October 29, 1999

Earliest Divorce Case: X and Y Chromosomes

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    Like archeologists exploring a succession of levels at a dig site, two Boston scientists have discovered four distinct layers of evolution in the structure of the human X chromosome. From the chronology of the layers, the scientists have inferred some of the landmark events in the evolution of sex chromosomes -- an epic battle of the sexes that stretches back to the dawn of mammalian time.

    Traces of distant evolution are discovered in the human genome.

    The layers correspond to increasing levels of evolutionary divorce between the X chromosome and its partner, the Y chromosome, which determines whether a person will be male.

    The findings underline the importance of the Y chromosome as a unique piece of genetic real estate for genes that favor males but would be detrimental to females. Despite this privileged source of power, however, males may be at risk from the unavoidable obsolescence of the Y chromosome, a process that has driven down its number of genes from equality to one-hundredth of those on the X chromosome.

    The scientists, David C. Page of the Whitehead Institute and his colleague Bruce T. Lahn, now of the University of Chicago, report in Friday's issue of the journal Science that they stumbled on the layers while studying the differences between the 19 genes of which copies are found on both the X and the Y chromosome.

    The two members of each pair had diverged from each other genetically because the X and Y chromosome do not exchange genetic material every generation, as do the other 22 pairs of human chromosomes, known as autosomes.

    This intergenerational exchange of material, a grand reshuffling of the genetic deck, gives each gene slightly different properties and is one reason children differ from their parents.

    Genes that cannot participate in the reshuffling eventually fail to contribute to an individual's survival and disappear from the genome.

    But human sex chromosomes must be excluded from the reshuffling process, at least in the region of the male-determining gene, to prevent this gene from sneaking into the X chromosome and fomenting the disaster of making everyone male.

    In fact, reshuffling is prevented not just at the male gene site but along the whole length of the two sex chromosomes. Only at their very tips do the two chromosomes join during the reshuffle waltz, the bare minimum of contact to keep them engaged as a pair.

    Dr. Page and Dr. Lahn have discovered that the no-shuffle region did not appear all at once but opened up in four separate stages during evolutionary history.

    The stages can be dated by the number of genetic differences between the 19 pairs of genes found on both the X and Y chromosomes.

    The first no-shuffle region appeared as long as 320 million years ago, according to their calculations, shortly after mammals evolved from reptiles. Sex in reptiles is decided not by having different sex chromosomes but, bizarrely enough, by environmental cues. In turtles and crocodiles, for example, the sex of the embryo is determined by the temperature at which it is incubated.

    Presumably a sex-determining gene activated by temperature or some other external influence became genetically dominant in some early mammalian ancestor, and at the same time the first no-shuffle zone arose around it. No-shuffle zones can be created by the genetic accident known as an inversion, in which a stretch of DNA springs loose from a chromosome and gets reinserted the wrong way around. The inverted DNA no longer corresponds to the DNA on its counterpart chromosome and cannot exchange genetic material with it.

    Three more of these inversions occurred as long as 170 million years ago, 130 million years ago and 50 million years ago, with each event expanding the region of the no-shuffle zone.

    Dr. Huntington F. Willard, a medical geneticist at Case Western Reserve University, said it was fascinating that the traces of such distant evolutionary events could be recovered from the human genome, especially ones that shed light on the logic of its construction. "One of the biggest questions for understanding the human gneome is whether it matters how it was put together," he said. "This is a glimpse that there is in fact substantial method to the madness."

    Though the lack of reshuffling makes it hard for the Y chromosome to keep its genes fit, it also creates a haven for any genes that may evolve to benefit males but harm females. Male guppies, for example, are brightly colored so as to attact females, but the colors also make the fish dangerously visible to predators. The color genes confer a net benefit to the males but would harm female fish.

    Almost all these gaudy genes, Dr. Page said, are located on the guppy's Y chromosome, where they cannot get into the female's genome.

    The human Y chromosome, sad to say, seems to contain no gaudy color-producing genes. And anyone expecting to find genes conferring special prowess in war, baseball or math will be disappointed: so far, at least, the Y chromosome seems to contain a very dull collection of genes. One category, with counterparts on the X, performs routine housekeeping tasks in the cell; the other, the genes special to the Y, seem to be involved mostly in sperm production and male fertility.

    "There has been speculation that the cognitive differences between males and females are hard-wired into the Y chromosome, but there is no evidence of that at present," Dr. Page said.

    But genes sometimes turn out to have unexpected second functions, and it could be that one of the boring sperm-related genes on the Y chromosome can also turn on a suite of more interesting genes located on the other chromosomes.

    "The Y can play a special role in the battle of the sexes, " said Dr. William R. Rice of the University of California, Santa Barbara, a biologist who studies the evolution of X and Y chromosomes. In fruit flies, he noted, "the Y chromosome is a powerhouse in determining male fitness."

    But the decay of the Y's original complement of genes "created problems for males that the species has had to come to grips with," Dr. Page said. The problem is that a gene's product must be delivered at just the right levels. With loss of a Y gene, its counterpart on the X had to work twice as hard. And that meant that in females, with two X chromosomes, each gene now needed to work half as hard as before, a problem that is solved in humans by randomly switching off one X chromosome in each cell.

    Although the X chromosome cannot reshuffle its genes when in males, it escapes the Y's obsolescence because, when transmitted to a man's daughters, it can exchange genetic material with the other X chromosome in a cell.

    Dr. Page and Dr. Lahn calculated the dates at which the 19 pairs of genes started to diverge from each other by counting the number of different DNA units between each pair. The dated genes fell into four distinct clusters. The genes occurred in an apparently random order along the Y chromosome, presumably because of the several inversions that occurred there. But their counterpart genes on the X chromosome turned out to be nearly arranged in chronological order stretching from one end of the chromosome to the other. "It was if we were looking at geology in an undisturbed sedimentary formation and these were the strata," Dr. Page said.

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