By Rick Weiss
Washington Post Staff Writer
Thursday, March 17, 2005; Page A03

She was slow to reveal her secrets, but the X chromosome has now bared it all. Researchers said yesterday they have determined with 99.99 percent accuracy the genetic code of the X chromosome, which lies at the core of human femaleness.

The newly completed picture of the X -- one of the last orders of business for the human genome project -- falls far short of explaining all the mysteries of what makes a woman.

But by determining the exact order of virtually all 155 million "letters" of code on the X -- the counterpart to the male Y chromosome -- scientists have confirmed how sex evolved and are much closer to explaining some of the differences between men and women.

The X's unveiling also brings into focus the molecular underpinnings of hundreds of genetic diseases, far more than have been discovered on any other human chromosome. And it appears to have revealed a long-sought role for much of the body's "junk DNA," which is especially prevalent on the X, and whose lack of apparent function has long baffled scientists.

Perhaps most tantalizing, the new work sheds light on one of the most astonishing acts of self-effacement in all of biology: the permanent shutting down of half of the X chromosomes in every cell of a girl's body -- an effort to match the activity of the single X that men inherit with their Y.

"It's more evidence that it's not so much what you've got as how you use it," said Mark Ross of the Wellcome Trust Sanger Institute in Cambridge, England, who led the gargantuan sequencing effort involving 282 scientists at 21 institutions in six countries, including the United States.

The new findings are described in a pair of scientific reports published in today's issue of the journal Nature and clarify preliminary findings of the past few years.

Like other chromosomes, X and Y are tangled skeins of DNA that bear genes, the operating instructions inside cells that direct the development and maintenance of the body. But unlike the other 22 pairs of human chromosomes, X and Y are crucial to sex determination. For humans and other mammals, every child inherits an X from its mother and either an X or Y from its father. Those who get a Y develop as boys.

With the X's complete code in hand, Ross and his colleagues were able to make detailed comparisons with the corresponding chromosomes of other animals, including chickens, fish and rats. The similarities and differences confirmed previous hints about how the X and Y -- and with them, sex as we know it -- arose.

It happened about 300 million years ago, long before the first mammals. A conventional chromosome in a forebear of humans -- probably a reptile of some sort -- apparently underwent a mutation that allowed it to direct the development of sperm-producing testes.

Sex already existed, but environmental cues such as temperature determined whether an animal developed as male or female -- a system still in place in turtles and other reptiles. When genes gained control, that freed animals from such vicissitudes and ensured a roughly one-to-one sex ratio.

With time, the altered chromosome -- today known as Y -- focused on male-making and dropped most of its previous duties, leaving them to be carried out by its unmutated partner, the X. By literally shedding all but a core of about 100 genes, the Y gradually shrank to about one-sixth the size of the X.

As it turns out, however, many of the more than 1,000 genes on X are also crucial to maleness. So although it is an exaggeration to say female is the "default" human form, arising spontaneously in the absence of a Y, it is also wrong to assume that the X is thoroughly feminine. After all, every man has one.

"It certainly does not seem to be the least bit true that the X is pink," said David Page, interim director of the Whitehead Institute for Biomedical Research in Cambridge, Mass. "The Y is certainly blue. But in many respects the X is blue, too."

Among the X's blue genes are about 100 intimately involved in sperm production and one that allows the body to respond to male hormones produced by the testes.

Defective genes on the X easily lead to diseases in males because males lack a second, healthy X to compensate. Although a disease's linkage to the X can be obvious by the pattern of unaffected mothers giving birth to affected sons, the newly completed sequence will speed discovery of the specific genes involved and the development of novel therapies, scientists said.

Already, 307 diseases including hemophilia, colorblindness and muscular dystrophy have been linked to genes on the X. In fact, more than 10 percent of known diseases of heredity have been linked to genes on the X even though that chromosome has just 4 percent of all human genes.

But that does not mean the X is especially laden with problems. Other chromosomes probably harbor as many diseases, experts said, but the genetic linkages are harder to trace.

One of today's two reports focuses specifically on the bizarre mechanism by which females inactivate, or chemically mask, one X chromosome in each cell -- a trick to balance the output of genes on the X with the output from countervailing genes in male cells. That report, by Laura Carrel of Pennsylvania State University and Huntington Willard of Duke, affirms two unexpected facts.

First, it appears that strange sequences of DNA previously thought to be useless are key to the inactivation process, suggesting that similar stretches in other chromosomes may similarly be involved in regulating gene activity.

Second, at least 15 percent of inactivated X chromosomes in women routinely remain at least partly active, and in some women the figure can reach 25 percent. That means as many as 300 genes on women's Xs may be outperforming their counterpart genes in men.

That could explain some of the biological differences between the sexes, researchers said, including differences in responses to drugs and susceptibility to some diseases. And because the gene activation patterns apparently vary considerably from woman to woman, it suggests that women as a group are more variable than men.