After searching for 7 years for a better way to inactivate mouse genes, Tian Xu and colleagues have some good news to report.

By inactivating each mouse gene one by one and assessing the biological consequences, geneticists can deduce a gene's functions. HHMI investigator Mario R. Capecchi of the University of Utah in Salt Lake City pioneered targeted mouse gene knockout technologies some two decades ago, unleashing a flood of knowledge about mammalian biology. Despite such successes, progress toward being able to delete all the mouse's 30,000 or so genes has been slow. The method is technically challenging, expensive, and time-consuming—it can take more than a year of full-time work to generate a single knockout mouse. So far, researchers have managed to inactivate only about 10 percent of mouse genes.

Tian Xu, an HHMI investigator at Yale University School of Medicine, has been searching for a faster and easier approach for the past 7 years. In the August 12, 2005, issue of Cell, Xu and collaborators—HHMI investigator Min Han of the University of Colorado at Boulder, Yuan Zhuang at Duke University Medical Center, and colleagues at China's Fudan University—reported they had finally succeeded.

The new method takes advantage of a transposon—a short segment of DNA that can "hop" to another position of an organism's genome and that is capable of landing squarely inside a gene and inactivating it. For decades, geneticists had exploited transposons to disrupt genes in plants, worms, and fruit flies, among other models, but they hadn't worked very well in mammals. "About 40 percent of the sequences in our genome, and in the mouse genome, are actually transposon sequences," Xu says. Those transposons are no longer active, however, but are the molecular relics of an era when transposons ran rampant through mammalian genomes. "Evolution managed to make all these transposons inactive, probably so that they wouldn't destroy our genomes," Xu says.

Photo: Richard Freeda

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