David Bainbridge is a reproductive immunologist at the University of Cambridge. His new book The X in Sex : How the X chromosome controls our lives is published by Harvard University Press.
The following article is reprinted from New Scientist 10 May 2003.
Two X chromosomes make you a girl, and also a genetic hybrid that sometimes falls out with itself - David Bainbridge explains
Throughout history, natural philosophers have wrestled with the conundrum of femaleness. Although women often occupied a lower status in society, it could not be denied that they were biologically more complex than men. Whereas men are simple sexual beings, women are the ultimate multitaskers, switching seamlessly between sexual, pregnant and nurturing states.
Geneticists have now confirmed what philosophers long suspected - women are more complex than men. As an unexpected side effect of the way we are assigned our sex, women are destined to live a strange double life. Almost every woman is a mixture of two genetically different types of cell, and sometimes these cells can come into conflict with dramatic effect. We now believe that women's dual nature can split them into identical twins, divide them into discrete zones of disease, and even make them attack their own bodies.
Most of us know the story of how chromosomes control our sex. Girls inherit two X chromosomes, one from each parent, and boys inherit an X from mum and a Y from dad. Sperm even-handedly deal out these bundles of genetic material to our descendants to ensure that maternity hospitals pour forth roughly equal numbers of girls and boys.
That is the basic story, but to understand why women are more complex than men we have to look a little more closely at those chromosomes. The Y is, to be honest, a rather pathetic little thing. Most chromosomes are full of genes that allow us to do all sorts of clever things - flex our muscles, clot our blood, see colours - but the Y is a wasteland. Apart from the gene Sry that makes embryos into boys, it carries very few useful genes at all. And the reason for this is simple: the Y cannot do many useful things because women must survive without it.
The X, on the other hand, is far more impressive. It is a bona fide chromosome, crammed with useful genes for doing things such as, well, flexing muscles, clotting blood and seeing colours. The X is as big, complex and important as a "normal" chromosome. Yet, for all the achievements of the X, its very usefulness causes a great deal of trouble for both men and women.
Almost as soon as the X chromosome was discovered, geneticists realised that it must be unusual. It is the only full-size chromosome that healthy people can possess in either one or two copies. This is a very unusual state of affairs - embryos are supposed to inherit two copies of most chromosomes from their parents, and any embryo unfortunate enough to receive only a single copy will die. So clearly the X must be especially potent so that men can cope with having just one copy.
Yet if men can cope with only one X, why are women not overloaded by having two ? Just as having too few chromosomes is fatal, the same is usually true of having too many. Yet the X seemed to be an exception to this rule. The ability of humans to survive with either one or two X chromosomes was the dirty little secret of genetics for several decades. How exactly do women cope with having two Xs ?
The puzzle was solved in the 1960s when Mary Lyon, a geneticist working at Britain's Medical Research Council Radiobiological Research Unit in Harwell, combined two seemingly unrelated facts. First, cell biologists had known for some years that cells in female mammals contain a little nugget that male cells do not - the enigmatic "Barr body". Second, the females of some strains of cats and mice can have mottled coat patterns, while their male litter-mates do not. Lyon took this rather unpromising information to forge an insightful unifying theory. She suggested that females simply switch off one X in every cell in their body, and that this inactivated X is bundled up to form the Barr body. Most presciently of all, she speculated that very early in the development of female embryos, each cell inactivates an X at random, and each of these cells eventually gives rise to a patch of cells in the adult female that maintains that same X chromosome in an inactive state.
This random inactivation has remarkable effects. It means that a woman is actually a mixture of two different cell types: some regions of her body use the X she inherited from her mother, the rest the X inherited from her father. A woman is a mixed-up mosaic of two cell populations, and "mosaic" is the scientific term for this phenomenon. And as the X chromosome carries roughly 5 per cent of our genetic material, those two different halves of a woman's body can be surprisingly different genetically.
Mosaicism explains why tomcats can be ginger or black, but their sisters can be ginger, black or a third possibility : tortoiseshell. The ginger gene, when present, is carried on the X chromosome, and the ginger flecks on a tortoiseshell cat show the patches of skin which use the X bearing a ginger gene.
There are no tortoiseshell women, but we occasionally see something similar in women with a condition called anhidrotic ectodermal dysplasia, which is caused by a faulty gene on the X chromosome. The disease reduces the number of sweat glands on the skin, and in women with just one affected chromosome the skin may be divided into hundreds of little patches, each either healthy or diseased depending on which X chromosome they are using. In these women the mosaic pattern becomes visible when they sweat - their skin becomes patterned with alternating patches of sweating and non-sweating skin, each around centimetre across.
So genetics'embarrassing secret has been explained, but it leaves women in a strange situation. Women are mysterious double creatures, a mixture of two different genetic identities. And geneticists are now showing just how difficult it can be for these two populations of cells to coexist in a single body. There may be no tortoiseshell women, but the effects of mosaicism go deeper than that.
When is a twin not a twin ?
Geneticists get very excited about identical twins, but for two contradictory reasons. Some are fascinated by them because they are ideal research tools for the "nature versus nurture" debate - they are thought of as genetically identical, so they can be used to distinguish the relative contributions of genetic and environmental influences. However, other geneticists study identical twins for the opposite reason : to discover why they are never truly genetically identical at all. It is for this reason that we shouldn't really call them "identical". A better term is "monozygotic" which simply means that they developed from a single fertilised egg.
There are several reasons why monozygotic twins never carry exactly the same genes, but by far the most significant is mosaicism. When a female embryo splits into two, the twins inherit very similar genetic complements. However, because X inactivation in the two embryos is random it can affect them differently. This is why "identical" twin girls are always considerably less identical than "identical" twin boys.
In the past few years, evidence has started to accumulate which suggests that mosaicism can lead to profound differences between monozygotic twin girls. Twins can be so different that one suffers from a genetic disease while the other does not. One of the most dramatic examples of this was a set of twins reported in the 1980s : one was an accomplished athlete while the other was wheelchair-bound with Duchenne muscular dystrophy. Both girls had inherited the same chromosomes, so how is it possible that they could be so different ?
The answer lies in the fact that Duchenne muscular dystrophy is caused by damage to a gene on the X chromosome which protects muscles when they shorten during exercise. The disease usually only affects boys, since girls have a back-up X. Surprisingly, it seems that the healthy twin was predominantly using her undamaged X, whereas the disabled twin happened to be using the damaged X. The nature of X inactivation had somehow consigned them to very different genetic fates.
More and more examples of this "discordant twins" phenomenon are showing up. There are monozygotic twin girls where one is colour blind and one is not, and others where one has haemophilia A and one does not. In theory there is no X-borne genetic disease that cannot afflict monozygotic twin girls in this way.
Yet one thing is clear : such unfair mismatches are unlikely to happen by random chance. X inactivation happens early on in embryonic development, around the blastocyst stage and when the embryo is implanting into the lining of the uterus. Yet even then the embryo already contains between a hundred and a few thousand cells. With this large number of cells already present, it seems statistically unlikely that if the embryo splits into two, then either twin will contain cells predominantly using one X or the other. Unless, that is, it is the differences in X chromosome use that are actively splitting the embryo asunder.
Indeed, some researchers now claim that X-borne diseases affect monozygotic twin girls unequally far more often than would be expected if twinning occurred at random, and this has led to the challenging hypothesis that X inactivation can cause twinning. Do female embryos sometimes split in two because their different cells actually repel each other ?
One tentative piece of evidence for this is the fact that monozygotic twinning and X inactivation both occur around the same time - in the first and second week of embryonic development. A further piece of circumstantial evidence is that some forms of twinning, where the embryo splits later on in those two weeks, are more common in girls than in boys. For example, conjoined twinning which occurs when an embryo splits very late and fails to separate completely, occurs three times as often in girls as in boys.
This idea that there is some sort of internal conflict going on inside every embryonic girl remains controversial, not least because no one has suggested a convincing mechanism by which the different cell populations might actively repel each other. Yet the surprising frequency of female monozygotic twins who differ in the severity of X-borne genetic disease remains to be explained, and the mosaic-driven theory is appealing. Could it even be possible that this split may actually occur to make sure that at least one healthy girl results from a fertilised egg unfortunate enough to have acquired a blighted X chromosome ?
If a girl resists her embryonic urge to split, her strange mixed mosaic nature may still be her undoing when she reaches adulthood. Not content with splitting embryos, the mosaic pattern of X-inactivation may also be responsible for causing a different form of internal conflict : autoimmune disease.
Autoimmune disease occurs when the immune system starts to attack an innocent part of the body as if it were foreign. Despite years of research we cannot explain most cases. We suspect that a group of immune cells fails to see part of the host's body as "self", but the mechanism of this failure is a mystery. Yet intriguingly, we know that a wide range of autoimmune diseases are more common in women than men, by a factor of 50 in some diseases. What is it about women's bodies that makes them so prone to self-destruction ?
A recent idea, championed by Jeffrey Stewart of Princeton University, suggests that, once again, mosaicism may be responsible. There is a special organ dedicated to telling immune cells what is "self" and what is "foreign" - an unprepossessing lump just behind the breastbone called the thymus. Early in their existence, a crucial set of immune cells, the T-lymphocytes, gravitates towards the thymus. Here, they are "educated" by being presented with all the molecules they are likely to encounter on their subsequent voyages around the body. Thymic education is incredibly harsh, and if a lymphocyte's surface receptors bind to anything in the thymus, then that lymphocyte is destroyed. Because of this, the only lymphocytes graduating from the thymic school are those that do not bind to self. If they later do bind to a molecule, then it is assumed to be foreign and the full wrath of the immune system is unleashed upon it.
Obviously, the cells in the thymus bear a heavy responsibility. If they fail to expose lymphocytes to any "self" molecules, then disaster could result. And indeed this is one model for how autoimmune diseases can start.
Stewart's theory is attractive because it suggests that thymic education may be less thorough in women than in men because women are mosaics. A lymphocyte is educated by more than one thymic cell - maybe 15 or 20 - but Stewart wondered what would happen if all those cells happened to use the same X chromosome. Such a thing is possible : thymic educator cells are derived from relatively few progenitor cells present at the time of X inactivation, and other cell types derived from the same progenitors have been shown to exhibit dramatic skews in their X chromosome use. Perhaps when lymphocytes graduate from such a biased thymus and then encounter cells using the other X, they see the products of that other X chromosome as foreign and attack them.
There is evidence to back up this theory. For example, the 0.02 per cent of the human population born with the abnormal chromosome complement XXY ( Klinefelter's syndrome ) appear male because they have a Y chromosome, but they undergo X-inactivation and become mosaics. And remarkably, they too seem prone to autoimmune disease. Also, other theories that provide a reproductive reason for the female tendency for autoimmune disease - suggesting female sex hormones, or even pregnancy, as a cause cannot explain why girls are more likely than boys to get these diseases even before puberty.
Researchers have tried to determine whether women with autoimmune diseases use one of their X chromosomes more than the other, but to no avail. A clear imbalance in X usage in these patients would support Stewart's theory, but the theory does not rely on it. the body at large need not be imbalanced, only the thymus. Also, I would argue that no imbalance at all is required for the occasional lymphocyte to encounter cells from only one half of the mosaic during its sojourn in the thymus. The idea that autoimmune disease is an internal war between the two factions that make up a woman is, I believe, alive and well.
Again and again, the dual nature of women has broken our neat, egalitarian ideas about the sexes being opposite, or even complementary. We must face the fact that women are simply more complex than men and get on with working out why this can pull a female embryo into two, or make a later attempt to tear her apart as an adult.
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