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Scene II

Capulet’s orchard, five million years hence. Romeo and Juliet’s faces are etched with pain.

Romeo: It’s not that I don’t love you, dearest Juliet. But I’m not what I seem…

Juliet: O Romeo, Romeo! Whatever can you mean?

Romeo: I’m a fraud, Juliet. We can’t be together because…because I’m not…well, because I’m a different sp…

Juliet: Species! Alas, say it is not so! You’re a different species?

The family feud between the Montagues and Capulets was bad enough. There might be nothing in a name, but this biological rift between our tragic lovers spells doom for their illicit romance.

IT is a tragedy that even Shakespeare couldn’t have imagined. In five million years we humans will face a crisis unlike any before. Not an ice age or a nuclear war, but an apocalypse from within our own genes that could eliminate men and threaten humanity with extinction. Even if we survive, evolution could shatter humankind into several different species, so that many a pair of gene-crossed lovers could never have children.

The ticking time bomb is the Y chromosome, the genetic apparatus that turns around half of us into males. Appearing on the scene millions of years ago, the Y ruled over a fine kingdom of 1500 genes, but that kingdom has been crumbling ever since. Today, the Y is but a foolish old man, a mere shadow of his former self, clinging desperately to the dwindling 40 or so genes that remain. And some researchers predict that in five million years even those will disappear, and the Y will falter and be extinguished. When that happens, humanity will lose its male half, and must either go extinct or scramble to evolve a new way of creating males.

The trouble began some 300 million years ago (long before the dinosaurs showed up) when mammalian sex chromosomes were invented. We store our genes in 22 pairs of regular chromosomes, but also have two chromosomes that determine our sex. If you have two Xs, you’re a girl, if you have one X and one Y, you’re a boy. This is because the Y contains a gene called SRY that makes embryos develop as males. This system of sex determination is shared by all mammals and similar schemes are used by many fish, reptiles, insects and even plants.

Sex may be at the root of all our Y-related woes, but sexual reproduction is vital for our species’ survival. It allows us to flush out genetic “parasites” and prevent harmful mutations from being passed to future generations while hanging onto really useful genes. Those two copies of each chromosome – one from Mum, one from Dad – back each other up. When sperm and eggs are manufactured, the pairs line up and swap corresponding sections, so damaged pieces of one chromosome can be replaced with intact sequences from the other. Natural selection then eliminates offspring unfortunate enough to end up with the dodgy bits. Parts-swapping, or recombination, also shuffles the deck of genes, ensuring the next generation always includes individuals with lots of different gene combinations capable of tackling any challenge the environment throws at them.

But there’s the rub. Somewhere along the long line of its evolution, the Y lost the ability to swap. Thereby hangs the tale of the Y’s rise to power as the ultimate old boys’ network of male genes (see “Why the Y”), and its inevitable corruption and fall.

In the beginning, there was no Y. The early, reptile-like ancestors of mammals probably didn’t use sex chromosomes. Instead, everyone carried all the genes they needed to become either male or female. With these genetic pathways in place, all they needed was a switch telling the embryo which one to choose. At first, they probably used environmental cues such as temperature to steer an embryo to go either butch or fem, much as reptiles do today. Some animals may even have lived as hermaphrodites with both male and female parts.

But 300 million years ago, evolution chucked a spanner in the works. A gene – the forerunner of SRY – mutated so that it arm-twisted any embryo carrying it into becoming male, regardless of temperature. It became the new switch triggering sex development. This mutation happened on one of the pair of chromosomes we now know as the X. That chromosome was destined to become the Y, and to this day, ancient X chromosome sequences can still be detected on it.

About the same time, part of the proto-Y chromosome broke off and reattached upside down. So its reversed DNA sequence no longer matched that of its partner, and it couldn’t line up and swap parts any more. Worse, as time went by, at least three more sections of the Y became inverted. Recombination had become all but impossible. Today, barely 5 per cent of the Y matches up with the X.

“That’s the death knell,” says Jennifer Marshall Graves, a marsupial geneticist at Australian National University in Canberra and the University of Melbourne. “All kinds of mutations accumulate, and they can’t be gotten rid of by recombination.” So ever since the Y lost its ability to recombine, it has been racking up a crippling collection of mutations that are slowly destroying the genes it carries. And this is already causing problems for men.

The biggest culprits are ancient virus-like DNA parasites called repetitive elements. These try to copy themselves as many times as possible and are hijacking the Y at the expense of legitimate genes. Unchecked by recombination, these elements insert more and more copies of themselves into the infested chromosome. The cell tries to silence them by locking up the infected DNA in an inactive form. Unfortunately, any legitimate genes nearby get permanently shut down too (see Diagram). Evolution keeps some balance by selecting Y chromosomes that have extra copies of these genes and so can compensate for the gagging – 28 copies of one called RBMY have accumulated. But this, say the pessimists, will merely delay the Y’s demise.

Going, going, gone

These parasites are already making mischief by rendering some men infertile. Repetitive elements can cause portions of the Y to be deleted – ironically through a recombination-like mechanism. Long stretches of these elements can loop around and line up with other stretches of elements on the Y. They then exchange DNA, and in doing so, cut out the DNA in the loop. No fewer than 15 per cent of all infertile men have lost a key group of sperm-manufacturing genes called AZF in this way.

Another reason the Y is mutation-prone is because it gets passed to the next generation via sperm, says John Aitken, a reproductive biologist at the University of Newcastle in Callaghan, Australia. The DNA in a 30-year-old man’s sperm has been copied about 350 more times than that in an egg – and every time a chromosome is copied, mistakes can creep in that lead to genetic mutations. “The Y is taking a hammering,” declares Aitken.

Even the almighty power of natural selection can’t rescue the Y, says Brian Charlesworth, a Y geneticist at the University of Edinburgh. Recombination allows natural selection to pick the chromosome with all of the best genes (and none of the faulty ones). But without it, natural selection cannot choose a Y gene without being lumbered with any mildly damaging mutations in the other genes on the same Y. And so a few choice Y genes evolve beneficially over time, while the rest are left to wither on the vine.

“The forces are lined up against the poor old Y,” concludes Marshall Graves. She has compared the sequences of the X and the Y to get an estimate of how fast the Y is degenerating. Her apocalyptic arithmetic is admittedly rough, but she figures the Y has lost 1500 genes in 300 million years – about five genes per million years. And so with 40 genes left today, old man Y should lose his final gene and disappear forever in 5 to 10 million years.

But what will happen when the Y takes its final bow? Will humankind bite the dust, or will the Earth become a sapphic Utopia, where men have disappeared and women use technology to create children with each other?

None of the above, says Marshall Graves. She expects that just as the Y is fizzling out, some newly evolved gene on another chromosome will replace SRY and rescue us from extinction – and possibly transform humanity overnight. It’s not as far-fetched as it might seem. In fact, some of the sorts of mutations that could save mankind already exist, carried in the people whose physical sex doesn’t match their chromosomal sex: for example, people who have two X chromosomes and no Y, and yet are male (see “Intersex saviours”). Unfortunately, these men are normally infertile, because the Y carries genes essential for male fertility. But that could change.

Although genes on the Y are currently essential for male fertility, as each Y gene degenerates, another elsewhere in the genome gradually evolves to take its place. This means that in a few million years, all the genes you need to be a fertile male will lie on other chromosomes. That only leaves the key switch – SRY – on the Y, and as that declines, it will be surprisingly easy to evolve a replacement. The reason, says Marshall Graves, is that even SRY is just a typical Y gene.

After all, being king of the dilapidated Y is like being king of a junkyard – with SRY as a junked auto that’s missing doors and seats, but still runs. When SRY was first identified, its protein product was thought to cause maleness by binding to specific DNA sequences and activating key genes. It belongs to a family of SOX genes that do just that. But further research showed that the SRY protein is shot full of mutations, apart from the small part that binds to DNA. The only way such a piece of junk could trigger maleness, says Marshall Graves, is by binding to genes (presumably female genes) and not activating them. It does this by competing with other proteins, preventing them from turning the genes on. Graves believes that SRY evolved from an older gene called SOX3 when a mutation transformed it from a trigger of female development into an inhibitor of it (see Diagram).

The beauty of this mechanism is that it should be simple to evolve another SOX gene to produce a new inhibitor to replace SRY: all you have to do is leave the part that binds to DNA intact, while disabling the part that actually turns the genes on. There are thousands of mutations that will accomplish just this. Oxford University geneticist Jonathan Hodgkin has shown that in worms, at least, sex determination is surprisingly malleable (see Diagram). Just by introducing a few mutations, he has swapped the sex-determination role between eight different genes, even getting the worms to adopt a turtle, bird or even human-like method of sex determination. “And anything I can do in the lab,” he says, “must be pretty easy in nature.”

Even if we dodge extinction, humankind will never be the same. As in Kurt Vonnegut’s novel Galápagos, that fateful SRY-replacing gene might arise in some remote corner of the world, and the few humans carrying it might be the only sliver of humanity to survive. If it happened in the Rift Valley, then future humans would all be Maasai; if it happened in the Khumbu, Sherpa features would become humanity’s hallmark.

But Marshall Graves imagines something even more shocking: several different SRY-replacing genes occurring in different locales. “You might very well get populations that have different sex-determining mechanisms,” she says. “It would be quite difficult for these populations to be interfertile, so this might become a speciating event.” In other words, populations mightn’t seem any more different than ethnic groups do today – or they could look as similar as Montagues and Capulets – but they would be unable to interbreed.

To begin with, though, humans with different sex-determination genes might not have too many problems interbreeding. But pretty soon, history would repeat itself and inversions would occur on chromosomes carrying sex-determination genes, says Marshall Graves. And because having unique sex chromosomes is such an evolutionary advantage (see “Intersex Saviours”), it wouldn’t be long before they took over, creating new species. What’s more, the dominant nature of sex-determining genes means these evolving populations wouldn’t have to be isolated from the rest of the world for this to happen. The gene could spread through populations with ease.

Hints of what may be in store come from other mammals that have already ditched their Y. The mole vole, a tatty brown rodent that lives in remote regions of Armenia, has already lost its Y and SRY and split into two species. And in eight species of South American field mice, SRY is clearly growing senile, not to mention the wood lemming of Scandinavia. Both species abound in XY females. In the lemmings this is because an upstart gene on the X chromosome is already grabbing the reins from SRY. This new gene makes any embryo carrying it female, beating SRY into submission if it happens to be there. As for the field mice, SRY is simply growing too frail to do its job. “The rodents,” concludes Marshall Graves, “are leading us into the new era of a Y-less existence.”

It sounds like alarming stuff – but scientists are by no means unanimous when it comes to writing off the Y. David Page, a geneticist at the Whitehead Institute and the Massachusetts Institute of Technology in Cambridge, is one of a number of researchers who think it’s all much ado about nothing. Although they concede that Y chromosomes – whether in people, plants or porcupines – naturally erode, they say that the question of whether the Y will ever burn down to nothing is far from settled.

Indeed, Page has found some evidence that the Y is staving off collapse thanks to genes immigrating from other chromosomes. Y gene loss is traditionally viewed as a one-way ticket, but Page has found that one major gene involved in sperm manufacture, called DAZ, has appeared on the Y. He has found a gene very similar to DAZ on chromosome 3 and concludes that it got copied to the Y. “So there’s restocking of the Y’s gene inventory,” asserts Page. “This is one of the stronger arguments against the apocalyptic vision.”

Page’s discovery forced a major reassessment of the doom-and-gloom scenario. But whether the Y imports enough genes to survive indefinitely remains unknown. “I think that might actually delay the process [of Y loss] rather than stop it,” observes Kenneth McElreavey, a reproductive geneticist at INSERM, France’s medical research agency in Paris. He points out that of 40 genes on the human Y, only one other immigrant has been discovered so far.

Even so, that’s not to say that the Y will erode away completely. It’s possible that Y-eroding forces diminish over time, or that the human Y has already hit rock bottom and won’t degenerate much further, says Deborah Charlesworth, an evolutionary biologist at the University of Edinburgh.

But the signs are that the Y still has some way to go before it hits that bottom. When it was born 300 million years ago, it started with around a thousand genes. A second chunk of 500 genes was added from another chromosome 200 million years later and this, says Marshall Graves, saved the Y from extinction. Of the 40 genes left on the Y, all but four come from that later addition, suggesting that without it, our Y would be nearly gone. The marsupial Y, which didn’t receive this top-up, is down to 6 or 7 genes and looking frail indeed. While marsupials dutifully carry their Y in their sperm-producing cells, some species lose it elsewhere in their bodies, as though it really contains little of use.

So in the end, there’s plenty of evidence to suggest that the Y is losing influence. “That is not under any debate,” proclaims McElreavey. But there’s uncertainty about when exactly the axe will fall. “I don’t think,” he says, “that you can start talking about figures of millions of years from now when there’s going to be an apocalyptic event.”

Whenever the change happens, it won’t be easy. After all, the Capulets and Montagues’ feud – fierce as it was – could at least be lightened now and then by a romantic, moonlit liaison. But what if interbreeding and interloving weren’t possible? History provides us with no clues about what that might be like. Yet it does provide one surprising observation: according to some anthropologists, humans have existed as multiple species before – as recently as 35,000 years ago when both Homo sapiens and Neanderthals walked the Earth. So perhaps splitting into separate species every so often is all part of being human.