Science Notes  -- Summer 1998
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CHROMOSOMES mostly appear translucent. They unfurl their delicate strands of DNA, the better to expose genes that direct the workings of cells. But in the cells of female mammals, which have two X chromosomes, one sister of the pair remains shut off in a corner, tightly bundled and dark.
      The dark sister sits subdued, not directing the production of thousands of proteins the way its voluble counterpart does--and indeed as the other 22 pairs of human chromosomes do.
      It didn't start out that way. Early in development, when the female embryo is still a clump of undifferentiated cells, the two X chromosomes are indistinguishable. But as the tiny female embryo begins to develop form, fate intervenes for one of the sisters. A crucial switch, known as the X inactivation center, turns on and a signal sweeps down the chromosome. Genes linked with that chromosome's X inactivation center become silent--never to be read into proteins.
      As the cells of the embryo divide, the inactivated X in each cell is duplicated like all the other chromosomes, but its descendants remain silent even after being copied for many cell generations

The Unity of Sex

SEX, when all is said and done, is a method for mixing up genetic material. Sex is such a good idea that species ranging from ferns to frogs have converged on near-universal methods of sexual reproduction.
      Considering how diverse the different sexually reproducing species are, how much they share in common is remarkable. Sexually reproducing species almost invariably have two genders--males and females, of course--which usually exist in equal proportions, and where opposites mate. In almost all sexually reproducing species, too, gametes come in two forms--fat eggs and tiny, mobile sperm. Usually, an organism inherits one complete set of genes from each parent. When the time comes to make its own gametes, the individual packages one complete gene set, shuffled from both parents, into each of its gametes.
      Sexually reproducing species widely rely on sex chromosomes to determine sexual fate. Some exceptions do exist--some reptiles, for example, rely on environmental cues instead. The alligator is one such reptile. The temperature an alligator is exposed to during a critical window of development determines whether it will wind up a male or a female. More commonly, however, heredity determines sex, which seems a more reliable way of producing even proportions of the sexes.
      Like sexual reproduction, sex chromosome systems have evolved independently but in common ways. For example, flies, worms, birds, and mammals (to restrict the examples to animals) all have sex chromosomes that share basic characteristics, yet their sex chromosomes are not related at the level of molecules (they use different genetic pathways to determine sex).
      Some themes guide the evolution and logic of sex chromosome systems. One such these is that chromosomes come in sister pairs, one inherited from the mother and one from the father. Sex chromosomes, for example the X and the Y in mammals, often look starkly different, yet are thought to derive from once-identical sister chromosomes. Generally, one sex chromosome (the X in mammals) looks like a standard-issue, medium-sized chromosome with thousands of genes, while the other (the Y in mammals) tends to be shrunken, clogged with junk DNA and almost bereft of genes. For example, the human Y may house only two dozen genes, whereas an average human chromosome houses one hundred times that number.
      A general characteristic of sex chromosomes is that they do not recombine as other pairs of chromosomes do, except at their tips. Recombination is a process where sister chromosomes align, intermingle, and trade fragments of genetic material before segregating into egg or sperm cells.
      Unrelated sex chromosome systems also invented methods of dosage compensation, which balance the dose of gene products derived from the sex chromosomes between males and females. Genes act in complex concert with each other, and the levels of gene products have been fine-tuned over the course of evolution. In many species, females (XX) inherit two X chromosomes while males (XY) inherit just one. Fruit flies that confronted this dilemma have solved it by elevating expression from the male's single X chromosome. Mammals, meanwhile, inactivate the second X chromosome in female cells--or, more precisely, they permit only one X chromosome to remain active in a cell.
      Despite differences in the specifics of how sex and sex chromosomes have evolved, various lineages, whether worms or flies or buffalo, have confronted similar problems and come up with similar solutions.

T HE INACTIVE X isn't altogether silent, however. In humans, at least 16 genes are known to escape X inactivation. These genes are read into proteins whether they dwell on the inactive or active sister. But many fewer genes seem to escape X inactivation on the mouse X.
     What came first--inactivation, as in mice, or escape from inactivation, as in humans? How did these genes behave in the mammalian ancestor? Did regulation switch during the evolution of primates or rodents? Tracing X inactivation affords a rare opportunity to reconstruct how a fundamental process in development evolved.
      Sex chromosomes, like sex, have arisen independently many times, in different kinds of organisms, yet have evolved in parallel ways (see sidebar).


BY MANY measures, the inactivated X is distinct from its sister and from other working chromosomes. For one thing, it just looks different under a microscope--condensed and segregated against the nuclear wall, instead of fanned out throughout the nucleus like the other chromosomes.
      Also, the inactivated X is chemically altered. Methyl groups tacked onto it appear to cement inactivation. The methyl groups serve as an inheritable marker, ensuring that copies made from the inactive X are also inactive.
      During development, X inactivation of a chromosome seems an indiscriminate process. If a fragment of an X chromosome with the inactivation center (or even the inactivation center alone) happens to become attached to another chromosome, the inactivating force can roll down the other chromosome too, silencing many genes with no previous experience of X inactivation. X inactivation spreading into other chromosomes in this way usually kills a cell.

SUCH IS THE view at the "forest" level. But at the "tree" level of individual genes, X inactivation appears less thorough, at least in humans. Some of the genes that evade inactivation are clustered at the ends of the chromosome, but others are sprinkled throughout the chromosome's body, among inactivated genes.
      The set of genes on the mouse X chromosome matches the set on the human X, so the activity of genes can be compared between the two species. And the mouse X chromosome appears to be more thoroughly X-inactivated than the human X. Nearly all the genes known to escape X inactivation in humans succumb to X inactivation in mice; only two genes escape X inactivation in mice as well as in humans. No additional genes that escape inactivation are known in mice.
      Again, the question arises, what came first? Were genes that escape X inactivation in humans active in the common ancestor of mammals as well, or were they already subject to X inactivation, as in mice? When did regulation change? To extrapolate ancestral conditions, our lab undertook a comparative study of X inactivation, looking at a host of mammalian species.
      Humans and mice are about as distantly related to each other as any two placental mammals can be. The placental mammals are thought to have begun diverging from one another about 100 million years ago. The various Orders--primates, rodents, carnivores, rabbits and hares, horses and their relatives, etc.--separated quickly, perhaps over the course of 30 million years. The precise sequence of their branching has been difficult to decode and remains unresolved. Still, surveying X inactivation in a range of placental mammals can reveal whether inactivation or escape is more likely to represent the ancestral condition.
      Whether one or two copies of a gene are switched on in any given female cell cannot be observed simply. Directly observing gene activity in a wide range of species would have been impossible, so our lab turned to DNA methylation as a way to assay X inactivation. In every case that we and others have examined, methylation of an X-linked gene in a region overlapping its start site correlates with X inactivation.
      We studied three genes. Close relatives--all the primates for instance, or subsets of rodents--always went together in activating or inactivating each of the genes. So switching between X inactivation and escape from inactivation does not appear to occur often. But knowing the X inactivation status of one gene proved a poor predictor of the X inactivation status of another gene in the same species or Order.
      Although X inactivation acts like a tidal wave during development, during evolution X inactivation may have advanced much more daintily--gene by gene or patch by patch. X inactivation may appear as sweeping as it does only because the patchwork acquisition of inactivation has become so complete that inactivation now appears seamless.

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