Through her work in roundworms, Barbara Meyer has revealed how a protein cluster adjusts gene activity on the X chromosome, a process called dosage compensation.

This disparity leaves our cells in a jam. A woman's cells carry twice as many copies of most X chromosome genes as a man's cells and—if the genes work at full throttle—can crank out correspondingly more of their protein products. Although genes on the X chromosome are essential for everything from filtering blood to repairing DNA (most of them have nothing to do with sex differences), a double dose of their proteins is disastrous for cells.

And that's not only true in humans. Animals as different as roundworms, fruit flies, and opossums face the same problem. “It's essential to have gene balance” between the sexes, says HHMI investigator Barbara J. Meyer of the University of California, Berkeley. If the numbers are out of whack, “the animals are dead, it's that simple,” she says.

Necessity, however, is the mother of adaptation. Animals have evolved myriad mechanisms to keep gene activity the same in the two sexes. Known as dosage compensation, this type of gender equality can work in several ways. For example, female mammals shut down one X chromosome, preventing most of its genes from yielding any proteins—what's termed X chromosome inactivation. This process is complete by the early stages of embryonic development, and the inactivated chromosome remains off for life. Fruit flies use the opposite approach: responsibility for dosage compensation falls on the male, where the output of the genes on its single X chromosome doubles, thereby ensuring the same gene expression as in XX female flies.

Two HHMI investigators, Meyer and Jeannie T. Lee of Harvard Medical School and Massachusetts General Hospital, are at the forefront of research on the intricacies of dosage compensation. In more than 20 years of experiments on nematodes, or roundworms, Meyer has shown how cells count the number of X chromosomes they contain and revealed the workings of a protein cluster that adjusts gene activity on the X chromosome. Studying mice, Lee has deciphered details of the molecules that regulate X inactivation. Both scientists say their results have surprised them at every turn.

Now their work is having an impact on biologists in other fields. Researchers are looking to dosage compensation for clues about how cells orchestrate changes to large tracts of DNA or entire chromosomes. And Lee's recent findings of peculiarities in X inactivation among embryonic stem cell lines have heightened concerns about the safety of these stem cells when used to develop replacement tissues and organs.

To pull off dosage compensation, cells need basic math skills. They have to be able to count the number of X chromosomes and non-sex chromosomes (called autosomes) they harbor. Meyer uncovered the basis for this arithmetic ability in roundworms.

Photo: Mark Likosky

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