Seeking Reasons For Disease Genes
By GINA KOLATA
Published: December 3, 1996
FATE may be cruel or indifferent but geneticists believe there are often good reasons for bad genes. Genes that cause diseases like cystic fibrosis are so common, some say, as to suggest they must confer, either now or at some time in the past, a powerful compensating advantage.
And so, seeking to understand mutated genes, some researchers like Dr. Stephen J. O'Brien, a geneticist at the National Cancer Institute in Frederick, Md., have embarked on a quest into medical history. Dr. O'Brien's current obsession is with a genetic mutation, reported earlier this year, that can confer immunity to the AIDS virus. Dr. O'Brien discovered that 1 percent of whites, but essentially no blacks or Asians, have two copies of this mutated gene. In the geneticist's scorebook, this is a very high percentage of the population that the mutated version of the gene has reached, especially as its function is to knock out an important protein of the immune system.
Do so many whites have the mutated gene, Dr. O'Brien asks, because it protected people in generations past from an ancient plague, or maybe a previous visitation of the AIDS epidemic?
Geneticists who study breast cancer are asking the same sort of questions about the two genes called BRCA1 and BRCA2, for breast cancer 1 and 2, which can cause breast and ovarian cancer. Both genes are found in 1 percent of Ashkenazi Jews, a surprisingly high percentage.
In seeking possible reasons, scientists are cornering each other at meetings or talking to each other on the telephone or writing provocative editorials in journals. So far, opinion is divided. Some are enthusiastically looking for subtle advantages conferred by these mutated genes. Others are more skeptical. Where, they ask, is the evidence for a selection effect? ''It's a debate that rages in the absence of any data,'' said Dr. Lawrence Brody, a geneticist at the National Center for Human Genome Research in Bethesda, Md.
Dr. O'Brien is on the side of those who think the mutations benefited populations in generations past. He noted that the great population geneticist, J. B. S. Haldane, said in the 1940's that probably the greatest selection pressure of all is not a changing environment or a scarce food supply but the harsh culling of infectious disease. Dr. O'Brien said he would not be surprised if mutations like the gene that protects against AIDS were preserved for this reason.
The mutated gene was discovered earlier this year by Dr. Nathaniel Landau of the Aaron Diamond Research Center in New York and his colleagues in three gay white men who had been exposed repeatedly to H.I.V., the virus that causes AIDS, but never became infected.
Then Dr. O'Brien and his colleagues studied 1,965 people who had been repeatedly exposed to the AIDS virus because they were gay men, intravenous drug users who shared needles or hemophiliacs who repeatedly injected themselves with blood products that were tainted with the AIDS virus. Most became infected. But among the few who escaped the virus, they found 18 whites with two copies of the mutated gene. They and others report that 1 percent of whites in the general population have two copies of the mutated gene, making them immune to AIDS.
The probability calculations that are basic to genetics indicate that in order for one out of 100 whites to have two copies of the gene, as many as one out of five in the white population must have a single copy of it. And it is even more common among northern Europeans, said Dr. Michael Dean, who is acting chief of the human genetics section at the cancer institute in Frederick. He now finds that as many as 23 percent of British, Swedish and Russian whites have at least one copy of the gene.
Yet the mutation would seem to be deleterious because it knocks out a protein, a chemokine receptor, that protrudes from the surface of white blood cells and allows them to respond to certain immune system hormones known as chemokines.
And so, Dr. O'Brien said, the first question he and others asked was, are people who have two copies of this mutated gene healthy? Dr. O'Brien began by studying the 18 people he had found who had double doses of the H.I.V. resistance gene.
''We're bringing people in and doing a complete clinical work-up,'' Dr. O'Brien said. As yet, he said, neither he nor others who are trying the same thing have found any evidence that people with the mutated genes are in ill health or that their immune systems are anything but completely robust.
That suggests, Dr. O'Brien said, that there is redundancy in the immune system, that something else can take over when the chemokine receptor protein is destroyed by mutations. And, he said, it also suggests that the AIDS resistance gene is in the population for a reason. It is almost unheard of, he said, for 20 percent of a population to have a single copy of a mutated gene and 1 percent to have two copies of a gene that confers no advantage.
Dr. O'Brien and his colleagues at the cancer institute are studying the mathematics of the AIDS resistance gene's spread. They assume, since the gene is not found in blacks or Asians, that it arose after Caucasians split off from blacks about 150,000 to 200,000 years ago. Anthropologists have determined that the ancestral white population may have had just a few thousand individuals. And so, the cancer institute investigators asked, if the mutation arose in that population by chance, and if there was no selective advantage or disadvantage to having the mutated gene, what is the likelihood that, by chance, its frequency would drift up to 20 percent of the white population today? ''The likelihood is almost zero,'' Dr. O'Brien said. ''The point is, you don't get that high numbers by genetic drift alone. You need selective pressure.''
But if the H.I.V. resistance gene protects against disease, it is still uncertain what disease it protects against. Some, like Dr. David Baltimore, a molecular biologist at the Massachusetts Institute of Technology, have suggested that perhaps there was an H.I.V. epidemic hundreds or thousands of years ago, and those who have the gene today are descendants of its survivors. Another possibility, Dr. O'Brien said, is that the gene might protect against the Black Plague or tuberculosis, a known scourge of European populations.
The tuberculosis hypothesis, Dr. O'Brien said, is particularly appealing because tuberculosis bacteria, like H.I.V., slip into a type of white blood cell called macrophages. Their entry might be hindered if the chemokine protein were absent, although that is yet to be determined, Dr. O'Brien said.
The breast cancer genes are a different sort of puzzle, researchers said. Women who inherit a single copy of either of these mutated genes, BRCA1 or BRCA2, have a significant chance, as high as 90 percent, of getting breast cancer in their lifetimes, and a 40 to 60 percent chance of getting ovarian cancer. So why, if there is no purpose to these mutated genes, would 1 percent of Ashkenazi Jewish women have them?
Dr. Mary-Claire King, a geneticist at the University of Washington, said, ''We know two things about BRCA1.''
''We know the gene controls cell proliferation,'' she went on, and though the evidence comes only from her impressions, that ''when you work with women with BRCA1 and BRCA2 mutations, you find out that they are the healthiest, fittest women that you would ever expect to meet.'' So, she added, ''I've come up with the following notion: Suppose a woman has a BRCA1 mutation. She will therefore have less BRCA1 protein available in her breast epithelial cells and the cells may grow faster. The most important thing for survival of your lineage is whether you can bear a child and whether you can lactate efficiently.''
The cells that proliferate rapidly in women with BRCA1 mutations are the same cells that make milk, Dr. King noted. ''Suppose that women with BRCA1 mutations are more likely to lactate under starvation conditions,'' she said. And suppose, further, that their ovary cells are more likely to produce eggs. Those women, then, would be more likely to produce broods of children during famines when other women's fertility dropped and their newborn babies starved, she suggested.
It is still just a wildly speculative hypothesis, Dr. King confessed, but she is taking it seriously enough to look for preliminary evidence that might support it. In a study of Jewish women in New York, she is testing for the BRCA1 and BRCA2 genes and is questioning the women about their fertility, asking how long it took them to become pregnant and whether they had difficulty producing enough breast milk to feed their children.
The breast cancer mutations join several other mutations that seem unusually common among Ashkenazi Jews. For example, said Dr. Arno G. Motulsky, a medical geneticist at the University of Washington in Seattle, Ashkenazi Jews tend to have genes that when present in a double dose, cause deadly neurological diseases, like Tay-Sachs disease, and debilitating metabolic diseases, like Gaucher disease or Niemann-Pick disease. Some have suggested, he said, that these genes, when present in a single copy, protect against tuberculosis. In that case, he said, the genes might have been advantageous to the population, even though anyone who inherited two copies of the genes would die.
Dr. O'Brien said that cystic fibrosis was another disease whose genes seemed too common, unless there was a reason for the mutation. Studies in animals, he said, suggest that people who inherit a single copy of the cystic fibrosis gene might be protected from cholera.
Dr. Brody, of the cancer institute, said he was skeptical. He noted that at least in the case of the Jewish diseases, there was another explanation. Ashkenazi Jews and certain other populations, like Finnish people or the Amish, started from a very small group and remained isolated, marrying within the group. Such populations, Dr. Brody said, ''have a whole host of diseases that are more represented in them'' than in larger groups that are not so isolated. A rare gene mutation can more easily become common in such insular populations, he explained. But, he added, ''having said that, there's a whole school that doesn't buy it.''
Dr. Neil Risch, a geneticist at Stanford University, is one who does buy that hypothesis. He says it is possible to explain virtually all the strikingly high gene frequencies that are now of such interest to geneticists simply by postulating that genes arose by chance and were maintained by chance. Yes, he said, ''it's an interesting debate'' to ask what the genes might be good for. But, he said, ''I think the burden is on the selectionists to produce the selective advantage.'' And so far, he said, for all their enthusiastic speculation, scientists have only found one incontrovertible example of a genetic mutation that causes a disease but also confers a selective advantage.
That example is the mutation that causes sickle cell anemia. Those who inherit two copies of the mutated gene get a potentially deadly disease. Those who inherit one copy of the gene are protected against malaria. ''That's the only convincing example I know,'' Dr. Risch said, and it was discovered years ago.
Others, like Dr. Motulsky, are on the fence.
''I'm withholding my complete judgment about it,'' he said. ''It makes good sense that some of these genes would have served a purpose,'' he said. ''On the other hand, there is this argument that in any limited population, there is this factor of chance. If a population has a relatively limited number of ancestors, then you would expect certain genes, by chance, to become relatively frequent.''