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Scientist Discusses Strategy for Finding Gene Function and Bioinformatics Role

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ATHENS, Ohio--Researchers in Thomas Wagner's lab at the Edison Biotechnology Institute at Ohio University announced last month they had discovered a new way to identify gene function in a matter of days. As an alternative to conventional techniques using knockout mice that can take months or years, Wagner, a principal scientist at the institute and a professor of molecular and cellular biology, told BioInform the technique his team discovered, "is so fast you can immediately repeat it."

The Ohio researchers' "knockdown" gene identification strategy, as they call it, was reported in a recent issue of the journal Proceedings of the National Academy of Sciences. It uses a nonviral gene expression system to inhibit the expression of specific genes in zebrafish.

Wagner spoke with BioInform recently about this new method for identifying gene function and about the role he sees for bioinformatics in aiding the success of faster gene function identification strategies.

Knockdown zebrafish

Wagner's team used ribozymes as the catalyst to stop protein production in zebrafish. "Ribozyme can recognize a sequence and match it and cut it. The ribozyme molecule cuts and stops the product from being expressed," he said.

"The system allows us to stop gene expression long enough to study the gene, then returns it to normal," Wagner said. The knockdown strategy requires only partial knowledge of the gene sequence, Wagner said.

Using knockout methods, genes cannot be identified until their entire sequence is known, Wagner pointed out. Sequence information is used to generate transgenic animals in which the gene of interest is disrupted and made nonfunctional. "To make an animal from an embryonic cell with a gene of unknown function knocked out takes two or three years," said Wagner. "We're talking 300,000 man-years to identify the function of the human genome."

Use of the knockdown method in combination with the T7 expression system, which Wagner and others at the Edison Institute invented several years ago, is what Wagner credits for his success using ribozymes in animals--until now such studies have worked only in cells. The T7 system is used to express large amounts of ribozymes targeted at specific genes.

"A ribozyme gene knockdown strategy could be as useful as the established gene knockout strategy to identify and elucidate gene function, while being much more efficient," Wagner said.

Bioinformatics' role

Bioinformatics will be integral to methods for function identification like his new knockdown strategy, Wagner said. "There's a very big place for bioinformatics in terms of generating information about the sequence which can lead to where to target this knockdown," Wagner said.

"Bioinformatics will analyze the sequence of genes of unknown function to attempt to determine the core regions which are ancestral, and to differentiate those parts of the sequence from the parts that are the dependent modification," he explained. That information would let scientists know what part of the sequence to target the ribozyme against.

"You can take a DNA sequence, immediately translate it into a protein sequence, and then you can even take the protein sequence and say what kind of 3-D molecule will be generated. When you start looking at the kinds of proteins that will be generated, you can begin to immediately see some common structural domains which are ancestral in nature. This is the role of the bioinformatics people: to try to take sequence to get this kind of information about it, compare it to other sequences of unknown function and ask, where are they similar, where different?"

By finding core regions that are similar, researchers can determine which proteins of the same common sequence must do the same thing. "That's where you take this sequence and target with the ribozyme," Wagner said.

Efficiency, he said, will be the key to the usefulness of genomic data. "We're euphoric about knowing the sequence of ATCG in genes, but we still don't know anything. What good does it do if you haven't a clue what the protein does? It's like you found a book and you put all the letters in order," Wagner said.

Now the hard part

"Now the hard part starts," he said. Wagner predicted determining gene functions will be the most challenging part yet of genomics.

"That's why the development of quick and efficient gene function identification systems is so important." He added, "I'm sure in a couple of years we'll think that two days to determine function is a long time."

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