Clues to the sex chromosome gender gap.

Two separate teams of geneticists have begun untangling the mystery behind one of the most fundamental differences between men and women -- the fact that whereas both of a man's two sex chromosomes stay active, only one of a woman's does.

The findings may improve researchers' understanding of so-called sex-linked genetic disorders. These disorders -- such as fragile X syndrome, the most common inherited cause of mental retardation (SN: 6/8/91, p.359) -- affect men more frequently and severely than women.

Women have two X chromosomes, and men have one X and one Y chromosome. While the X chromosome contains genes that direct a broad range of functions, such as blood clotting and some aspects of color perception, the Y chromosome for the most part bears only those genes responsible for male sexual characteristics.

In the 1960s, geneticists discovered that female mammalian embryos randomly inactivate one of their X chromosomes. Although researchers are still not sure exactly why this occurs, many assert that X inactivation initially arose to prevent the genetic inequity that would result if females had a double dose of active X chromosome genes.

A group led by Huntington F. Willard at Stanford University and another led by Neil Brockdorff of the Medical Research Council Clinical Research Center in Harrow, England, have isolated two forms of a gene that may play a role in X inactivation in females. Both groups report their discoveries in the Oct. 30 CELL. Willard -- who is now at Case Western Reserve University in Cleveland -- also discussed his team's results at this week's annual meeting of the American Society of Human Genetics in San Francisco.

Willard and his colleagues compared DNA taken from inactive human X chromosomes with that taken from active human X chromosomes. The researchers found a gene -- which they named XIST, for X inactive-specific transcript -- that functions only in inactive X chromosomes. They concluded that the gene may control the inactivation process.

Brockdorff's team used a similar procedure to isolate a candidate X-inactivation gene from mouse cells. Because the mouse gene's DNA sequence closely resembles that of the human gene, Brockdorff and his colleagues also named their gene xist, but in lower-case letters to differentiate it from the human gene.

Both Willard's and Brockdorff's groups also determined that their newly identified genes have something else in common. While both genes actively produce messenger RNA -- the chemical intermediary that genes use to tell a cell to make proteins -- these messages never get delivered to the protein-production apparatus outside the cell's nucleus. Instead, the RNA accumulates inside the nucleus, where the researchers suggest it may stick to the X chromosome that produces it, permanently shutting off that chromosome.

The RNA "might literally be caging up one of the X chromosomes," says Willard. But he cautions that neither group has proven that XIST inactivates X chromosomes. "We haven't come up with the answer [to X inactivation] yet," he says, "but it's our best guess that this gene is at least part of the puzzle."