Hox box…

by Jim Caryl

[ratings]

WHAT do hedgehog, merlin and okra have in common with jelly belly, pimples and Genghis Khan? What if I said that hedgehog is not just a cute, spiny mammal? That Merlin is not just the name of a bird and a wizard? That okra is not just a vegetable? Would you be interested to learn that “jelly belly” is crucial for gut muscle development? “Genghis Khan”, far from being a Mongol lord who conquered Asia, is involved in the stimulation of structural components in cells. Oh, and we can look to “Merlin” to restrain cell proliferation.

Confused? Don’t be. They are all names of genes – sequences of DNA that exert influence on a creature by encoding and regulating the production of a protein. These particular genes are found in Drosophila melanogaster, otherwise known as the fruit fly.

Scientists are interested in a region of the fruit fly chromosome called the “homeobox”. The homeobox (“homeo”, from the Greek for “similar”, and “box” as the sequence is in a defined package) contains “Hox genes”. First identified in fruit flies in the early 1980s, they control the different aspects of body development: head, legs, wings or other structures. Interestingly, many other creatures, including humans, possess these genes, where they carry out similar functions. We are all basically running on the same genetic software.

Research in this area is helping us to understand why our head is where it is, why we have two arms joined to our upper body and not to our hips, and why we have feet, rather than hands, at the ends of our legs. More significantly, they are helping to identify the genetic basis of certain human diseases by helping us understand the mechanisms of this genetic control; errors in embryonic development account for a large number of spontaneous abortions in humans.

Hox genes produce simple proteins that govern the activities of other “target” genes, which result in the development of a specific body parts at specific locations; it is those “target” genes that contain the specific information about how and what appendages look like,  and the hox genes control the degree to which those target genes are switched on or off. The arrangement of genes mirror the arrangement of the body parts they control, starting with the head at one end, followed by the mid-sections, and so on. It’s a logical blueprint that works because it represents economy of information.

In the above figure the hox gene clusters of the fruit fly are colour coded for the respective sections of head-bottom development they control, and below are the homologous (performing the same function) genes in a mouse. Whilst we mammals have four clusters of these gene groups, some of which have become redundant or lost due to compensation by one of the other clusters, the startling similarity with the fruit fly hox cluster is unmistakable.

So over the course of millions of years, despite the changes to body form and function (the changes to the specific genes that the above clusters control) in the course of animal evolution, the controlling elements themselves have been conserved. This says something important about the blueprint of animals on Earth; if it works, keep it.

One set of genes under being studied is the hedgehog gene (Hh); this is not a gene from an actual Hedgehog though, it is merely named for the spiky appendages that appear on the fly embryo when the gene is mutated. The hedgehog gene in the fruit fly has three counterparts in Humans, the best studied called “sonic hedgehog” (SSH), which has little to do with the fuzzy computer-console character. This gene is involved in limb and central nervous system development and has already shown promise as a means of gene therapy.

Drs Bill McGinnis and Mike Levine, performed a classic experiment to see how universal the power of the Hox gene was. They took a mouse egg and extracted the genes controlling the formation of the eyes, but without labouring the distinction, not the actual genes for an eye. They then transferred those genes into the comparable genetic position in a fruit fly larva. The mouse and the fruit fly last had a common ancestor five hundred million years ago, so they expected only the smallest genetic effect. What emerged was a complete surprise. The mouse gene made a complete eye, but rather then a mouse eye it made a fly eye; it was perfect in every detail, a control gene had worked in two creatures separated by half a billion years of evolution.

In the interest of brevity, and because I will probably write about hox genes again at a later point, I’ll finish by returning to my opening paragraph. In the course of their work, geneticists often assign rather arbitrary names to genes, often governed by the phenotype (physical appearance) of the organism when that gene has been knocked out (prevented from working); or because they’ve found a couple of genes that work in tandom, and they want to be a smart-arses. In addition to these trivial names, they also assign more assiduous genetic names, which are generally the ones reported in databases and journal articles. The net result is a bit of a laugh for those doing the naming (and their mates), and those of us with the familiarity to find these names. For the rest of the genomics community, it is a constant headache as both genetic and trivial names are often recycled in different organisms.

Here are some classics:

smaug: The gene represses activity of the nanos gene (Greek for “dwarf”). In J.R.R. Tolkien’s Hobbit, the dragon Smaug drove dwarves away from their caves.

british rail: A dominant suppressor of the always early* gene. Not in FlyBase yet (22.7.2001), information directly from researchers.

(*always early: regulates cell cycle progression and terminal differentiation during male gametogenesis).

sunday driver: Neuronal molecule traffic is mixed up when the sunday driver gene is mutated.

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