They have also tracked down the molecular “dimmer switch” responsible for dosage compensation in roundworms. Meyer's lab first learned that the process operates differently in worms than in mice and humans. Instead of turning off one of its two X chromosomes, a hermaphroditic worm dials down the activity of all genes on both Xs by half, on average. Meyer's group went on to discover that worms rely on a cluster of proteins called the dosage compensation complex (DCC) to achieve this feat. The complex attaches to the X chromosome and turns gene activity down. But the DCC's proteins don't unite and start working until the cell inactivates xol-1.

Some of the DCC's proteins are similar to proteins that help chromosomes compact and then separate during cell division. That finding suggests that the DCC is derived, evolutionarily, from a protein combination that performs a completely different task. In other words, when cells in some ancestral worm needed a dosage compensation system, “they stole it” from another cellular mechanism, Meyer says, thus avoiding the need to evolve entirely new molecular machinery to do the job.

Her lab has answered the key question of how the DCC distinguishes X chromosomes from autosomes. To find out, the researchers attached different chunks of an X chromosome to an autosome and determined which ones attract the DCC. In 2004, the team first revealed that the DCC homes in on several DNA stretches along the X chromosome. One stretch was about 800 nucleotide bases long. In a 2006 follow-up study, Meyer and colleagues whittled that segment down and dissected others, demonstrating that the DCC recognizes two specific DNA sequences, or motifs, each about 8 nucleotide bases long.

The surprising fact, Meyer says, is that these motifs appear on autosomes as well as on the X chromosome. The arrangement of motifs, not just their presence, might dictate whether the DCC latches on, a possibility Meyer's lab is now exploring.

Once a cell has finished counting chromosomes, it's ready to take action. In female mammals, that means muffling one of the X chromosomes. How cells turn on dosage compensation when it's needed—and keep it off when it's not—has occupied Jeannie Lee for 13 years. When she began her experiments as a postdoc in Rudolph Jaenisch's lab at the Massachusetts Institute of Technology, she didn't envision that the work would take this long. “I thought it would be solved by now,” she says. Yet scientists are far from having all the answers, in part because their studies keep throwing them curve balls, including odd molecular pathways, backward DNA silencing, and unexpected chromosomal liaisons.

British geneticist Mary Lyon galvanized research into dosage compensation in 1961, when she determined that the Barr body, a shadowy structure lurking at the edge of the nucleus in mammalian cells, was an inert X chromosome. On the basis of that finding, researchers posited that cells must have an “X inactivation center” that closed down the chromosome. But the responsible genes were elusive. It wasn't until 1991 that Huntington Willard, now an HHMI professor at Duke University in Durham, North Carolina, and colleagues identified a gene, named Xist, that instigates dosage compensation (see sidebar). Lee cites that finding as one of her motivations for switching to X inactivation research in 1995.

Her first big discovery came four years later, when she and her colleagues pinpointed the gene Tsix, which blocks Xist. Tsix's existence makes sense—cells need to keep Xist under control to prevent it from shutting down both X chromosomes in females or the only X in males. Xist and Tsix aren't just opposites in function. Their nucleotide sequences are mirror images, what researchers call complementary. The name Lee's team chose for their new gene reflects this inverse relationship: Tsix is Xist backward.

How Tsix and Xist work caught researchers off guard. Unlike the genes that control the color of our eyes or allow our cells to break down sugars, Tsix and Xist don't encode proteins. When a cell needs to perform a task, it typically makes an RNA copy of a gene, which in turn codes for a protein that takes care of business. But for Xist and Tsix, the RNA molecule itself is all that's needed to carry out functions in the cells. Willard's lab demonstrated this unusual behavior for Xist, whereas Lee's group showed it for Tsix.

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