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The Once and Future Male
Natural History, September 2002

What does it mean to be a man? Part of the answer depends on where you ask the question. In some places, being a man may include spending Sundays watching football. In others, it may include completion of a rite of passage, such as getting buried up to your chin in an ant nest on your thirteenth birthday. Of course, there's some biology involved, too, and crucial to that biology is a peculiar chromosome called the Y. Men and women normally carry twenty-three pairs of chromosomes. Each pair consists of two matching chromosomes, with one exception: men normally have one chromosome called X paired with a dramatically smaller one called Y. Women, on the other hand, have two X's. A child (again, normally) inherits one chromosome from each matching pair belonging to each parent, including an X from its mother. From the father it receives either an X or a Y. If the father bequeaths a Y chromosome, the child will be a boy. Yet it's wise not to put too much faith in the simple equation Y = male. There are people who are XY, for example, but who look for all the world like women. That's because they have a faulty copy of a gene that builds a receptor for testosterone; as a result, their sex organs never get the signal to take on a male form.

The same kind of cautionary tale has emerged as scientists have begun to piece together the history of the Y chromosome. To be a man does not depend on some fixed, unchanging stretch of DNA. In vertebrate history alone, we have male ancestors going back at least 500 million years, but the Y chromosome is less than 310 million years old. And some of the genes on the Y chromosome that are now essential for making males may have emerged less than 170 million years ago. All the genes on the Y chromosome probably have only a few million years left before they vanish. But there will still be males. Strangest of all, it will be maleness itself that makes those male-making genes vanish.

The Y chromosome is as old as the mammalian lineage. It can be found today in just about every mammal, from human to elephant to bandicoot. But reptiles and birds, the closest living relatives of mammals, don't have a single Y among them. They rely on completely different ways of determining sex. Turtles and alligators, for instance, lay sexless eggs, which become either male or female depending on the temperature at which they incubate. Birds, like mammals, use sex-determining chromosomes, but theirs aren't related to ours. Biologists call them W and Z. While our two X's make a woman, two Z's make a male bird; a W and a Z make a female. Without any version of the Y to be found other than in mammals, there's only one conclusion to draw: our ancestors must have evolved after they branched off from the ancestors of birds and reptiles--a split that paleontologists think happened about 310 million years ago.

As the human genome has come into focus in the past few years, the Y has held on to its title as an oddball chromosome. It is a genomic runt, containing only 60,000 nucleotides, the organic compounds that make up DNA. (With 165,000 nucleotides, the X chromosome is nearly three times as long.) And when you look at the actual number of working genes on the Y, the difference is even more stark: the Y has only 50, while the X has 1,500. Yet X and Y are apparently cousins, descended from an ancestral pair of matching chromosomes. Scientists have discovered that a number of the Y genes have strikingly similar counterparts on the X chromosome. The simplest explanation for this is that a matching pair of chromosomes in some primordial mammal diverged to become the X and the Y.

Scientists suspect that these chromosomes began to part ways when one of them acquired a single gene that could turn a mammal into a male. Building a male is a complex business, probably requiring the cooperation of hundreds of genes, but a single gene can actually act like a trigger for an entire process. In 1990 a team led by Peter Goodfellow, then working at the Imperial Cancer Research Fund, discovered such a trigger in humans: a gene on the Y chromosome that they named SRY. If a Y-bearing sperm carries a defective copy of SRY--and it can take as little as one incorrect nucleotide to disable the gene--a child will grow into a female despite its Y chromosome. The reverse is true, too. In a neat experiment, a team headed by Robin Lovell-Badge at the National Institute for Medical Research in London plucked an SRY gene from a male mouse and added it to the paired X chromosomes of a fertilized mouse egg. The mouse embryo grew into a male.

SRY controls sex determination not just in humans and mice but in many other mammals, from dogs to kangaroos. But Jennifer Marshall Graves, a geneticist at the Australian National University in Canberra, and her colleagues have discovered that SRY is absent in monotremes, a group of mammals that branched off from the ancestors of all other living mammals about 170 million years ago. The modern representatives of this group, the platypus and the echidna, still manifest their ancient heritage: they lay eggs rather than bearing live young, and have a low, fluctuating body temperature--traits left over from mammals' reptilian ancestors. Monotremes do have Y chromosomes, and the males develop a penis and testicles and produce sperm. But they do not have the crucial gene on the Y that creates males in just about every other species of mammal.

Scientists are now searching for the trigger gene that actually does build male monotremes. In the meantime, Graves has come up with a surprising hypothesis concerning the early evolution of mammals (she presented it this past May in the journal Trends in Genetics). The story begins before the Y chromosome existed, when our ancestors--some kind of early mammal or perhaps a reptilian forerunner--used another system for determining sex. Somehow, one copy of a gene on what would become the X/Y chromosome pair changed into a form that happened to trigger the network of male-building genes. That trigger gene, according to Graves, may not have been SRY. Over the generations, males spread this trigger gene, and the old way of making males disappeared. During this time, the Y chromosome became increasingly distinctive and isolated.

Then, about 170 million years ago, when the monotremes branched off, they kept their Y chromosome. Perhaps they continue, to this day, to use the original trigger gene. An ancestor of all the other living mammals (marsupials and placentals) took a different route, however. Sometime after the split, this branch acquired a brand-new trigger gene on the Y chromosome. This new gene was SRY, and according to Graves, it must have appeared no later than 130 million years ago, when the last common ancestor of all living mammals apart from monotremes is believed to have lived. SRY then spread, generation after generation, until it drove the older trigger gene extinct.

How the Y chromosome became so different from its partner is another element of this story. In cells that give rise to eggs and sperm, the chromosomes in each matching pair embrace and trade stretches of their DNA, a process called recombination. Initially, the X/Y pair-to-be swapped genes too. But as new genes that helped build male anatomy evolved in the X/Y pair, there would have been an advantage to keeping these male-building genes close together on the same chromosome, allowing them to form stable partnerships over millions of years.

One mechanism that would have ensured that these genes passed intact from one generation of males to the next was for the X and Y chromosomes to become increasingly isolated from each other. And as the Y became more isolated, male-building genes arising on that chromosome would have been especially favored. Over time, such genes were able to coevolve, forming into ever more effective coalitions. For example, many of these male-building genes on the Y chromosome began to be expressed in the testicles and nowhere else. Today, only a short stretch at one tip of the Y and X chromosomes can recombine--a vestige, presumably, of a far more intermingled past.

The Y chromosome we now inherit has a skimpy, junk-laden code. In the 1960s, biologist Susumo Ohno proposed that as the Y became isolated, evolution drove its decay. When a gene on a more typical chromosome mutates, the chromosome can still recombine with its twin. Children are equally likely to inherit either the mutant gene or its unchanged counterpart; this slows the spread of the mutant gene over the generations. But if a mutation strikes the solitary Y chromosome, it always gets passed down intact from a father to every one of his sons. And as the Y gathers up mutations, fewer and fewer of its genes continue to work; they lose their integrity and ultimately disappear or get overrun with junk DNA. In time, Ohno argued, only the handful of genes responsible for building males survived.

Scientists can't check Ohno's hypothesis by watching the DVD of the Y's life story, complete with quadraphonic sound. But it is possible to look for parallels elsewhere in nature. Consider, for instance, the fact that the sex chromosomes of birds function like a mirror image of our own. The W chromosome, which makes female birds, does not recombine. And like the Y in male mammals, the W of birds is a tiny wastrel compared with its Z counterpart. The same evolutionary process seems to be at work in both birds and mammals, although it is affecting different chromosomes.

The SRY trigger gene has ruled our male-making process for at least the past 130 million years, but that doesn't mean it has been frozen in time. On the contrary, it and many other genes on the Y chromosome have been evolving far faster than genes on other chromosomes. For one thing, Y chromosomes accumulate mutations quickly because they can't recombine. For another, because far more sperm are produced than eggs, the germ cells in males must divide many more times, increasing the potential for copying errors. And while X chromosomes get passed on to the next generation through either an egg or a sperm, a Y always goes the sperm route--and sperm cells provide a riskier environment. They have evolved into fast, lightweight swimmers; in the process, they've jettisoned most of the proteins that normal cells carry, including the enzymes that repair mutations.

Mutated genes provide raw material for natural selection, and here, too, genes on the Y have a knack for speed. The fertility of a male is the core of his reproductive fitness, and any mutation that improves it--for example, by making him more attractive to females or providing him with faster-swimming sperm--brings a huge evolutionary advantage. Scientists suspect that when a gene that gives its owner a big advantage appears on the Y, copies of the chromosome may spread through a species in a Darwinian eye blink. Our own species may have experienced this sort of selective sweep just 60,000 years ago (see "The Evolutionary Front: After You, Eve," March 2001).

The evolution of Y genes may be fast, but it's also reckless, and ultimately the chromosome as a whole is doomed. It has shrunk for millions of years and has lost almost all of its original genes. Consider, for example, the sperm-building gene UBE1. Almost all mammals use it, and our own distant ancestors no doubt used it as well. But Michael Mitchell, of the Faculty of Medicine at the University of the Mediterranean in Marseille, and his colleagues have found that we lack UBE1, as do chimps and some other primates. Some 40 million years ago, they propose, our primate ancestors lost the UBE1 gene. Its job was taken up by another gene on another chromosome.

The path of evolution is usually so quirky and complex that scientists shy away from making predictions. But the future of the Y chromosome seems clear. Graves points out that, on average, three to six genes have disappeared from the Y every million years since the chromosome emerged. At that rate, the Y has only 10 million years left. It's an old chromosome, at death's door.

Yet the death of the Y doesn't mean the death of men. Men need only look to the mole vole for comfort. Burrowing through the soil of western Asia are two species of these rodents (Ellobius tancrei and E. lutescens) that have lost all the genes from their Y chromosome--in fact, they no longer have a Y chromosome at all. In one of these species, both males and females have been left with just the unpaired X; in the other, both sexes have two X's. No one knows how mole voles ended up being the first mammals to cross over into the Y-free future. But along the way, they must have evolved new genes--on other chromosomes--that are responsible for making males. One of those genes took over the job of SRY, and the chromosome on which it resides is probably on its way to becoming the new Y.

If our species manages to survive for another 10 million years, our descendants will go on making men even after their Y chromosome vanishes. But the change may not be smooth. Graves speculates that several new systems for determining sex could emerge within the global human population. People conceived under one system might be genetically incompatible with those conceived under others. As a result, the human species could fragment into separate populations and, ultimately, separate species. Which of them will prefer football and which the ant nest, we'll have to wait and see.

Copyright © 2002 Carl Zimmer. Reproduction or distribution is prohibited without permission from the author.

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