescence photograph — and the spider embryo has had yolk removed and been flattened (it’s usually curled backward to wrap around a ball of yolk), and you can probably see the expected difference in limb number, but the cool thing is that they look so much alike. The affinities in the body plans just leap out at you. (You may also notice that it doesn’t seem to resemble a certain other rendition of spider development).
Yesterday’s discussion of future biological advances that will piss off the religious right had me thinking about other innovations that I expect will happen within a few decades that might just cause wingnuts to freak out. First thing to come to mind is that it will be something to do with reproduction, of course, and it will scramble gender roles and expectations…so, how about modifying men to bear children? It sounds feasible to me. Zygotes are aggressive little parasites that will implant just about anywhere in the coelom — it’s why ectopic pregnancies are a serious problem — so all we need to do there is culture a bit of highly vascularized tissue in the male abdomen that will serve as a secure home for a few months. We’ll have to play some endocrine games, too, which may effect his love life but will also prepare him to lactate post-partum. There’s the minor anatomical problem that the vagina is a unique tissue, and no, the urethra is not homologous or analogous (fortunately; we wouldn’t want to have to push an 8 pound baby through the penis, even if female hyenas can manage it) — but that’s what c-sections are for. Given money, time, and a few weird volunteers, it could be done.
The next question is, has it been done? Are there any other vertebrates that have males doing the hard work of pregnancy? There were the gastric brooding frogs, which one would think could have made the leap easily — the eggs were just swallowed and developed in the stomach — but only the mothers seemed to have done the job. They’re all extinct, anyway. Male frogs of the genus Rhinoderma brood their young in their mouths, but this is after external fertilization and development, so they’re actually simply holding larvae in a safe place — and they’re also endangered. The precedents aren’t promising.
There is an extremely interesting and successful example, though: the syngnathid fishes, sea horses and pipefish. In all 232 species, the female lays her eggs in a specialized male structure called the brood pouch, where they are fertilized and develop. It’s a true male pregnancy!
