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A tip for finding elusive genes: use less bait
Edward R. Winstead

Researchers have refined a popular strategy for identifying novel genes. They say the modified technique is better at detecting hard-to-find genes than current methods.

The subtraction technique removes already identified genes from a sample by inserting messenger RNA as bait. Longer strands of bait may snare novel genes as well as known genes. In this illustration, messenger RNA (red) binds with complementary sequences from two different genes (blue).

The genes not yet discovered by techniques that analyze gene activity are likely to be expressed at very low levels or are expressed only at certain times in some cells. Although they are elusive, these genes may be important in regulating growth and development.

Researchers from the University of Chicago Medical Center and Johns Hopkins University School of Medicine say they have improved a popular method for detecting gene activity in cells by using shorter strands of messenger RNA as gene bait. The current method, known as subtraction, involves screening cells for the messenger RNA that translates DNA into proteins. To find novel genes, the researchers remove the bulk of already identified genes from a sample, using short strands of messenger RNA that bind with complementary sequences.

The proposed innovation shortens the strand of messenger RNA used as bait. The researchers show that shorter strands are more effective because they are less likely to tangle indiscriminately with messenger RNA and inadvertently select out novel genes. A paper describing the work appears in the current issue of the Proceedings of the National Academy of Sciences.

“This research is proof of the principle,” says San Ming Wang of the University of Chicago Medical Center, Illinois, and lead author of the paper. Wang and his colleagues tested the strategy by looking at five genes that are expressed at extremely low levels in normal colon cells. Compared with the unmodified technique, the new approach increased the detection of four of the five genes, according to the paper.

The technique could prove useful in developing tools for diagnosing disease based on gene expression in tissue and blood, says Katherine J. Martin of the Dana-Farber Cancer Institute in Boston. “Gene expression technology has recently been used to classify different sub-types of cancers,” she says. “Knowing which genes are expressed in which cells is valuable information that you don’t get from knowing the DNA sequence.”

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Wang, S.M. et al. Screening poly(dA/dT)- cDNAs for gene identification. Proc Natl Acad Sci 97, 4162-4167 (April 11, 2000).

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