Chromosomes X And Y

Conflict

Xq28 — Thanks for the genes mom.

T shirt sold in gayand lesbian bookstores in the mid-1990s

A detour into linguistics has brought us face to face with the startling implications of evolutionary psychology. If it has left you with an unsettling feeling that something else is in control, that your own abilities, linguistic and psychological, were somewhat more instinctively determined than you proudly imagined, then things are about to get a lot worse. The story of this chapter is perhaps the most unexpected in the whole history of genetics. We have got used to thinking of genes as recipes, passively awaiting transcription at the discretion of the collective needs of the whole organism: genes as servants of the body. Here we encounter a different reality. The body is the victim, plaything, battleground and vehicle for the ambitions of genes.

The next largest chromosome after number seven, is called the X chromosome. X is the odd one out, the misfit. Its pair, the chromosome with which it has some affinity of sequence, is not, as in every other case, an identical chromosome, but is the Y chromosome, a tiny and almost inert stub of a genetic afterthought. At least that is the case in male mammals and flies, and in female butterflies and birds. In female mammals or male birds there are instead two X chromosomes, but they are still somewhat eccentric. In every cell in the body, instead of both expressing their genetic message at equal volume, one of the two at random packs itself up into a tight bundle known as a Barr body and remains inert.

The X and Y chromosomes are known as the sex chromosomes for the obvious reason that they determine, with almost perfect predestination, the sex of the body. Everybody gets an X chromosome from his or her mother. But if you inherited a Y chromosome from your father, you are a man; if you inherited an X chromosome from your father, you are a woman. There are rare exceptions, superficially female people with an X and a Y, but they are exceptions that prove the rule. The key masculinising gene on the Y chromosome is missing or broken in such people.

Most people know this. It does not take much exposure to school biology to come across the X and Y chromosomes. Most people also know that the reason colour-blindness, haemophilia and some other disorders are much more common in men is that these genes are on the X chromosome. Since men have no 'spare' X chromosome, they are much more likely to suffer from these recessive problems than women — as one biologist has put it, the genes on the X chromosome fly without co-pilots in men. But there are things about the X and Y chromosomes most people do not know, disturbing, strange things that have unsettled the very foundations of biology.

It is not often that you find language like this in one of the most sober and serious of all scientific publications, the Philosophical Transactions of the Royal Society: 'The mammalian Y chromosome is thus likely to be engaged in a battle in which it is outgunned by its opponent. A logical consequence is that the Y should run away and hide, shedding any transcribed sequences that are not essential to its function.'1 'A battle', 'outgunned', 'opponent', 'run away'? These are hardly the sort of things we can expect molecules of D N A to do. Yet the same language, a little more technically phrased, appears in another scientific paper about the Y chromosome, entitled 'The enemies within: intergenomic conflict, interlocus contest evolution (ICE), and the intraspecific Red Queen'.2 The paper reads, in part: 'Perpetual ICE between the Y and the rest of the genome can thereby continually erode the genetic quality of the Y via genetic hitchhiking of mildly deleterious mutations. The decay of the Y is due to genetic hitchhiking, but it is the ICE process that acts in a catalytic way to continually drive the male versus female anatagonistic coevolution.' Even if most of this is Greek to you, there are certain words that catch the eye: words like 'enemies' and 'antagonism'. Then there is a recent textbook on the same material. Its title, quite simply, is "Evolution: the four billion year war'.3 What is going on?

At some point in our past, our ancestors switched from the common reptilian habit of determining sex by the temperature of the egg to determining it genetically. The probable reason for the switch was so that each sex could start training for its special role at conception. In our case, the sex-determining gene made us male and the lack of it left us female, whereas in birds it happened the other way round. The gene soon attracted to its side other genes that benefited males: genes for big muscles, say, or aggressive tendencies. But because these were not wanted in females — wasting energy they would prefer to spend on offspring - these secondary genes found themselves at an advantage in one sex and at a disadvantage in the other. They are known in the trade as sexually antagonistic genes.

The dilemma was solved when another mutant gene suppressed the normal process of swapping of genetic material between the two paired chromosomes. Now the sexually antagonistic genes could diverge and go their different ways. The version on the Y chromosome could use calcium to make antlers; the version on the X chromosome could use calcium to make milk. Thus, a pair of middle-si2ed chromosomes, once home to all sorts of 'normal' genes, was hijacked by the process of sex determination and became the sex chromosomes, each attracting different sets of genes. On the Y

chromosome, genes accumulate that benefit males but are often bad for females; on the X accumulate genes that are good for females and deleterious in males. For instance, there is a newly discovered gene called DAX, found on the X chromosome. A few rare people are born with one X and one Y chromosome, but with two copies of the DAX gene on the X chromosome. The result is, that although such people are genetically male, they develop into normal females. The reason, it transpires, is that DAX and SKY — the gene on the Y chromosome that makes men into men — are antagonistic to each other. One SRY defeats one DAX, but two DAXes defeat one SRY.4

This outbreak of antagonism between genes is a dangerous situation. Lurching into metaphor, one might begin to discern that the two chromosomes no longer have each other's interests at heart, let alone those of the species as a whole. Or, to put it more correctly, something can be good for the spread of a gene on the X chromosome that actually damages the Y chromosome or vice versa.

Suppose, for instance, that a gene appeared on the X chromosome that specified the recipe for a lethal poison that killed only sperm carrying Y chromosomes. A man with such a gene would have no fewer children than another man. But he would have all daughters and no sons. All of those daughters would carry the new gene, whereas if he had had sons as well, none of them would have carried it. Therefore, the gene is twice as common in the next generation as it would otherwise be. It would spread very rapidly. Such a gene would only cease to spread when it had exterminated so many males that the very survival of the species was in jeopardy and males were at a high premium.5

Far-fetched? Not at all. In the butterfly Acrea encedon, that is exactly what has happened. The sex ratio is ninety-seven per cent female as a result. This is just one of many cases known of this form of evolutionary conflict, known as sex-chromosome drive. Most known instances are confined to insects, but only because scientists have looked more closely at insects. The strange language of conflict used in the remarks I quoted above now begins to make more sense. A

piece of simple statistics: because females have two X chromosomes while males have an X and a Y, three-quarters of all sex chromosomes are Xs; one-quarter are Ys. Or, to put it another way, an X chromosome spends two-thirds of its time in females, and only one-third in males. Therefore, the X chromosome is three times as likely to evolve the ability to take pot shots at the Y as the Y is to evolve the ability to take pot shots at the X. Any gene on the Y chromosome is vulnerable to attack by a newly evolved driving X gene. The result has been that the Y chromosome has shed as many genes as possible and shut down the rest, to 'run away and hide' (in the technical jargon used by William Amos of Cambridge University).

So effectively has the human Y chromosome shut down most of its genes that the great bulk of its length consists of non-coding DNA, serving no purpose at all - but giving few targets for the X chromosome genes to aim at. There is a small region that seems to have slipped across from the X chromosome fairly recently, the so-called pseudo-autosomal region, and then there is one immensely important gene, the SRY gene mentioned above. This gene begins the whole cascade of events that leads to the masculinisation of the embryo. Rarely can a single gene have acquired such power. Although it only throws a switch, much else follows from that. The genitals grow to look like a penis and testes, the shape and constitution of the body are altered from female (the default in our species, though not in birds and butterflies), and various hormones go to work on the brain. There was a spoof map of the Y chromosome published in the journal Science a few years ago, which purported to have located genes for such stereotypically male traits as flipping between television channels, the ability to remember and tell jokes, an interest in the sports pages of newspapers, an addiction to death and destruction movies and an inability to express affection over the phone - among others. The joke is funny, though, only because we recognise these habits as male, and therefore far from mocking the idea that such habits are genetically determined, the joke reinforces the idea. The only thing wrong with the diagram is that these male behaviours come not from specific genes for each of them, but from the general masculinisation of the brain by hormones such as testosterone which results in a tendency to behave this way in the modern environment. Thus, in a sense, many masculine habits are all the products of the SRY gene itself, which sets in train the series of events that lead to the masculinisation of the brain as well as the body.

The SRY gene is peculiar. Its sequence is remarkably consistent between different men: there are virtually no point mutations (i.e., one-letter spelling differences) in the human race. SRY is, in that sense, a variation-free gene that has changed almost not at all since the last common ancestor of all people 200,000 years ago or so. Yet our SRY is very different from that of a chimpanzee, and different again from that of a gorilla: there is, between species, ten times as much variation in this gene as is typical for other genes. Compared with other active (i.e., expressed) genes, SRY is one of the fastest evolving.

How do we explain this paradox? According to William Amos and John Harwood, the answer lies in the process of fleeing and hiding that they call selective sweeps. From time to time, a driving gene appears on the X chromosome that attacks the Y chromosome by recognising the protein made by SRY. At once there is a selective advantage for any rare SRY mutant that is sufficiently different to be unrecognised. This mutant begins to spread at the expense of other males. The driving X chromosome distorts the sex ratio in favour of females but the spread of the new mutant SRY restores the balance. The end result is a brand new SRY gene sequence shared by all members of the species, with little variation. The effect of this sudden burst of evolution (which might happen so quickly as to leave few traces in the evolutionary record) would be to produce SRYs that were very different between species, but very similar within species. If Amos and Harwood are right, at least one such sweep must have occurred since the splitting of chimp ancestors and human ancestors, five to ten million years ago, but before the ancestor common to all modern human beings, 200,000 years ago.6

You may be feeling a little disappointed. The violence and conflict that I promised at the beginning of the chapter turn out to be little more than a detailed piece of molecular evolution. Fear not. I am not finished yet, and I plan to link these molecules to real, human conflict soon enough.

The leading scholar of sexual antagonism is William Rice of the University of California at Santa Cruz and he has completed a remarkable series of experiments to make the point explicit. Let us go back to our putative ancestral creature that has just acquired a distinct Y chromosome and is in the process of shutting down many of the genes on it to escape driving X genes. This nascent Y chromosome, in Rice's phrase, is now a hotspot for male-benefit genes. Because a Y chromosome will never find itself in a female, it is free to acquire genes that are very bad for females so long as they are at least slightly good for males (if you still thought evolution was about the good of the species, stop thinking so right now). In fruit flies, and for that matter in human beings, male ejaculate consists of sperm cells suspended in a rich soup called the seminal fluid. Seminal fluid contains proteins, products of genes. Their purpose is entirely unknown, but Rice has a shrewd idea. During fruit-fly sex, those proteins enter the bloodstream of the female and migrate to, among other places, her brain. There they have the effect of reducing the female's sexual appetite and increasing her ovulation rate. Thirty years ago, we would have explained that increase in terms of the good of the species. It is time for the female to stop seeking sexual partners and instead seek a nesting site. The male's seminal fluid redirects her behaviour to that end. You can hear the National Geographic commentary. Nowadays, this information takes on a more sinister aura. The male is trying to manipulate the female into mating with no other males and into laying more eggs for his sperm and he is doing so at the behest of sexually antagonistic genes, probably on the Y chromosome (or switched on by genes on the Y chromosome). The female is under selective pressure to be more and more resistant to such manipulation. The outcome is a stalemate.

Rice did an ingenious experiment to test his idea. For twenty-nine generations, he prevented female flies from evolving resistance: he kept a separate strain of females in which no evolutionary change occurred. Meanwhile, he allowed males to generate more and more effective seminal fluid proteins by testing them against more and more resistant females. After twenty-nine generations he brought the two lines together again. The result was a walkover. Male sperm was now so effective at manipulating female behaviour that it was effectively toxic: it could kill the females.7

Rice now believes that sexual antagonism is at work in all sorts of environments. It leaves its signature as rapidly evolving genes. In the shellfish the abalone, for instance, the lysin protein that the sperm uses to bore a hole through the glycoprotein matrix of the egg is encoded by a gene that changes very rapidly (the same is probably true in us), probably because there is an arms race between the lysin and the matrix. Rapid penetration is good for sperm but bad for the egg, because it allows parasites or second sperm through. Coming slightly closer to home, the placenta is controlled by rapidly evolving genes (and paternal ones, at that). Modern evolutionary theorists, led by David Haig, now think of the placenta as more like a parasitic takeover of the mother's body by paternal genes in the foetus. The placenta tries, against maternal resistance, to control her blood-sugar levels and blood pressure to the benefit of the foetus.8 More on this in the chapter on chromosome 15.

But what about courtship behaviour? The traditional view of the peacock's elaborate tail is that it is a device designed to seduce females and that it is in effect designed by ancestral females' preferences. Rice's colleague, Brett Holland, has a different explanation. He thinks peacocks did indeed evolve long tails to seduce females, but that they did so because females grew more and more resistant to being so seduced. Males in effect use courtship displays as a substitute for physical coercion and females use discrimination to retain control over their own frequency and timing of mating. This explains a startling result from two species of wolf spiders. One species has tufts of bristles on its forelegs that it uses in courtship. Shown a video of a male spider displaying, the female will indicate by her behaviour whether the display turns her on. If the videos are altered so that the males' tufts disappear, the female is still just as likely to find the display arousing. But in another species, where there are no tufts, the artificial addition of tufts to males on the video more than doubled the acceptance rate of females. In other words, females gradually evolve so that they are turned off, not on, by the displays of males of their own species. Sexual selection is thus an expression of sexual antagonism between genes for seduction and genes for resistance.9

Rice and Holland come to the disturbing conclusion that the more social and communicative a species is, the more likely it is to suffer from sexually antagonistic genes, because communication between the sexes provides the medium in which sexually antagonistic genes thrive. The most social and communicative species on the planet is humankind. Suddenly it begins to make sense why relations between the human sexes are such a minefield, and why men have such vastly different interpretations of what constitutes sexual harassment from women. Sexual relations are driven not by what is good, in evolutionary terms, for men or for women, but for their chromosomes. The ability to seduce a woman was good for Y chromosomes in the past; the ability to resist seduction by a man was good for X chromosomes in the past.

This kind of conflict between complexes of genes (the Y chromosome being one such complex), does not just apply to sex. Suppose that there is a version of a gene that increases the telling of lies (not a very realistic proposition, but there might be a large set of genes that affect truthfulness indirectly). Such a gene might thrive by making its possessors into successful con-artists. But then suppose there is also a version of a different gene (or set of genes) that improves the detecting of lies, perhaps on a different chromosome. That gene would thrive to the extent that it enabled its possessors to avoid being taken in by con-artists. The two would evolve antagonistically, each gene encouraging the other, even though it would be quite possible for the same person to possess both. There is between them what Rice and Holland call 'interlocus contest evolution', or ICE. Exactly such a competitive process probably did indeed drive the growth of human intelligence over the past three million years. The notion that our brains grew big to help us make tools or start fires on the savannah has long since lost favour. Instead, most evolutionists believe in the Machiavellian theory — that bigger brains were needed in an arms race between manipulation and resistance to manipulation. 'The phenomena we refer to as intelligence may be a byproduct of intergenomic conflict between genes mediating offense and defense in the context of language', write Rice and Holland.10

Forgive the digression into intelligence. Let's get back to sex. Probably one of the most sensational, controversial and hotly disputed genetic discoveries was the announcement by Dean Hamer in 1993 that he had found a gene on the X chromosome that had a powerful influence on sexual orientation, or, as the media quickly called it, 'a gay gene'.11 Hamer's study was one of several published about the same time all pointing towards the conclusion that homosexuality was 'biological' — as opposed to being the consequence of cultural pressure or conscious choice. Some of this work was done by gay men themselves, such as the neuroscientist Simon LeVay of the Salk Institute, keen to establish in the public mind what they were convinced about in their own minds: that homosexuals were 'born that way'. They believed, with some justice, that prejudice would be less against a lifestyle that was not a deliberate 'choice' but an innate propensity. A genetic cause would also make homosexuality seem less threatening to parents by making it clear that gay role models could not turn youths gay unless they had the propensity already. Indeed conservative intolerance of homosexuality has recently taken to attacking the evidence for its genetic nature. "We should be careful about accepting the claim that some are "born to be gay", not just because it is untrue, but because it provides leverage to homosexual rights organisations', wrote the Conservative Lady Young in the Daily Telegraph on 29 July 1998.

But however much some of the researchers may have desired a particular outcome, the studies are objective and sound. There is no room for doubt that homosexuality is highly heritable. In one study, for example, among fifty-four gay men who were fraternal twins, there were twelve whose twin was also gay; and among fifty-six gay men who were identical twins, there were twenty-nine whose twin was also gay. Since twins share the same environment, whether they are fraternal or identical, such a result implies that a gene or genes accounts for about half of the tendency for a man to be gay. A dozen other studies came to a similar conclusion.12

Intrigued, Dean Hamer decided to seek the genes that were involved. He and his colleagues interviewed no families with gay male members and noticed something unusual. Homosexuality seemed to run in the female line. If a man was gay, the most likely other member of the previous generation to be gay was not his father but his mother's brother.

That immediately suggested to Hamer that the gene might be on the X chromosome, the only set of nuclear genes a man inherits exclusively from his mother. By comparing a set of genetic markers between gay men and straight men in the families in his sample, he quickly found a candidate region in Xq2 8, the tip of the long arm of the chromosome. Gay men shared the same version of this marker seventy-five per cent of the time; straight men shared a different version of the marker seventy-five per cent of the time. Statistically, that ruled out coincidence with ninety-nine per cent confidence. Subsequent results reinforced the effect, and ruled out any connection between the same region and lesbian orientation.

To canny evolutionary biologists, such as Robert Trivers, the suggestion that such a gene might lie on the X chromosome immediately rang a bell. The problem with a gene for sexual orientation is that the version that causes homosexuality would quite quickly become extinct. Yet it is plainly present in the modern population at a significant level. Perhaps four per cent of men are definitively gay (and a smaller percentage bisexual). Since gay men, are, on average, less likely to have children than straight men, the gene would be doomed to have long since dwindled in frequency to vanishing point unless it carried some compensating advantage.

Trivers argued that, because an X chromosome spends twice as much time in women as it does in men, a sexually antagonistic gene that benefited female fertility could survive even if it had twice as large a deleterious effect on male fertility. Suppose, for example, that the gene Hamer had found determined age of puberty in women, or even something like breast size (remember, this is just a thought experiment). Each of those characteristics might affect female fertility. Back in the Middle Ages, large breasts might mean more milk, or might attract a richer husband whose children were less likely to die in infancy. Even if the same version of the same gene reduced male fertility by making sons attracted to other men, such a gene could survive because of the advantage it gave daughters.

Until Hamer's gene itself is found and decoded, the link between homosexuality and sexual antagonism is no more than a wild guess. Indeed, it remains a possibility that the connection between Xq28 and sexuality is misleading. Michael Bailey's recent research on homosexual pedigrees has failed to find a maternal bias to be a general feature. Other scientists, too, have failed to find Hamer's link with Xq28. At present it looks as if it may have been confined to those families Hamer studied. Hamer himself cautions that until the gene is in the bag, it is a mistake to assume otherwise.14

Besides, there is now a complicating factor: a completely different explanation of homosexuality. It is becoming increasingly clear that sexual orientation correlates with birth order. A man with one or more elder brothers is more likely to be gay than a man with no siblings, only younger siblings, or with one or more elder sisters. The birth order effect is so strong that each additional elder brother increases the probability of homosexuality by roughly one-third (this can still mean a low probability: an increase from three to four per cent is an increase of thirty-three per cent). The effect has now been reported in Britain, the Netherlands, Canada and the United States, and in many different samples of people.15

For most people, the first thought would be a quasi-Freudian one: that something in the dynamics of growing up in a family with elder brothers might predispose you towards homosexuality. But, as so often, the Freudian reaction is almost certainly the wrong one. (The old Freudian idea that homosexuality was caused by a protective mother and a distant father almost certainly confused cause and effect: the boy's developing effeminate interests repel the father and the mother becomes overprotective in compensation.) The answer probably lies, once more, in the realm of sexual antagonism.

An important clue lies in the fact that there is no such birth-order effect for lesbians, who are randomly distributed within their families. In addition, the number of elder sisters is also irrelevant in predicting male homosexuality. There is something specific to occupying a womb that has already held other males which increases the probability of homosexuality. The best explanation concerns a set of three active genes on the Y chromosome called the H-Y minor histocompatibility antigens. A similar gene encodes a protein called anti-Mullerian hormone, a substance vital to the masculinis-ation of the body: it causes the regression of the Mullerian ducts in the male embryo — these being the precursors of the womb and Fallopian tubes. What the three H-Y genes do is not certain. They are not essential for the masculinisation of the genitals, which is achieved by testosterone and anti-Mullerian hormone alone. The significance of this is now beginning to emerge.

The reason these gene products are called antigens is because they are known to provoke a reaction from the immune system of the mother. As a result, the immune reaction is likely to be stronger in successive male pregnancies (female babies do not produce H-Y antigens, so do not raise the immune reaction). Ray Blanchard, one of those who studies the birth-order effect, argues that the H-Y antigens' job is to switch on other genes in certain tissues, in particular in the brain - and indeed there is good evidence that this is true in mice. If so, the effect of a strong immune reaction against these proteins from the mother would be partly to prevent the masculini-sation of the brain, but not that of the genitals. That in turn might cause them to be attracted to other males, or at least not attracted to females. In an experiment in which baby mice were immunised against H-Y antigens, they grew up to be largely incapable of successful mating, compared with controls, though frustratingly the experimenter did not report the reasons why. Likewise, male fruit flies can be irreversibly induced to show only female sexual behaviour by the switching on at a crucial point in development of a gene called 'transformer'.16

People are not mice or flies, and there is plenty of evidence that the sexual differentiation of the human brain continues after birth. Homosexual men are clearly not, except in very rare cases, 'mental' women trapped inside 'physical' men. Their brains must have been at least partly masculinised by hormones. It remains possible, however, that they missed some hormone during some early and crucial sensitive period and that this permanently affects some functions, including sexual orientation.

The man who first set in train the ideas that led to sexual antagonism, Bill Hamilton, understood how profoundly it shook our notions of what genes are: 'There had come the realisation', he wrote later, 'that the genome wasn't the monolithic data bank plus executive team devoted to one project - keeping oneself alive, having babies - that I had hitherto imagined it to be. Instead, it was beginning to seem more a company boardroom, a theatre for a power struggle of egoists and factions.' Hamilton's new understanding of his genes began to affect his understanding of his mind:17

My own conscious and seemingly indivisible self was turning out far from what I had imagined and I need not be so ashamed of my self-pity! I was an ambassador ordered abroad by some fragile coalition, a bearer of conflicting orders from the uneasy masters of a divided empire ... As I write these words, even so as to be able to write them, I am pretending to a unity that, deep inside myself, I now know does not exist. I am fundamentally mixed, male with female, parent with offspring, warring segments of chromosomes that interlocked in strife millions of years before the River Severn ever saw the Celts and Saxons of Housman's poem ['A Shropshire Lad'].

The idea of genes in conflict with each other, the notion of the genome as a sort of batleefield between parental genes and childhood genes, or between male genes and female genes, is a little-known story outside a small group of evolutionary biologists. Yet it has profoundly shaken the philosophical foundations of biology.

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