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Jeannie Lee has identified key genes involved in X chromosome inactivation and has uncovered details of how molecules regulate that inactivation in fruit flies.
The discovery began with an Alexander Fleming moment. Fleming, a Scottish bacteriologist, stumbled on penicillin in 1928 when he took a close look at some moldy bacterial cultures, rather than tossing them out as he usually did. The Meyer lab version of this event occurred 60 years later and involved a flask of misbehaving worms.
In the late 1980s, the lab was studying animals with a genetic mutation called dumpy that disables dosage compensation and sickens or kills the worms. But the nematodes in one container were hale, and their population was booming. Thinking that the culture had been contaminated, Meyer's lab technician started to throw the animals away. “He was literally pouring the culture down the sink,” recalls Meyer, “when I said, `Stop!'” Under the microscope, any nematodes that survived the mutation should have appeared short and squat, but she noticed that they were long and sleek. Investigating the animals' mysterious survival led Meyer and colleagues to a gene called xol-1. “That broke it open for us,” she says.
As she and her co-workers have revealed over the last 20 years, xol-1 serves as a cellular abacus, with its tallies dictating not only whether dosage compensation kicks in, but also the animal's sex. Worm sexuality differs from our own. Male worms carry one X chromosome, but no Y. The other sex, with two Xs, is a hermaphrodite (an organism with male and female reproductive systems).
By hunting down mutated genes that turn xol-1 on or off at the wrong time, Meyer's team identified the “counters” that tell worm cells how many sex chromosomes they have. Several genes on the X chromosome, the researchers found in a series of studies, code for proteins called X signal elements that can shut down xol-1. The researchers also found genes on the autosomes whose proteins, known as autosomal signal elements, can activate xol-1. In other words, worm cells simultaneously fashion proteins that can turn xol-1 off and proteins that can turn it on.
The fate of an X chromosome depends on a molecular scuffle between the X signal elements and the autosomal signal elements. The battle occurs at xol-1's promoter, its on-off switch. “They're all duking it out for xol-1's promoter,” says Meyer. In the free-for-all, numbers prevail. Male worms have one X chromosome but two copies of each autosome. So their “on” signals from the autosomes overwhelm their “off” signals from the solitary X. Thus, xol-1 is active and thwarts dosage compensation. This allows cells to turn on another gene that triggers the animal to develop male characteristics.
With a pair of X chromosomes, a hermaphrodite produces twice as many X signal elements as does a male. In this case, the “off” proteins from the X chromosomes win out over the “on” proteins from the autosomes, quieting xol-1 and permitting dosage compensation.
Meyer and colleagues continue to refine this story. In a November 2007 paper, for instance, they reported identifying another X signal element, the fifth found so far.
Photo: Leah Fasten