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Human X Chromosome Coded

Sequence Confirms How Sex Evolved and Explains Some Male-Female Differences

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.

Unraveling the X Chromosome
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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."

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