The Y and Mighty
Jerome Berne
It's the chromosome that has for years been relegated to the sidelines of science. But now this tiny cell particle is providing the answers to some very big cultural questions - and putting a match to political time bombs.
It's the runt of the genome. A comma of a chromosome that might be called in evidence to show that the Creator has a feminist sense of humour. It has to be a joke. To design the one chromosome that appears only in male bodies, that sets the developing embryo off on the path of bigger muscles and more aggression, and then to make it such a weedy and insignificant thing.
Not only does it look like an afterthought, but even geneticists have traditionally had little positive to say about the Y chromosome. "There's nothing very interesting on it, is there? Just a few genes coding for sperm," says one researcher, crouched over her computer at the Department of Pathology in Cambridge, investigating the genes involved in breast cancer. "My colleagues thought I was really odd when I started studying it 15 years ago," adds Dr Nabeel Affara, the department's Y expert.
But the runty Y is enjoying the last laugh. Having sand kicked in its face by dismissive researchers will soon be a thing of the past. In recent years, it has been undergoing a Clark Kent-like transformation. A shrimp it may be, but it is turning out to be the wild frontier of the genome, where strange and important things happen.
"There has been almost a century of ignorance and misunderstanding of it," says David Page of the Whitehead Institute in Cambridge, Massachusetts, who is currently working on a major study of the Y. "It has been regarded as a wasteland but I see it more as a natural park with as many unusual features as Yosemite or Yellowstone." Right now, these quirks are providing answers to such very big questions as where did we come from? How did we develop language? What is it that makes us so different from the apes? Is the sex war hard-wired into our genes?
Y's power to shock has only recently been revealed. There have been reports on the way it can be used to track down the "ancestral" Adam, the one man from whom all males are descended, suggestions that the Native Americans didn't come from Siberia, as all the textbooks say, and, equally controversially, a theory put forward that it is a gene on the Y that accounts for man's ability to speak. What's more, that gene, and a few others nearby, are unique to humans. Although apes have them on the X chromosome, they jumped over to the Y around the time that apes and humans separated. This suggests that Y may hold the secret of what it is that makes us human, which must put the feminist Creator to flight.
But to begin at the beginning, which in the Y's case we can do because we know that there was a time, around 300 million years ago, when there wasn't a Y chromosome. Instead, most animals had a pair of identical Xs and gender was determined by other factors, such as temperature. (In some amphibians, such as turtles and crocodiles, eggs still hatch out as males above a certain point and as females below it.) Then, in one of those dramatic evolutionary transformations that are a feature of the Y, a gene on an X chromosome in a particular mammal mutated. "This mutation became a tyrannical male-determining gene," Page explains. "It said, in effect, 'I will no longer respond to these environmental cues; if I am present, the male pathway will be followed.'"
It survived, but it could do so only by putting a block on the process of swapping genes with the other X of its pair, otherwise it would have been weeded out. Gradually, the X with the rogue gene was able to do less and less trading with its unaltered partner, and took on an identity of its own, as the Y.
These ancient events around its birth conferred on the Y one of the special features responsible for its current stardom: it appears only in males. Any egg that was fertilised by Y-carrying sperm became male; eggs that got the X stayed female. That is why the Y is a unique source of information about the male line. It's a genetic version of those famous biblical begats.
By measuring the differences in the mutations that have crept into the Y, researchers can show that the males of two different ethnic groups are more or less related to a common ancestor. The bigger the differences, the longer they have been separated. Some of the results, reported early last year, were surprising. For instance, the Lemba are a black, Southern African, Bantu-speaking population whose oral tradition says they were originally Jewish. According to their stories, they were once craftsmen in metal who lived in the Yemen. The men would travel south to trade but when a disaster struck back home, some of the men took local wives and settled down. Researchers reported that the pattern of mutations on the Y chromosomes among men of the Lemba was close to that found among a Jewish priestly group known as the Cohens. Similar research suggests that the Israelis and the Palestinians came from a common stock around 7,800 years ago.
Such striking but isolated results suddenly became integrated into a broader picture last November when the whole field of "archogenetics" took a quantum leap forward. A leading science journal, Nature Genetics, published a new human family tree, based on a previously unknown set of variations - haplotypes - on the Y. It confirmed that modern humans had originally migrated out of Africa, but raised what, at first, looked like a ridiculous puzzle. If the dates were correct, the genetic Eve, the one from whom all humans are descended, was 84,000 years older than the genetic Adam, as measured by the Y.
The female equivalent of the Y - genetic information passed only from mother to daughter - is known as mDNA. This is the DNA of the mitochondria, the powerhouse of every cell. For a few years there has been broad agreement that the mitochondrial Eve lived around 143,000 years ago, which seems to make nonsense of the 59,000 years ago that Nature Genetics reported for the "Y-Adam".
In fact, it's not as daft as it seems. What the research shows is that the different chromosomes now found in the human genome were not selected for all at once. Around 143,000 years ago, a variation of mDNA emerged from the pre-human gene pool and proved to be, in computing terms, a "killer application", driving all the others out of business. Like any successful mutation, it popped up in more and more bodies, until all the other versions died out. That's why women today all have variants on the new, improved "Eve" mDNA. The same thing happened with men and the Y, only it took another 84,000 years for the evolution of the super-successful version that eventually wiped the floor with its rivals.
Exactly what it did isn't clear, but it was probably something to do with fertility.
"Something happened to the record between 50,000 and 60,000 years ago," says Peter Oefner, a biologist at the Stanford DNA Sequencing and Technology Centre in California, and an author of the study in Nature Genetics. "We started at ground zero again."
Buried in the paper, and virtually unnoticed by all commentators, is a political time bomb involving the Native Americans. Everyone has seen those pictures of fur-clad mammoth hunters arriving in the virgin territory of North America at the end of the last ice age. The notion that they were the first has always been an important part of Native American mythology, but evidence has been growing that the continent was well-populated long before their arrival. In the past few years, a dozen or so ancient skulls have been unearthed in North America, and not only do they date from a time before the arrival of the mammoth hunters but their shape and proportions have little in common with those of northern Asians. Instead, they look like people from south-east Asia and the Pacific. The issue is politically very sensitive and there have been bitter disputes between Native American groups and various archaeological teams, but genetics is now confirming the story of the skulls.
Two years ago, Douglas Wallace of the Centre for Molecular Medicine at Emory University School of Medicine, based in Atlanta, Georgia, tackled the Native American issue head-on. Working with mDNA, he reported discovering a set of variations known as "haplogroup X" whose implications were dynamite. This X factor is found among Native Americans and among Europeans but not - and this is the important bit - in Siberian groups. Attempts to find it among south-east Asians failed.
The implication of the Nature Genetics paper is that the smoking gun has turned up. Possibly because of the political tensions involved, you have to look hard to find it, but buried at the end of the article is the following: "Native Americans are located between Eurasians and East Asians, indicating common ancestry with both." In other words, they are descended not only from people of the Pacific but from a group that also travelled east and became the founders of European stock. The arrival of Columbus could be seen as just the final stage in a circumnavigation of the globe that had begun 20,000 years earlier.
In a paper published earlier this year, Dr Spencer Wells of the Wellcome Trust Centre for Human Genetics, based in Oxford, who was involved in this research, suggests what might have been going on. "One of the very old Y markers we are studying, known as M45, originally came from southern central Asia around 40,000 years ago," he says. "It looks as if these people are the common ancestor of both the western Europeans and the Native Americans."
But the new tools that are bringing the Y into sharper focus don't just tell us about the movements of ancient people - they can also tell you, if you are a man, how much of your genetic code you share with other men of the same name. "We have found that a person's genotype and their surname are incredibly closely linked,: says Professor Bryan Sykes of the Institute of Molecular Medicine in Oxford. The link comes from the fact that men inherit both their name and their Y chromosome from their father.
In a preliminary study, investigating the genetic make-up of men called Sykes, the professor found that 50% had the same Y chromosome. That means that for 700 years, since surnames began in England, the Sykes lineage has been largely unbroken. Further research has shown the same proportion for other names, too. One implication is that infidelity, leading to children calling the wrong man Daddy, is not as common as other surveys have suggested. Previous estimates put the figure at between 5% and 10%, while the work on Sykes suggests it is nearer 1%. Another implication is that it may soon be possible to make a guess at the name of a criminal from the traces of DNA he leaves at the scene of the crime.
The new findings confirm that the battle of the sexes is rooted in our genes. The idea that men and women have different agendas is now fairly familiar. While men can theoretically father an almost infinite number of children, women are strictly limited in the number they can have, so it makes sense for men to be more promiscuous and women more choosy.
What is not so widely appreciated is that the breakaway by the Y allowed for the development for two rival enclaves where genes that benefited one sex or the other could take refuge. A gene that finds a home on the Y chromosome doesn't have to worry about the effect it has on females, because it is only going to find itself in male bodies.
Perhaps the most devilish example of this comes from fruit flies. The male's sperm contains a poison that damages the sperm of any other male it encounters, giving it an edge in knocking out rival suitors. An unfortunate side effect for the female is that this sperm is also toxic to her, which means that the more often she copulates, the shorter her life span.
It doesn't seem that human sperm can directly affect women in this way, but there is evidence that males go in for sperm competition. Among primates, this is most famously practised by chimpanzees who are prodigious sperm producers because when females regularly have sex with a number of males, the one who can most effectively pump up has a greater chance of fertilising the egg.
Last year, Dr Chung-I Wu and his colleagues at the University of Chicago reported finding that the genes involved in making sperm protein, in both humans and gorillas, were mutating very fast. "This suggests that they are under intense competitive pressure," he says. The Y contains the largest concentration of sperm-producing genes and researchers are now looking to see which ones are involved in this competition.
Having a Y chromosome may put male children at risk from the mother's immune system while in the womb. Last year, Ray Blanchard, professor of psychiatry at the University of Toronto, made a surprising discovery. He found that younger brothers, but not sisters, are more likely to be slightly asymmetrical than their older siblings, and the more older brothers you have, the more asymmetrical you are likely to be. As if that wasn't strange enough, other research had already shown that the same is true of homosexuality--the more older brothers you have, the more likely you are to be gay.
What is going on here? Blanchard believes that something in a womb that has already held a male responds increasingly strongly to the next one. As females are untouched, he thinks the Y chromosome is probably involved.
Now, there is a gene on the Y chromosome that produces a masculinising protein called AMH (anti-Mullerian hormone) which stops the development of the glands that would otherwise turn into womb and ovaries. But AMH can also trigger the mother's immune system, and the antibodies she produces can interfere with AMH's other job of switching on the genes that are involved in masculinising the brain. So the reason for the birth order effect could be that the mother's immune responses get stronger the more often they are triggered.
Y's unilateral declaration of independence not only placed it in permanent conflict with X, but also transformed it into an island. It is this isolation that is the other distinctive feature of the Y. Gradually, it became the wild frontier of the genome, where the normal housekeeping rules did not apply. However carefully it is done, copying always creates errors in the end, whether it's monks with manuscripts or DNA. When egg and sperm cells are being produced, the pairs of chromosomes can swap genes back and forth, weeding out ones that have been damaged. But the breakaway Y had closed its borders, creating badlands where there is no updating or repairing of genes. So, like abandoned settlements, the structures gradually decay and once-functioning genes turn into useless shells as the irresistible entropy of copying errors gradually accumulates.
But just as ruined buildings tell stories to archaeologists, so these ruined genes allow genetic archaeologists to spot, say, who are the black Jews of Africa. And just as decaying societies depend on immigrants to renew themselves, so it is the new arrivals on the Y that are emerging as the chromosome's most remarkable secret. The popular picture of DNA as a sort of blueprint fails to capture the dynamism of the whole genome. Although enormous care is taken to ensure that the genetic instructions are accurately copied, thousands of generations of this painstaking precision can be wrecked in an instant by a stray chunk of code crashing like an asteroid into a chromosome. The intruder is known as a jumping gene or transposon.
While the vast majority of genes are stay-at-homes, never venturing from their native chromosome, jumping genes are the wanderers of the genome. After years in one place, they can suddenly uproot a stretch of code on either side of them, leap out of one chromosome and land at random in another. They may crash into the middle of a coding gene, causing havoc, or barge in beside one, subtly changing its function.
Once again, it is Y's stereotypically masculine avoidance of housekeeping that makes the difference. While the new arrivals are often swept away on other chromosomes as they endlessly mix their genes, those that parachute into the badlands of the Y may survive for millions of years, like the craters of asteroids on the moon. Just occasionally, that allows them to do something remarkable. The markers on Y's genetic relics can trace people's roots, but the jumping immigrants may have made the Y a tiny starter button driving evolution.
The first of the immigrants to be spotted on the Y was DAZ, detected by David Page. Until he started working on the Y, conventional wisdom was that it contained a gene called SRY, the master switch that turns on the boy-making machinery in the womb, but that was about it. Now we know that the Y contains about two dozen genes, compared with 2,000 or more on the X, and that it specialises in a way that is unique among the chromosomes. Most of its genes are involved in making sperm or helping cells do essential housekeeping tasks, such as building proteins.
DAZ probably arrived on the Y somewhere between 20 and 40 million years ago, just about the time the early primates branched off from their cousins, possibly because of the boost DAZ gave them. It has been described as a "turbo-charged sperm producer" (the initials stand for "Deleted in Azoospermia") because men without it have no sperm or reduced sperm in their semen. For men whose sperm-producing genes are damaged, the results can be tragic. Around one in six couples have problems conceiving and for 20% of those, the key factor is a problem with the man's sperm.
Modern IVF techniques have provided a solution: a single sperm can be extracted from the testes and injected directly into an egg for fertilisation in a test tube. But this solution comes with a curious penalty. Suddenly, for the first time, infertility becomes something that can be inherited. "Assisted reproduction can turn infertility into something that runs in families," Page says. "All males in such families will never be able to reproduce without help. The counselling issues are huge."
While sperm production is the Y's major role, the latest and most audacious thinking about it comes from a couple of British researchers. Their controversial suggestion is that it was a jumping gene, arriving on the Y, that was a crucial factor in allowing humans to develop language.
The boost to sperm production provided by DAZ may have allowed our primate ancestors to flourish, but something in our genes must also mark the point at which we split off from the ape line. What were the few fragments of protein that allowed us to inherit the Earth? The brute force way to find them is to churn through vast stretches of chimp and human genome, looking for differences. The more elegant solution is to imagine what such mutations might do and where they might be found, then go in search of them, like the astronomers who predicted the existence of Pluto from perturbations in the movement of other planets.
This is just what Dr Tim Crow, of the Department of Psychiatry at Oxford, has done. In a number of academic papers, he has proposed that there was a gene that emerged relatively late in human evolution, which changed the way the brain developed and so gave us the ability to produce language. What's more, he suggested that this gene takes a slightly different form in men and women.
That may sound like an impossibly complex job for a single gene, but at a conference in London in 1999, another research group announced that they had found an actual gene that appeared to be a candidate for doing all those things and that it lived on the Y.
"The gene we've found is expressed in the human brain but not in the ape's brain," says Dr Nabeel Affara of the Department of Pathology at Cambridge, "which means that it is a good candidate for a language gene." Apes have the X version (PCDHX), but at some point in human evolution it jumped into the Y. It's this travelling version that is missing in apes.
Scientists are naturally cautious, but it may be possible to link the Y version (PCDHY) with two of the major turning points in human evolution. The date of the jump was probably around three million years ago - just when brain size was increasing and tools were starting to appear. Even allowing for the caveat that genetic dating is a far from precise science and that the date could be one million years either way, that's a remarkable tie-in.
But there is more. In the unregulated territory of the Y, the travelling chunk of DNA carrying PCDHY was able to transform itself again, splitting in half and reversing its position. It is hard to say exactly when this happened but research is underway to ascertain whether it coincided with the period 120,000 to 200,000 years ago - a time when big changes in tool-making were going on and signs of symbolic ability began to emerge in Africa.
Circumstantial evidence is all very well, but what does the gene actually do? At the moment, there are still more questions than answers, but nothing that has been found so far rules out the possibility that it is a gene involved in language. "It is one of a family of genes known as cadhedrins," Affara says. "These make proteins that go on the surface of nerve cells and are involved in signalling. PCDHX/Y genes are active in the foetus and are turned on only in certain regions of the brain." Once again, all features you would expect to find in a language gene.
But there is a big mystery still lurking behind all these new discoveries on the Y. That's because the Y is a model of capitalist economics. Winners - genes that confer advantages - take all, because there is no mixing with any other chromosome. Losers, because they are most likely to affect fertility, almost instantly go to the wall. Which means the genes that do survive there must be doing something valuable.
"The Y is essentially about sex," Affara says, "and it has lost most of its genes over evolution. So the big question is: why are those that have been retained still thriving? They must be doing something subtle that we don't understand yet." The implication is that the differences genetic archaeologists are picking up in men around the globe today could point to differences in abilities. "The different markers that allow us to distinguish between lineages may also point to functional differences," Affara says.
It is an idea that clearly has the potential to become a political minefield, but it might be the Y's biggest surprise of all.
The genomea glossary
Chromosomes - The genetic material (DNA) in each one of our cells is arranged into 46 chromosomes, which form 23 pairs.
Autosomes - The 22 pairs of chromosomes, numbered 1 to 22, which are essentially identical. We each inherit one of each pair from our mother and one from our father.
Recombination - This is the way sex helps to weed out harmful mutations. When sperm and egg cells are created, all autosomal pairs of chromosomes can swap genes or parts of genes, keeping the two chromosomes in working order. This removes harmful genes and creates useful variations. Also known as meiosis.
Sex chromosomes - The remaining unequal pair - X and Y. Each sperm carries either an X or a Y, all eggs carry an X. An egg fertilised by an X-carrying sperm will produce a woman, so all women have two X chromosomes. An egg fertilised by a Y-carrying sperm will become a male, so males are XY. During egg production, X chromosomes (above, left) can exchange genes, but during sperm production, the Y (above, right) exchanges almost nothing with the X.
Nucleotides: - These are the letters of the DNA 'alphabet' - A (adenine), T (thymine), C (cytosine) and G (guanine).
Base pairs: - The 'words' of DNA. Each is made up of combinations of the four nucleotides.
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