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Planet Earth


Cheer up, guys. Your favorite chromosome is turning out to be not just an X with something missing. It's a sperm-producing powerhouse.

By Peter RadetskyNovember 1, 1997 6:00 AM


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Pity the poor Y. it’s tiny, the runt of the chromosome litter. It’s pinched and bent over, like a crooked old man. Unlike all our other chromosomes, which bundle up a multitude of genes for many important and complex tasks, this sad excuse for a gene carrier seems to do nothing other than determine the male sex. Most researchers think that, like an appendix or little toe, it’s well on its way to becoming extinct--eventually humans will just have to determine gender some other way. This is progress? What a waste of a perfectly good chromosome. What a failure of design. What a botch natural selection has made.

Or so it was thought until David Page came along. Four years ago, Page, a biologist at MIT, the Howard Hughes Medical Institute, and the Whitehead Institute in Cambridge, Massachusetts, helped map the Y chromosome. Two years ago he and his colleagues determined that establishing the male sex isn’t the Y’s only function after all--it also plays a fundamental role in male fertility. Far from being a nearly useless evolutionary memento, the Y is a mighty mite, a turbocharged, superspecialist sperm producer. Then, in November 1996, Page and his team discovered that in becoming such a potent fertility factory, the Y has traveled a singular and surprising evolutionary path. Thanks to Page, no one will ever be able to malign the Y again.

But there’s still good reason to distrust it. All this impressive muscle, Page has found, has a downside: instability. Genes on the Y tend to mutate like crazy, sometimes preventing any production of sperm at all. The upshot is infertility. A powerhouse fertility producer and erratic fertility preventer all in one package--is this any way to run a reproduction business? Add to all this the Y’s distinction as the only chromosome that shows up in just half the population--men--and the only chromosome that does not swap genes during reproduction, and you’ve got quite an eccentric character. The Y is a compromise of evolution, says Page. It’s as though Nature is saying, ‘I’m going to throw in this unique chromosome. It’s powerful, but it has problems. Lots of luck.’

It wasn’t always thus. Some 250 million years ago the Y was no different from any of our other chromosomes, which are distributed in our cells as 23 pairs. Today one of those pairs is made up of two sex chromosomes, which we know as the X and Y. Embryos that inherit two X chromosomes, one from each parent, develop into females. Those that inherit an X from their mother and a Y from their father become males. Originally, though, there was no Y and no X, just two identical chromosomes. The proto- Y was loaded with a variety of genes just like its peers, and it had nothing in particular to do with determining sex or making sperm. In fact, during this stage in our evolution, before mammals branched off from our reptilian ancestors, gender was probably determined by conditions in the environment (it still is in animals such as crocodiles and turtles, which have no sex-determining chromosomes). Then interesting things began to happen.

A sex-determining gene arose, says Page. An existing chromosome was somehow tweaked so that it became the decisive switch to determine the maleness or femaleness of the developing embryo. Perhaps a gene that used to be switched on by certain environmental cues became stuck in the on position, so the gene, rather than the environment, became the determining factor. All of a sudden we moved from a system in which whether an egg develops in shade or in sun determines if it’s male or female, to hard-wiring gender into a chromosome.

That tweak could have been a spontaneous mutation of a gene already on the chromosome. Or a gene from another chromosome might have emigrated to the Y to take up a new function in a new neighborhood. Genes do that. No one quite understands how--it may involve faulty recombination- -but over long periods of evolutionary time they may move aimlessly about the genome, occasionally finding a welcome home. Whatever the reason, suddenly the Y became different from its corresponding X. Now it harbored a brand-new gene, one unlike any other. And now it could no longer recombine with its former partner.

Recombination is the ace in the hole of evolution. When germ cells produce eggs in a woman or sperm in a man, their chromosomes are copied for inclusion in the nascent eggs and sperm; one set comes from the mother, one from the father. In this process, which is called meiosis, the chromosomes line up with their opposite numbers and sometimes swap genes. A swath of genes on a maternally derived chromosome number 3, say, may swap places with the corresponding bunch of genes on the paternal chromosome 3. Similar shuffling may occur in other chromosomes. That’s recombination, and it has two chief consequences: first, it ensures variety in our species; and second, it allows us an opportunity to remain healthy by getting rid of bad genes. If one of Dad’s genes is damaged, for example, there’s a chance that it might be jettisoned for Mom’s wholesome copy. In the long run, such random salutary switches prevail over recombinations that cause harm because embryos with healthy genes are more likely to develop into healthy, fertile people, while those with damaged genes may never even be born. As Page says, Recombination is the fountain of youth for genes. It lets you do housecleaning along the chromosome.

Once the Y acquired its unique male sex-determining gene, however, it took the first step toward being unable to perform that kind of housecleaning. Now there was simply no corresponding gene on the X with which it could recombine. Over time, other vagabond genes, finding in the newly distorted Y a safe haven from unimpaired recombination, settled in. So did nomads with male-related functions. They established the Y as a halfway house for wandering genes, expanding the stretch of distinct DNA that had no resemblance to genes on its sister X chromosome. As the Y became more and more idiosyncratic, the original genes still scattered about the chromosome found it more and more difficult to pair up with their remaining counterparts on the X. Finally, no longer able to benefit from the health-maintaining effects of recombination, they rotted and disappeared, leaving behind a depleted chromosome dominated by misfit immigrants (while the X, its dual copies continuing to recombine in women, remained healthy and intact). The final product was the Y we know today.

When page came along in the early 1980s, a wandering Harvard medical student looking for a little research on the side, he found himself recruited into early efforts to map the human genome. By chance, the first bit of DNA he happened upon belonged to the Y chromosome. He became hooked. The X and Y have a deep intellectual history, he says. Their origins have been studied and debated for decades. Most of that effort focused on the relative limitations of the Y, as well as the nature and identity of the male sex-determining gene itself. In the late 1980s, Page, by this time ensconced at the Whitehead Institute, was among those who pursued that gene. He and colleagues in Britain discovered that whether a child turns out to be male or female depends on a brief signal from a Y chromosome gene called sry that directs the developing fetus to produce the hormone testosterone.

There are a whole bunch of genes that make testosterone scattered throughout the genome, and they’re indirectly under the control of sry, Page says. sry probably functions for a few days around week six or seven of fetal development, and after that the making of a male depends on the other chromosomes. All they need is this little transient signal from the Y. The fleeting signal triggers genes that regulate the formation of the testes and their production of testosterone, generating male genitalia and eventually the muscle development, beard growth, and other characteristics associated with the gender.

And that’s it. After that brief couple of days, the Y might as well pack it in--or so went the accepted wisdom. It was then that Page began to delve into biological heresy. The emphasis had been on what the Y doesn’t do. We began to think about what it does do. And not just what it does do, but the evolutionary opportunity the Y chromosome affords. Given that genes can move from one chromosome to another, and given this strange piece of real estate that finds itself only in males, what kinds of genes ought to end up living there?

In other words, instead of continuing to focus on the Y’s shortcomings, it was time to explore its upside. The chromosome had endured for millions of years. Surely not all had been degradation and doom. Surely not all the genes that had migrated to the Y had been busts. What sorts of talents might this unique contraption have acquired? It was a notion that should have been staring us in the face, says Page. But it’s only in the last year that we’ve come to focus on these evolutionary possibilities. The impetus came from Page’s interest in male infertility. In the 1970s a group of researchers in Italy suggested that the Y might be involved in sperm production. After mapping the Y, Page and his colleagues decided to investigate further.

One in six couples is infertile, and in a fifth of those couples a key factor is a defect in sperm production, Page says. But in only a very few cases do we know the basis of the defect. Most of the time we don’t have any idea if it’s chemical exposure, the result of an infection, or whether there might be a genetic influence.

In August 1995, Page and his team announced that there is indeed a genetic influence in infertility--specifically, a gene he named DAZ, for deleted in azoospermia, the condition of having no sperm in the semen. In fertile males, Page discovered, DAZ is switched on in sperm-producing cells in the testes. But in men in whom the gene happens to be missing, the testes make no sperm at all, or very little. DAZ, therefore, is necessary for normal sperm production--as is its host, the Y chromosome.

And then last year Page discovered that DAZ was quite a curious gene. It was strung along the Y in multiple copies, one after another, as though stamped out by a cookie cutter. Even more strange was that DAZ appeared to have taken up residence not only on the Y but also on another chromosome. Page found an almost identical gene, which he called DAZL (for daz-like, pronounced dazzle) on chromosome 3. Like DAZ, this gene switched on in the testes--but it was also expressed in the female ovaries. And unlike DAZ, DAZL was present in just one copy.

Finding that DAZ--and therefore the Y chromosome--was a sperm producer had been very exciting, but everything else about the discovery was puzzling. Why should the gene show up on two different chromosomes at once? Why should it appear as a discrete, normal gene on chromosome 3 and an expanded behemoth on the Y? If both chromosomes’ versions of the gene were expressed in the testes, clearly a location specific to men, why did DAZL also switch on in ovaries? And if the function of DAZ was to make sperm, what in the world was the purpose of DAZL?

Some of the answers weren’t long in coming. Because DAZL showed up in every mammal Page examined, and in frogs, fruit flies, and other animals as well, he deduced that it’s an old gene, present in our ancestors long before DAZ came along. Bit by bit he pieced together an intriguing evolutionary scenario that not only explained the dual appearance of DAZ and DAZL but shed new light on the development of the Y chromosome itself.

Some 20 to 40 million years ago, in the ancestor of humans and other primates, a gene that eventually became DAZ migrated to the Y chromosome. It was a singular event. All mammals have Y chromosomes. All these Y’s probably specialize in male fertility. But no animals except primates boast the superspecialist sperm-producer DAZ. Where did this ancestral DAZ come from? From chromosome 3. In fact, it was probably DAZL itself. Because the old-timer DAZL shows up in many kinds of animals, but only primates have the newly minted DAZ, Page suspects that the ubiquitous DAZL must have been the precursor gene.

DAZL is the ancestor of DAZ, says Page. At some point, as a result of some fluky event, DAZL found itself on the Y chromosome. What might that fluky event have been? A foul-up in recombination. Perhaps a chromosome 3 somehow got paired up with a Y. Perhaps a copy of DAZL was swapped between a 3 and a Y. Then the gene underwent a transformation that was quite spectacular.

Almost immediately, DAZL bulked up. What was once a modest little gene exploded to more than ten times its size, hiccuping out copies of itself until it became a monster. Genteel DAZL, expressed in both testes and ovaries, became rambunctious DAZ, the specialized testes sperm producer.

Nowhere but the Y would DAZ have been able to become a supergene so dramatically. The reason, once again, involves recombination--or the Y’s lack of it. With no partner to check and balance its behavior, the Y can go bonkers. And if our continued reproduction demands that we build a powerhouse of a sperm producer, a specialist chromosome, the Y is the place to do it.

The Y became something never before seen: a designated sperm- producing chromosome in which the usual genetic rules no longer applied. This may have been a sound, if tenuous, strategy in the long term. After all, as a species we humans seem to have no major problems on the reproductive front. Indeed, we’ve overrun the planet. But all this genetic deregulation has also led to the downside of the Y, its instability. The other side of the coin of rapid growth is rapid deterioration, and the Y exhibits that in spades. It’s one thing for migrating genes to find a new home on the Y--it’s quite another for them to settle in the neighborhood for the long haul.

Again, the culprit is the lack of restraint normally provided by recombination. The same unfettered degenerative forces that winnowed the Y’s population of original genes continues to liquidate the immigrants. The Y is like a sloping beach, Page says. Because there’s water flowing out and water flowing in, the sand is constantly being eroded, constantly being replenished, constantly being reshaped. In the Y, there are genes flowing out and genes flowing in. It’s constantly being reinvented.

In the short run, however, these high-wire antics can result in disaster--that is, infertility. Because Y genes tend to mutate readily, a son can inherit a nonfunctioning DAZ, or even no DAZ at all, from a perfectly fertile father. The breakdown can take a single generation. At least one in every 8,000 newborn boys is missing this part of the Y chromosome, says Page.

He wants to do something about it. While a total absence of DAZ may be insurmountable, it may eventually be possible to enhance a partial gene with drugs, or perhaps even gene therapy or other high-tech procedures. Such treatment generates ethical considerations, however. It has recently become common practice to circumvent the unhappy consequences of an aspiring father’s low sperm count by extracting a single sperm and injecting it directly into the mother’s egg. This strategy does a good job of producing offspring, and researchers are beginning to use it in cases where the father’s low sperm count is due to DAZ deletion. But if any of the babies born to DAZ-less fathers are boys (so far, the few born have been girls), the technique will pass the father’s genetic defect to his son, something impossible in nature. The result of such well-intentioned interference may be families in which all males, down through the generations, are infertile and will require state-of-the-art reproduction techniques to have children.

In the past, in the absence of these fancy methods, these newly arising mutations would disappear from the population in every generation, says Page. But now, with assisted reproduction, you can turn genetic infertility into something that runs in families. Couples with whom I’ve spoken are terrified at the prospect that their infertility could be a legacy passed on to their children. In their minds it’s an Orwellian nightmare--their offspring must forever reproduce by unnatural means. The counseling issues here are huge.

Isn’t it just like the Y to throw modern medicine a curve like that? Strength and capriciousness, power and attitude--it’s the bargain evolution has made with this unruly superspecialist of a chromosome. Thanks to Page, it’s finally getting the kind of attention it deserves--wary attention, prudent attention, attention that allows for the possibility of raucous events. Page is now trying to pin down DAZ’s precise function in the production of sperm. During which part of the process does it kick in? He’s also trying to figure out the role of DAZL. Is it simply a redundancy? What’s it doing in ovaries, anyhow? And he’s looking for other Y chromosome genes that may be involved in male fertility. daz may be the first gene on the Y for which there’s solid evidence of a role in sperm production, but there will be others. (Australian researchers have recently corroborated Page’s prediction by finding that another sperm-producing gene migrated to the Y long before DAZ did.)

The Y is a work in progress, a grand experiment, says Page. You think the organism might get rid of it, but it’s like one of those discretionary budget programs that Congress flails at, usually at the last minute: ‘Hey, let’s keep the Y around for another hundred million years. . . .’

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