Research Makes It Official: Women Are Genetic Mosaics

The cocktail-party bore who laces his chatter with the tiresome cliche about "crazy, mixed-up women" has more medical science on his side than he knows--and more than medical scientists themselves have recognized until recently. Even normal women, it appears, are mixtures of two different types of cells, or what the researchers call "genetic mosaics." If both cell types are normal, so is the woman. But if one is defective, though a woman may seem to enjoy good health herself, she may pass on hereditary disorders to her children. And oddly, the victims will nearly always be her sons, not her daughters.

From what they have slowly and painstakingly pieced together about mosaicism in female cells, medical geneticists are getting a better understanding of several inherited disorders including some forms of anemia and hemophilia, and color blindness. The research has a direct bearing on cases of genetically confused sex, in which both males and females may have an extra female sex chromosome. And this in turn may have surprising importance in mental deficiency, in which sex-chromosome abnormalities are now being detected more often. The cell studies are also tied in with some forms of cancer, especially a form of chronic leukemia.

Exquisite Chemistry. Geneticists who looked through microscopes at chromosomes taken from cell nuclei had noticed long ago that in some of their slides there was an unusually dark spot. Not until 1949 did Canada's Dr. Murray Llewellyn Barr realize that the spot appeared only in female cells. This discovery alone was invaluable for determining the true or nuclear sex in many cases involving various degrees of hermaphroditism.* But what was the spot?

In a cancer-research project at the City of Hope Medical Center in Duarte, Calif., a Japanese-born geneticist nailed the answer down. Dr. Susumu Ohno showed that the spot was an X (female) chromosome. But he also determined that it was only one of the X chromosomes.

The normal human's 46 chromosomes are classified as 22 pairs of autosomes (nonsex chromosomes), one of each pair being derived from the father and one from the mother, and two gonosomes (sex chromosomes). In a woman, the gonosomes are both Xs, one each from father and mother; in a man, they are an X from mother and a Y from father. Among the autosomes, the two members of each pair behave alike. But the Ohno team showed that a woman's two Xs behave quite differently (except in her egg cells). One acts like an autosome, and so does a man's single X. But a woman's second X curls up on itself and becomes condensed, so that it appears as a heavy, dark spot under the microscope.

The explanation: most of the genes in the big X chromosome have nothing to do with sex. They dictate whether the multiplying cells will produce a variety of enzymes, the complex organic catalysts that are essential to the body's exquisitely delicate chemistry. If a woman, in her double load of X chromosomes, has twice as many of these enzyme genes as a man, why doesn't she produce twice as much of the enzymes? The City of Hope researchers' conclusion: after the second X has done its job of determining that the fetus will develop as a female, it apparently becomes inert. But when does this happen? Dr. Ohno went back to Japan, where abortion is legal, to study normal human fetuses. He concluded that it takes a few days, or possibly weeks, for the second X to be deactivated. Until that happens, the enzyme genes of both X chromosomes pass on their chemical patterns to some of the tiny body's multiplying cells.

Beans & Anemia. This knowledge dovetailed neatly with other studies made at the City of Hope by Dr. Ernest Beutler. Half a dozen blood disorders are the result of defects in autosomes, which are alike in men and women, but Dr. Beutler was interested in one particular inborn error of metabolism resulting from an X-chromosome defect --a deficiency of the enzyme glucose-6-phosphate dehydrogenase, known as G-6-PD. It leaves its victims vulnerable to a fulminating and potentially fatal anemia if they ever eat certain types of fava or broad beans, and also makes them liable to severe illness if they take some of the modern antimalarial drugs. The disorder is especially common among Sephardic Jews and increases in frequency with the purity of the racial stock, topping 50% among long-isolated Kurdish Jews.

In a man, G-6-PD is an all-or-nothing substance: the enzyme is either produced in the normal amount, or it is not produced at all. But Dr. Beutler noted that many women victims have approximately half the normal enzyme concentration in their blood. These proved to be women who had one affected and one normal parent. Could it be that they had red blood cells (which carry the enzyme) derived from both parents? By delicate laboratory tests, Dr. Beutler satisfied himself that they did. These women, he concluded, were genetic mosaics, with roughly half their blood cells descended from their fathers and half from their mothers. For the red-cell lines are created soon after conception, while both X chromosomes are still fully active.

Whether it will be the father's or the mother's X chromosome that is relegated to the status of a dark, inert spot is apparently a matter of chance. Certainly it is not always the father's, or always the mother's, Dr. Beutler points out, because if that were so a galaxy of characteristics would be inherited in a different pattern from that which actually exists.

Asset for Longevity? In the human X chromosome, the gene for red-green color recognition is located fairly close to those for G-6-PD and for the blood factor that gives protection against hemophilia B. So color blindness, G-6-PD deficiency and this form of hemophilia are inherited according to the same pattern. Nearly always, in the conception of a female, the X chromosome from one healthy parent will carry the normal gene, and one is enough. But a man must get his X chromosome from his mother, and if she carries the defective gene, he is in for trouble.

When sperm and ovum unite abnormally to produce a human being with 47 chromosomes, the supernumerary is often an extra X. There are XXX girls who have two dark spots in their body cells--one for each of the deactivated Xs, for only one can remain fully functional. In one form of sex abnormality, the chromosome composition is XXY. Such a child may have some male characteristics, but will also show the typically female dark spot of the second X chromosome.

Because the X chromosome is so much bigger than the Y, women with two Xs have 4% more genetic material--the vital deoxyribonucleic acid, or DNA--than men. Geneticists have speculated that this might explain women's longer life span. Whether or not the speculation proves correct, the genetic mosaicism reflected in red blood cells definitely gives women an inherent advantage over men.

* It also won Dr. Barr an award from the Joseph P. Kennedy Jr. Foundation (TIME, Dec. 21).

This file is automatically generated by a robot program, so reader's discretion is required.