Mass Screening ID's Early Genes

15 November 2000 7:00 pm

Object of scrutiny. A powerful technique knocks out genes one by one, for instance, in C. elegans.

The industrial revolution has hit genetics: Rather than study genes one at a time, researchers are mass-producing information about the functions of hundreds of genes. Now two groups report that this relatively new approach works especially well on genes that govern development. Understanding how these genes work in worms, researchers say, will help clarify the roles of unknown genes in other organisms, including humans.

A worm called Caenorhabditis elegans holds the distinction of being the first animal to have its entire genome sequenced and all its genes tentatively identified. To find out what some of these genes do, researchers disable them--normally a laborious task. A new technique, called RNA interference (RNAi), can quickly knock a gene out of action by binding it with strands of RNA and preventing it from being expressed as protein. The function of the disabled gene may be revealed by strange appearances or behaviors in the worm.

Starting at the beginning, a team led by developmental geneticist Julie Ahringer at the University of Cambridge in the United Kingdom knocked out, one by one, 90% of the genes on C. elegans' chromosome 1. The researchers made almost 2500 strains of bacteria--each one producing RNAi targeted to a specific gene--and fed each strain to a different set of worms. About 14% of the worm groups responded. Many of the genes inactivated by RNAi caused offspring to die as embryos, the researchers report in the 16 November issue of Nature. Others sterilized the worms, delayed their development, or made them uncoordinated in some way. As a result, the team now has a clue about 378 of chromosome 1's genes, quite a jump from the 70 that had already been interpreted.

The second team, led by cell biologist Anthony Hyman at the Max Planck Institute for Cell Biology and Genetics in Dresden, Germany, used RNAi to explore unknown genes on chromosome 3. They injected RNA specific to 2232 of the predicted genes on that chromosome into different adult worms, then studied the first cell division in those animals' embryos a day later. By comparing high-resolution images of normal and RNAi-treated embryos, Hyman and his colleagues could detect even tiny irregularities. All in all, 133 genes altered cell division, they report in Nature. Some had already been linked to cell division in the worms, others had been implicated by test tube experiments. But 18 of the genes had been absolute mysteries.

To be able to look at thousands of genes this way "is very impressive," says Gary Ruvkun, a developmental biologist at Harvard Medical School in Boston. But equally interesting to him are the genes that remain mysterious despite RNAi analyses. Many of these genes are found only in C. elegans. Like other genetic screens, the RNAi work suggests that "the worm-specific genes are doing subtle things," he says.

WormBase, home of genetic info on C. elegans; also contains the Ahringer team's RNAi screens

RNAi screening information from the Max Planck Institute

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