Genetics moves on

Genetic building blocks

Making medicines match

Proteins first, genes second

Like scrap steel, genes can be recycled. The protein in the eye's lens is patterned by a gene that once made enzymes.
Courtesy U.S. Department of Transportation.

Cryptic.

To interpret this alphabet soup, you can breed a mouse lacking a particular gene and see what goes wrong. You can find a mutation -- a defective version of the gene -- and do the same thing. Or you can trace a family's genetic disease to that gene.

All these steps are expensive and time-consuming, and genetic scientists, being no more ambitious than the average Joe, use them only as a last resort. To save time and money, scientists prefer to search genetic databases on other species for similar genetic sequences whose job is known. Thus, if we find that a fruit fly has a gene similar to one that we already know yeast uses to repair its DNA, we can conclude that this gene also repairs DNA in fruit flies.

Still unknown is why a fruit fly would want to bother fixing its DNA, since, even after the big repair job, it's still going to be feasting on rotten bananas...

You read it here first: Is nature a lazybones?
It's not just simple copying. Genetic searches show that nature is rather miserly when it comes to inventing genes, preferring to modify an existing gene to suit different organisms and environments over minting a fresh gene. Thus, as many as 90 percent of yeast genes have counterparts in humans.

Humans do the same thing. After inventing the automobile, for example, it was easier to put a flat bed on the back than to invent a whole 'nother machine to haul cargo.

Although scientists have known about this natural parsimony for years, now it's becoming clear that nature also recycles the subunits of genes. Temple Smith, a professor of biomedical engineering at Boston University, likens these subunits to "Lego" building blocks of life. Like Legos, he says, these subunits can be mixed and matched as needed to meet a huge variety of needs.

Such reuse of components should not be surprising, as Smith points out: "We've known for a long time that nature uses modules -- the four bases that make up DNA, or the 20 amino acids that make all proteins."

Genes eventually serve as templates for molecules called proteins, so these genetic sub-units form the building blocks -- the subunits -- of proteins. Proteins determine the structure and function of life, and these protein subunits have specific functions. Some punch holes in membranes. Others grab hold of specific molecules. Some are biological I-beams, others help switch genes on or off.

Smith figures that when a particular protein is needed -- say to seize an invading cell and kill it by punching a hole in its side -- the protein would be formed through an evolutionary process that places the genetic tools for grabbing and punching on one gene.

Fissured tongue has prominent furrows, which are more common in people with the genetic defect Down's Syndrome. Genetic research may help scientists understand the condition.Courtesy National Skin Centre.

It's a mod, mod, modular world Nonetheless, the natural and labor-saving preference for recycling genetic modules has produced some curious results over the eons. The crystal-clear protein in an eye's lens, for example, is patterned by a gene that once made enzymes. At some point, Smith explains, a chance genetic mutation formed enzyme molecules deficient in water, creating an extremely clear substance with the ability to focus light.

Recognizing a good thing when it saw one, evolution somehow tapped those enzyme-making genes to make lenses in animals (which presumably already had light-detecting cells).

Moral of the story: Nature may be lazy, but it improvises like a jazz saxophonist.

Another example of "natural fun with protein building blocks" is a module Smith calls a "self-deactivating switch." This handy module is found in taste-receptive cells in our tongues and in light-receptive nerve cells in our eyes. What's the use of this switch? Without it, we might look once at the Why Files and never be able to erase the image... The horror, the horror!

Using tools from the Human Genome Project, an international team tracked the gene for hereditary nonpolyposis colon cancer to a region of chromosome 2.Courtesy National Institutes of Health.

Tootsie meets Cheers...
Most memorably, the self-deactivating switch shows up in a mechanism that helps yeast detect the sex of its neighbors. Yeast have a peculiar sex life, Smith points out. After swaggering into a fungal singles bar, they size up the situation, then mix and mingle. If the bar stools are crammed with guys, a clever stud yeast will become, temporarily, a female.

If it were unable to reset the switch, the yeast would be stuck in that fem role even when natural selection would prefer it to act more manly. (Salmon do weird sex too!)

Dragging ourselves away from this flexible sexual behavior, Smith says the modular understanding may also explain why multi-cellular life took so long to develop. The first fossils of single-celled life appeared within a billion years after the planet coalesced from a disk of whirling space junk. So why was life stuck at the single-cell level for more than two billion years?

To Smith, that sluggishness reflects the time needed to build more sophisticated machinery. Before they could live with other cells, single-celled organisms had to learn to stick together, to recognize friend from foe, and to flawlessly reproduce DNA. All these talents are more or less optional for single-cell organisms, and a lot of trial and error was needed to join genes for all essential functions in a single organism.

Once the modules were in place, Smith says, "Cells could talk to each other and recognize each other, and you could do things you could not do before." Cells that could live together could specialize and grow larger and more interesting, a development that lead to the corals and sponges and eventually to the giant ferns and dinosaurs that came to dominate the planet.

Seen under a neutron beam instrument, the double-helix of DNA looks like this. Courtesy Spallation Neutron Source.

Are we confused?
Beyond helping explain the past, however, genetic modules may point to errors in our understanding of what particular genes do. These subunits can apparently contribute to jobs beyond their known function. Take the case of the estrogen receptor. The receptor's job is to relay the estrogen signal from outside the cell to the nucleus, then trigger a specific section of DNA to act in a certain way, generally to stimulate growth. The receptor protein contains three main modules that: environmental estrogen.)

To understand this notion, let's say you bent your car key and can't drive to the bowling alley, irritating your teammates. Nor can you chauffeur the kids to Golfers Gulch Discount Mall, producing a wave of kvetching on the home front. Should we conclude that mangling a car key causes griping and whining? Yes, but only indirectly. More specifically, it prevents driving, and the other effects follow from that.

Smith thinks that a similar confusion has caused problems with existing genetic knowledge. Geneticists, remember, deduce the function of genes by looking at what happens when they're damaged or deleted, which may be as misleading as assuming that damaged car keys cause whining. He thinks this misunderstanding, "Has polluted our [genetic] databases, and it will take a very long time to work it out."

Rapid-fire genetic sequencing -- read the robot solution.

receive the estrogen signal (where the estrogen binds)

bind the receptor to DNA and

switch the cell's protein-making apparatus "on".

When a molecule of estrogen binds to the signal-receiving domain, the protein moves to the nucleus and the second domain binds to a specific site on a gene. Then the third domain recruits the machinery that turns on this specific gene and makes the correct new protein molecules.

But what would happen if we found another gene containing a sequence like that on the estrogen receptor signal-receiving domain? We might assume that the whole gene has the same function as the known estrogen-receptor gene. Yet it's recently been shown that the signal-receiving module also appears on another estrogen receptor gene. And that gene has a different DNA-binding region, meaning it activates different genes, and thus has a different overall function.

Here's more on matching medicines.

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