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Thursday, Sept. 9, 2004

NATURAL SELECTIONS

BRIDGING THE MEDICAL-EVOLUTIONARY GAP

Heartening news for some from an Ice Age gene mutation


In Terry Gilliam's 1985 film "Brazil," a tiny printing error in a bureaucratic document leads to the mistaken arrest and detention of an innocent man. A single letter is changed in a file and the set of instructions are automatically followed by the authorities.

In some ways, this is analogous to the way the machinery of our cells reads the instructions contained in our DNA. Here, too, a single change can have unexpectedly far-reaching consequences but unlike the Orwellian machinery depicted in "Brazil," changes to the DNA code are not always for the worse.

A good example of this was in a paper published this week in the journal Current Biology. It concerns a gene called MMP3, which makes a protein that affects the elasticity and thickness of blood vessels. More specifically, the researchers were looking at a length of DNA that determines how much of the blood-vessel protein is produced.

This regulatory part of the gene is 1,600 genetic units, or nucleotides, in length. If each nucleotide is thought of as a word on a page, that's equivalent to text about twice the length of this article. Researchers found that a change of just one nucleotide in the regulatory sequence -- one word in a story twice this long -- is enough to retard the progress of coronary-artery heart disease.

What's surprising about this is that the change in the gene doesn't affect the shape of the protein itself, which is what geneticists usually mean when they refer to gene "mutations." In this case, the tiny change only influences how much of the protein is produced.

There are many factors that influence the risk of heart disease, and this is one of the more subtle. Heart disease is the leading cause of death in Europe, with Britain having one of the worst records. For example, in 1998, 150 out of every 100,000 adult males in the population died of heart disease. Japan, by contrast, has the lowest level of heart disease in the world, with only 17 men per 100,000 succumbing.

The differences are largely due to environmental factors, mainly diet. The average Japanese diet contains far less saturated fat than the British one. I say "average" because in Okinawa, for example -- which has 44 branches of McDonald's and was the first prefecture in Japan to welcome the American fast-food chain -- 47 percent of men aged 20-60 are classified as obese.

Despite the poor health record in Britain, though, the new research findings on MMP3 show that heart disease would have had a much greater death toll but for natural selection in the relatively recent past.

The researchers, led by Matthew Rockman at Duke University, N.C., found there has been positive selection for the variant of MMP3 that causes more blood-vessel protein to be made. Individuals with the low-expression version of the gene are slightly more prone to atherosclerosis, a narrowing of the arteries associated with the accumulation of plaque in the arterial walls.

The research found that the high-expression variant increased rapidly in frequency among the ancient European population, though not elsewhere. This rapid increase -- which is estimated to have begun around 24,000 years ago -- is attributable to the action of natural selection favoring the variant, according to statistical analyses of genetic variation in several human populations.

Rockman and colleagues estimate that the incidence of heart disease among modern European males would have been more than 40 percent higher than it is, had there not been selection for the high-expression variant of the MMP3 gene.

However, since heart disease usually occurs late in life, after the individual has reproduced, there is probably another reason why the high-expression variant was favored by natural selection.

And in trying to pinpoint this reason, we can hardly blame fast-food eating habits for evolutionary change some 20,000 years ago. Or can we?

"Although coronary heart disease is considered a recent phenomenon, dependent on contemporary diets and behaviors," write the authors, "it is possible that the diet of Ice Age Europeans, rich in the atherogenic fats of large mammals, could have contributed to early-onset coronary heart disease."

Even in the Ice Age, it seems, we were gorging ourselves on fatty foods.

Rockman emphasized that evolutionary studies should include not just the segments of genes which code for the structure of proteins that make up the cell's machinery. They should also take account of the large fraction of the genome that is involved in gene regulation.

A broader approach such as this would then bridge the gap between medical scientists' detailed molecular understanding of the genetic mutation underlying a disease and evolutionary biologists' insights into how natural selection acted on the gene to propagate that mutation in the population.

And the take-home message is that mutations in genes aren't always bad.

"Our research, and that of other evolutionary biologists, is directing us toward a new, more nuanced view of genetic variants, which is that, in fact, variation is part of what it means to be human," said Rockman. "And that this variation is not just harmful mutation but really a process that contributes to the health of populations."

Genes, unlike the authorities in Gilliam's "Brazil" or George Orwell's "1984," aren't out to get us.

A book of Natural Selections columns translated into Japanese, "Nou to sekkusu no seibutsugaku (Evolution, Sex and the Brain)," is published by Shinchosha. Rowan Hooper is a biologist at Trinity College, Dublin. He welcomes readers' comments at rowan.hooper@tcd


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