counterpoints

Why the Y

Jerold Lowenstein

Sex and politics make an intoxicating brew for the public and the paparazzi. Lately scientists have joined the cocktail party too, adding a shot of genetic snooping to the mix. Within a few short years, DNA fingerprinting has become a standard technique for determining paternity. Now, thanks to cutting-edge chromosomal research, prying geneticists have established that Thomas Jefferson fathered at least one son by his slave Sally Hemings. Sally herself was the daughter of Jefferson's father-in-law.

Rumor and speculation about a sexual relationship between the author of the Declaration of Independence and his wife's half-sister has been rife for two centuries, but it took a molecular analysis of the Y chromosome, that icon of masculinity, to prove the case. The Y chromosomes of male descendants of the Jefferson and Hemings families are identical, which practically clinches Jefferson's paternity.

Why use the Y chromosome for this historical outing?

Of our 23 pairs of chromosomes, the Y is unique in several respects. It is the smallest by far. Males have it, females don't. It is passed down virtually unchanged from father to son, while the other 22 chromosome pairs "recombine," a process that mixes up the genes of each pair like shuffling two decks of cards together. The shuffle makes sure that we get some of our genes from both parents and all four grandparents. But if we're male, we have our daddy's Y pretty much as he got it from his daddy. That's why it was possible to match up the male Jeffersons and Hemings after so many generations. Their Y's had hardly changed at all from each other but were different from those of other families. Any chromosome besides the Y would have been a muddle of genetic footprints from 30 or more ancestors, and the trail would have been lost.

The Y chromosome tags male lineages the way mitochondrial DNA tags female lineages. Mitochondria, the energy-producing "batteries" of the cell, reside in the cytoplasm rather than in the cell nucleus where the chromosomes are. The sperm, the male reproductive cell, is basically a cell nucleus with a propulsive tail. It has virtually no cytoplasm, so no mitochondrial DNA.

The female reproductive cell, the ovum, has lots of cytoplasm and with it the mitochondrial DNA. Therefore, all of us, male and female, get our mitochondrial DNA from our mother's fertilized egg. Like the Y, mitochondrial DNA doesn't recombine. It is passed down unchanged from mother to offspring. Males can't pass it on to their offspring, so it goes strictly through the maternal line, just as the Y chromosome goes through the paternal line.

All humans on Earth today have the mitochondrial DNA, altered by a few evolutionary mutations, of an ancestral woman ("Eve") who lived about 140,000 years ago in Africa. All human males have the Y chromosome of one male ("Adam") who lived in Africa at about the same time. We don't know whether "Adam" and "Eve" ever met, or whether they were even members of the same generation. We only know that their genes have met in us.

Mitochondria provide the energy that drives that cell. Exactly what it is that the Y chromosome does is a long-standing mystery, only slowly being revealed by recent genetic discoveries.

The main function of the Y is to switch the growing embryo from female, the default anatomy, to male. It does this by creating testes, which then set off a hormonal and physical chain reaction that creates a baby boy.

It took 30 years of intensive searching before the testis-determining gene was finally located on the Y chromosome in 1990. What this gene does on the biochemical level to trigger testicular growth is still a puzzle. It's not a straightforward process like turning on a light switch. It seems that there is a repressor gene, a lock that prevents the light switch from turning on. The testis-determining gene somehow represses the repressor, unlocks the lock, and thereby lets the light turn on. Got it? Genes often behave like Rube Goldberg devices, A acting on B in order to make C happen.

The average chromosome contains about 3,000 genes, each of which has a role in growth, development, or function. The little Y chromosome, the runt of the litter, has the fewest genes. Until recently, geneticists saw the Y as a DNA desert with one major oasis, the testis-determining gene. How many genes the Y actually possesses, and how they function in the body, was unknown.

Geneticists Bruce T. Lahn and David C. Page of the Massachusetts Institute of Technology made a systematic exploration of "Desert Y" and reported their results in Science magazine, 24 October 1997. After an exhaustive search using the latest techniques, Lahn and Page were able to identify 20 different genes. Eight had been found previously. Twelve were new.

Eleven of these genes are related to testicular function and fertility. In this respect, the Y chromosome is different from all other chromosomes, in that most of its genes, few as they are, have a coherent theme: male fertility. Several of these genes contribute to sperm production. If a particular one is missing or mutated in mice, the male has no sperm at all. Mutations in some of the others may cause a low sperm count or testicular cancer.

Nine of the Y genes match genes on the X, the female sex chromosome. The male genotype is XY, an X and a Y that includes the nine X-matching genes; the female genotype is XX, two X's. This match-up tells us that way back in evolutionary history, several hundred million years ago, the X and Y chromosomes were identical, as they still are in many reptiles. These XX reptiles can be either male or female, depending on the environmental temperature when they hatch. With turtles, for instance, more females hatch when it's warmer and males when it's colder. With crocodiles it is just the opposite (see Pacific Discovery, Fall 1992). At some point in vertebrate evolution, one of the two X's underwent mutations that gave it testis-determining potency, and it became a Y.

Since both males and females have at least one X, the Y doesn't need to continue duplicating all of the X genes. One of the iron laws of natural selection is: use it or lose it. The Y didn't use it, so the thousands of genes originally strung out on it were gradually eroded away. Those nine matching genes that remain prove that X and Y were once the same.

No babies can live with just a Y and no X. They can and do live with a single X and no Y, a genotype called XO. If the Y did nothing other than form testes, XO babies should grow up to be normal females. However, their development is not normal. Their ovaries remain immature and infertile, and XO adult females are unusually short, with widened "webbed" necks.

This condition, called Turner's syndrome, is one of those "natural experiments" that shows something about how genes work. We used to think that in normal females, one of the two X chromosomes was chemically "switched off," so that the female wouldn't receive a toxic double dose of X genes. One set of X genes would seem to be enough. Therefore, we would expect that the single X chromosome in Turner's syndrome would produce a normal female. But it doesn't.

We deduce that those nine genes on the Y that match X genes are actually essential, not just vestigial, and that those nine genes on the second X are essential as well. Recent research confirms this to be true. A male needs a single dose of X genes plus all of the Y genes (including the nine-X-matching genes) for normal development. A female needs a single dose of X genes plus those nine matching genes on the other X that the Turner's syndrome baby doesn't have. Genetic biochemistry is so subtle that in normal females the second X chromosome isn't completely inactivated, as we used to believe. Those nine critical genes are spared from being switched off, so the normal female gets the extra dose she needs for normal anatomy and reproduction. It turns out that Desert Y hides secrets of female as well as male fertility.

Hemophilia, color-blindness, and many other genetic diseases are known to be X-linked and passed on through the maternal line, but no convincing cases of Y-linked human inheritance have yet been identified.

I expect that some will be discovered within the next few months or years, now that we're finding out more about the functions of those 20 genes. It's likely that some males will have a nine Y-linked predisposition to infertility or testicular tumors. Study of the nine Y-matching genes on the X chromosome may help to clarify some of the frequent, but mysterious, cases of female infertility.

We've made progress surveying the unknown territory of the Y chromosome in the past decade, and even in the past year, but nooks and crannies of this odd macho desert remain uncharted. Thomas Jefferson, the most scientific of American presidents and a great promoter of exploration, would have been fascinated by the latest findings, though he might have had mixed feelings about their application to his own once-private life.

Jerold M. Lowenstein is professor of medicine at the University of California in San Francisco and chairman of the Department of Nuclear Medicine at California Pacific Medical Center in San Francisco. jlowen@itsa.ucsf.edu