Scientists close to deciphering Y chromosome: Will it finally get some respect?

Scientists are close to deciphering the makeup of the Y chromosome, that essential core of maleness that's saddled with a bad reputation, a weird past and an uncertain future.

It's true, guys: Millions of years from now, your descendants might not have a Y chromosome at all.

But first things first. By this winter, scientists hope to have worked out the DNA sequence of the Y chromosome - the identity of its DNA building blocks. They plan to publish their analysis of the sequence sometime next year.

The work should help researchers learn about causes of male infertility, because it'll help them identify genes on the Y that men need to make sperm.

It should also give a big push to understanding the evolution and functions of the chromosome, a quest that went nowhere for decades until just the 1980s. In fact, one expert says earlier failures to understand the Y have given it a bad rap as a genetic couch potato, and he hopes new DNA studies will finally gain it some respect.

''There's been almost a century of ignorance-based misunderstanding of the Y,'' says David Page of the Whitehead Institute in Cambridge, Mass. ''There aren't that many chromosomes that have an intellectual history'' of thought and study by scientists, he said. ''It's just that most of its intellectual history sounds like the life story of Rodney Dangerfield.''

The Y chromosome probably didn't get much respect from your high school biology teacher. You did learn that chromosomes are the microscopic rods that hold genes. Chromosomes generally come in matched pairs, with one member of each pair from Mom and the other from Dad.

But men have one wildly mismatched pair, the X and the Y. The Y chromosome makes males. If you inherit it from your dad, you'll become a boy. If you get an X chromosome from Dad instead, you'll be a girl.

What else is there to say about the Y, this dinky chromosome with a paltry number of genes? Even now among scientists, Page concedes, beyond its sex-determining role ''the general feeling is that it's at best a landfill.''

But having studied it for about 20 years, Page sees it as more of a national park, full of unusual natural features.

''There's no doubt in my mind,'' he said, ''that the Y will stand out as much as Yosemite and Yellowstone stand out from the landscape.''

The sequencing of the Y is being overseen by Page and Robert Waterston and Rick Wilson of Washington University School of Medicine in St. Louis. The sequence will cover 20 million to 30 million of its 60 million building blocks, because the missing portion resists current sequencing technology and appears relatively inert anyway. Under scientific standards, the sequence will still be considered complete.

The effort is part of the Human Genome Project, which seeks to reveal the 3 billion chemical building blocks that make up all 24 of the human chromosomes. Only two chromosomes have been completely sequenced so far by the project, which announced in June that it had finished a rough draft of all the human chromosomes.

Also this summer, Celera Genomics said it had sequenced all the human chromosomes, the collection called the human genome. But Celera shares its data only with paying clients. So for most scientists, data on the Y chromosome sequence will come from the efforts of Page, Waterston and Wilson.

The idea that men had their own chromosome was recognized in the early 1920s, and the Y was one of the first to be identifiable under a microscope. But while researchers could figure out what kinds of genes the X chromosome carried by studying generations of families, this approach failed spectacularly when applied to the Y.

Not that researchers didn't try. In the first half of the 20th century, there were lots of claims about physical traits that seemed to pass from father to son, and so seemed to arise from Y chromosome genes. Hairy earlobes and a particular kind of scaling called porcupine skin were among them, Page noted.

But at a 1957 meeting of the American Society of Human Genetics, the group's president stood up and demolished all the claims.

''That was sort of a defining moment in the intellectual history of the Y chromosome,'' Page said.'' At the end of his talk, there were no genes left standing.''

For decades after that, scientists regarded the Y as a wasteland, Page said. Yes, it carried some gene that determined gender in a fertilized egg, ''but it was otherwise perceived to be ... the empty dance partner for the X chromosome in males.''

That view has largely held on, even though evidence has emerged in the past three years that the chromosome carries at least two dozen genes or gene families. That's meager compared to maybe 2,000 or more genes on the X, Page concedes, but it shows the Y deserves more credit than it usually gets.

In fact, he said, the Y is unique for its degree of specialization. Nearly all its genes do one of just two things: help make sperm, or help cells do essential housekeeping tasks like build proteins. In addition, of course, there's the gene SRY, the master switch that turns on the boy-making machinery.

To understand today's Y chromosome, it helps to consider its evolution - both where it came from and where it's going. That story is inextricably linked with the X.

''The story of the evolution of the sex chromosomes is as rich as any novel ever written,'' Page declares.

Here's the plot line that has emerged in just the past few years:

The ancestors of the human X and the Y were a pair of identical chromosomes. They were found some 300 million years ago in reptiles, long before mammals arose. Genes didn't decide sex on their own in these creatures. They responded to some environmental cue like temperature. That still goes on today in turtles and crocodiles.

But in a single animal, an odd thing happened. One of those sex genes became altered. As Page puts it, this mutated version became ''a tyrannical male-determining gene that said, 'I will no longer respond to these environmental cues. If I am present, the male pathway will be followed.' ''

This rogue gene made trouble for its chromosome because the other DNA in its immediate vicinity became altered. Later in evolution, this zone of alteration got bigger and bigger.

Normally, the pairs of identical chromosomes in people and other animals trade little bits of corresponding DNA back and forth. This reshuffles the genetic deck and helps species get rid of harmful mutations.

But as that zone of altered DNA widened around the rogue gene, the chromosome was able to do less and less of this trading with its unaltered partner. As a result, the once-identical chromosomes grew more and more unlike over time. In fact, they eventually became the X and Y chromosomes.

This was a better deal for the X than the Y. Every female inherited two X chromosomes, just like today, so those two could carry out the DNA exchange normally. That left the X in good shape for the long haul.

But the Y chromosome never got a chance to pair up with another Y. Just like today, it kept being paired up with an X instead, in males. And as the X and Y chromosomes grew more dissimilar over time, that poor Y chromosome became less and less able to trade DNA with its partner.

The result? Genes on the Y began to suffer minor mutations they couldn't get rid of, and these nicks and scratches built up. ''It's like the genes are being nickeled-and-dimed to death,'' explained William R. Rice, who studies the Y chromosome at the University of California, Santa Barbara.

Eventually, these genes simply stopped working. And once genes stop working, they tend to disappear. That's why the Y chromosome is only one-third the size of the X.

For a gene, Page notes, the Y chromosome is a very hard place to make a living.

And that's the threat to the Y's existence in the future. It's a toxic neighborhood. Will any genes survive? Even the master sex switch or the genes required for making sperm aren't guaranteed a free ride. If necessary, genes on other chromosomes might take over their jobs, leaving them free to slip into oblivion without taking the human race with them.

In fact, the Y chromosome has disappeared in hundreds of other species, Rice said.

But there is hope for this beleaguered chromosome: immigration.

Remember that trading between matched chromosome pairs? That isn't the only way DNA can move between chromosomes. Genes can also jump from one chromosome to a completely different one. And in the last few years scientists have discovered that during the last 30 million to 50 million years of primate evolution, the Y has been an alluring destination.

The immigrants are genes that are essential for making sperm. That makes sense, according to theory, because they would naturally accumulate on a chromosome that appears only in men, where they'd avoid any potential side effects from operating in women.

So, over the next 100 million years or so, the balance between the death of Y chromosome genes and the arrival of new ones will decide if the Y chromosome sticks around.

''There's new stuff coming on all the time,'' Rice says. The Y is ''not about to blink out.''

But the Y has so few genes to justify its existence, he said, that ''if we last long enough we will probably lose it.''

Page isn't placing any bets.

''The experiment is continuing,'' he said, ''and its outcome is unpredictable.''

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On the Net:

Description of David Page research: www.hhmi.org/science/genetics/page.htm

Progress on sequencing chromosomes: www.ncbi.nlm.nih.gov/genome/seq