Hidden Benefits

By Josie Glausiusz|Wednesday, March 01, 1995
When humans left the Near East and invaded Europe around 40,000 years ago, they took with them bone and stone tools for hunting and engraving, early art in the form of beads and pendants, and social skills that were probably superior to those of Europe’s resident Neanderthals. It now seems they also took with them a mutant gene: the gene for the deadly disease cystic fibrosis. So robust is this gene that it spread all over Europe; cystic fibrosis is now the most common fatal genetic disorder among Caucasians. How could the disease have been passed from generation to generation for so long, when until the advent of modern medicine it generally killed people before they could have children? Recent experiments on mice offer an answer. They suggest that the 5 percent of all Caucasians who carry just one copy of the cystic fibrosis gene--and thus don’t suffer from the disease--are protected against another deadly scourge: diarrhea.

The gene for cystic fibrosis was discovered in 1989. It codes for a protein that forms channels in cell membranes, especially the cells lining the intestines and airways. Normally these channels funnel chloride ions out of a cell, thus making its surroundings saltier; that in turn draws water out of the cell by osmosis. In the lungs this fluid washes away bacteria and other unwanted debris. In the intestines it does the same and also brings digestive enzymes into contact with food. In sweat glands chloride channels have an additional function; they recycle salt out of the glands and back into the skin before it can be lost to the outside world.

Excessively salty sweat, in fact, is the definitive diagnostic test for cystic fibrosis, which strikes about 1 of every 2,500 white babies. A baby with cystic fibrosis lacks functional chloride channels, having inherited mutated copies of the crucial gene from both parents. Salty sweat is not the worst of it: a thick, sticky, and relatively dry mucus clogs the lungs and gut because the cells that line those organs aren’t secreting water. The mucus obstructs breathing and digestion and becomes a prime breeding ground for bacteria and viruses. Even today, with antibiotics and other forms of treatment available, cystic fibrosis sufferers rarely live beyond their forties. The males among them are usually sterile.

Yet somehow, medical geneticist Xavier Estivill of the Institute of Cancer Research in Barcelona announced last June, the most common cystic fibrosis mutation has survived a long time. According to Estivill and his colleagues, the mutation, known as delta-F508, arose at least 52,000 years ago--before the settlement of Europe by modern humans. It must also have originated after humans spread out of the Near East in other directions, sometime after 100,000 years ago, otherwise cystic fibrosis would be as prevalent elsewhere as it is among Europeans. In fact, it is much less common among Africans, and it is extremely rare among East Asians, only 1 in 100,000 of whom develop the disease.

Estivill and his colleagues examined more than 1,700 delta-F508- carrying chromosomes taken from families all over Europe. They didn’t look at the tiny mutation itself--a deletion of three DNA base pairs from among the 250,000 that make up the gene. Instead they focused on a set of easily recognizable markers in that huge sequence--places where the same two bases were repeated numerous times. Among the chromosomes they examined, the researchers identified more than 50 variations in the pattern of these markers. The variations did not affect the function of the gene. But for Estivill’s team they functioned as a kind of evolutionary clock. Since the first human to acquire the delta-F508 mutation had one particular marker pattern, the researchers reasoned, enough time must have elapsed since then for more than 50 variations to have evolved from that original.

How much time? In their entire study group, Estivill and his colleagues found no case in which a child had a different marker pattern from his parents. That allowed them to calculate the maximum rate at which new variations might appear in the general population. And it told them the minimum amount of time it would have taken the original cystic fibrosis gene to spawn 50-odd variations. The mutation, Estivill and his colleagues concluded, must have happened at least 52,000 years ago.

If the cystic fibrosis mutation were merely a killer with no redeeming features, natural selection should have eliminated it from the population long ago. The fact that this is very old tells us there must be a selective advantage for this disorder, says Estivill. A few months after Estivill announced his results, cell physiologist Sherif Gabriel of the University of North Carolina at Chapel Hill reported evidence, from experiments with mice that carried the cystic fibrosis mutation, of what that advantage might be. He thinks the mutation offers increased resistance to cholera--or rather to the diarrhea that often kills people with cholera. For people who have just one copy of the mutated gene and thus are not going to die of cystic fibrosis, that resistance would be an important benefit.

When the bacteria that cause cholera sneak into the human small intestine, Gabriel explains, they release a potent toxin that attacks the cells that line the gut. The cells respond by permanently opening their chloride channels, causing the gut to secrete as much as three or four gallons of fluid a day. The point is to flush out the toxin--but the effort often backfires. Unless the lost salts and fluids are fast replaced, the afflicted person can die of dehydration.

Gabriel pumped a small amount of cholera toxin into the stomachs of his experimental mice, killed them six hours later, and weighed their intestines to find out how much fluid they had secreted. Not surprisingly, mice with two copies of the mutant gene secreted no fluid at all, because they lacked chloride channels altogether. But mice that carried just one mutated gene, Gabriel found, had half as many chloride channels as normal mice and secreted only half as much fluid. Presumably the same pattern would hold true in human carriers of the cystic fibrosis gene.

Half as much fluid, Gabriel speculates, might be just enough to rid someone of the cholera infection without making him succumb to diarrhea. In the dark European past, when cholera epidemics were more common, this would have given carriers of the cystic fibrosis gene a selective advantage and would have allowed the gene to spread. When the Western European population was much smaller, if a cholera epidemic came through, it would wipe out the vast majority of the people, Gabriel explains. But it might not have wiped out people who carried one copy of the cystic fibrosis gene. The gene might then increase to a very high level within the population.

For Gabriel’s explanation to work, however, the cystic fibrosis gene must have protected its carriers against more than just cholera; the first documented European cholera epidemic dates only to 1817. Gabriel thinks the gene’s protective effect probably extends to other diarrhea- inducing bacteria, such as Escherichia coli and Salmonella. If cystic fibrosis carriers have only half as many chloride channels, then regardless of what turns on chloride secretion, you still have only half the number of gates to open, he says. Therefore you would still be protected.

If that’s the case, then why did the cystic fibrosis mutation survive only in Europe, when its protective effect would presumably have been helpful wherever diarrhea strikes? The strain of E. coli that causes diarrhea, for instance, is found all over the globe and still kills as many as 1.5 million children every year. Moreover, delta-F508, although the most common cause of cystic fibrosis, accounts by itself for only half of all cases. Some 400 other, less common mutations exist that also disable the chloride-channel gene. Since the gene mutates that often, similar mutations probably arose in other parts of the world but didn’t survive. Why not?

According to physiologist Paul Quinton of the University of California at Riverside, the cystic fibrosis mutation may not have survived outside Europe because in hot climates it entailed an additional disadvantage, one that outweighed its defense against diarrhea: salty sweat. Experiments have shown that carriers of one mutated cystic fibrosis gene lose slightly more salt in their sweat than those who carry two normal genes. Salt, at least until very recent times, was an extremely precious commodity, says Quinton. We are really designed to conserve it. But if you can’t do that, and you’re a predator animal that spends a lot of time running, you’re going to lose salt, and it’s not very easily replaced. In my mind, that’s the force that would place the cystic fibrosis carrier at a disadvantage. You would expect that in climates where there’s a lot of sweating, even though the disease might be spontaneously arising, it wouldn’t have had the selective pressures that it has had in northern Europe.

In warmer climes, according to this argument, one’s chances of reproducing are jeopardized less by occasional bouts of life-threatening diarrhea than by chronic excessive salt loss. So cystic fibrosis mutations never gain a foothold in the population. In chilly old Europe the logic worked the other way--and so Europeans acquired the scourge of cystic fibrosis as the price of protecting at least some of their number against diarrhea. What’s good for survival varies depending on local conditions; but everywhere, it seems, natural selection forces us to take the bad with the good.
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