What intrigues Meyer these days is the connection between dosage compensation and other cellular events that involve large-scale alterations to chromosomes. One example is crossing over, which occurs during meiosis, the type of cell division that leads to sperm and eggs. During crossing over, chromosomes pair up and swap DNA. The exchange is important from an evolutionary standpoint because it boosts the genetic diversity of offspring. But it's also important to get the chromosomes in position for meiosis.

Meyer and colleagues revealed this January that a protein that's part of the all-important dosage compensation complex has another job—helping govern the number of times crossing over happens. According to Meyer, this link is “completely unexpected” and suggests that crossing over and dosage compensation in worms use a similar molecular mechanism to make big changes to the chromosomes.

As they've investigated the details of dosage compensation, Lee, Meyer, and other researchers have wandered into strange territory. They've come across molecular battles, take-charge RNA molecules, and furtive liaisons between chromosomes. And that's just the beginning. Plenty of unknowns remain. Mammal cells, for example, count their X chromosomes and randomly pick one for inactivation. Nobody knows how they manage either task. Whatever the answers turn out to be, Lee and Meyer say they're expecting more surprises.

		“This is a subject that people fall in love with,” says Huntington Willard, an HHMI professor at Duke University in Durham, North Carolina. Willard, who describes himself as “the old guy” in the field, says that his attraction to dosage compensation and X chromosome inactivation began in the early 1970s, when he was a Harvard undergraduate working on a lab project with the late HHMI investigator Sam Latt. During mitosis, cells copy their chromosomes and then divide, and Latt and Willard wanted to determine whether silenced and active X chromosomes behaved differently during this process. They did—the inactive X was slower to duplicate and copied its sections in a different order than did its active partner. When he moved to Yale University for grad school, Willard kept up his work on X inactivation—but only by moonlighting. By day, he worked on his official dissertation project, studying the genetics of an inherited metabolic disorder called methylmalonic acidemia. Willard has divided his effort between X inactivation and other genetic projects ever since. He was part of the team that nailed down the DNA sequence of the X chromosome in 2005, for instance, and in 1997 his group designed the first artificial human chromosome. In 1991, he and his co-workers jump-started molecular investigation into X inactivation by identifying the first mammalian gene that controlled the process. They called it Xist. Three years ago, Willard and his colleague Laura Carrel of Pennsylvania State University gave the field something else to explore. They measured the activity of 95 percent of the X chromosome genes—the most comprehensive survey so far. Ten to 15 percent of the genes escaped inactivation entirely, and another 10 percent sometimes shut down. How cells manage to inactivate most X chromosome genes but leave some working is a mystery. Scientists had thought that Xist RNA spurs shutdown by enveloping the X chromosome. In fact, if researchers tag the RNA with a fluorescent marker, these Xist molecules show up as a luminous cloud swaddling the chromosome. The question is how this cloud clears over the genes that remain active. One of the many seductive mysteries, Willard says, that captivate and keep researchers coming back for more. —M.L.

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