A Rapid New Way to Learn What Genes Do

UNIVERSITY OF UTAH MEDIA RELEASE

Embargoed by the journal Nature for release at noon MDT Weds. Sept. 5, 2001

Contacts:-- University of Utah biologist Erik Jorgensen and former postdoctoral fellow Jean-Louis Bessereau can be reached at Bessereau's lab at Ecole Normale Superieure in Paris, usually between 2 a.m. and 10 a.m. MDT (10 a.m. to 6 p.m. Paris time) - 011-33-1-4432-2306 or [email protected]-- Daniel Williams, Kim Schuske and M. Wayne Davis can be reached at the Jorgensen laboratory at the University of Utah - (801) 585-3304 or (801) 585-3692.-- Lee Siegel, science news specialist - (801) 581-8993, cellular (801) 244-5399, [email protected]

A RAPID NEW WAY TO LEARN WHAT GENES DOUtah Biologists Take Days to Do What Once Required a Year or More

Sept. 5, 2001 - University of Utah biologists devised a new technique to rapidly determine the job performed by particular genes in laboratory animals, according to a report in the Sept. 6 issue of the journal Nature.

The researchers removed bits of DNA known as transposons or "jumping genes" from fruit flies, then inserted them into nematode worms and used an enzyme to activate them.

The transplanted genetic material not only induced genetic mutations in the worms, but also "flagged" the mutant genes so they could be found easily. By observing what malfunctioned in worms due to a particular mutant gene, the biologists could determine the gene's normal function.

Conventional genetic mapping can take a year or more to identify the job a gene performs, but the new method requires only days and promises to speed identification of what specific genes do in mice, worms, zebrafish and other animals used to study genetics, said Erik Jorgensen, an associate professor of biology at the University of Utah.

The method cannot be used in people because it is unethical to breed people with mutations, although it could be used on human cells in culture dishes to learn what genes influence human cell growth, Jorgensen said.

The study in Nature was conducted by Jorgensen, former Utah postdoctoral researcher Jean-Louis Bessereau, technician Ashley Wright, graduate student Daniel C. Williams, research assistant professor Kim Schuske and postdoctoral researcher M. Wayne Davis.

Bessereau - who holds medical and doctoral degrees - now works for INSERM, the French Institute of Health and Medical Research, with his laboratory based at the Ecole Normale Superieure, a university in Paris. Jorgensen recently started a one-year sabbatical working with Bessereau in Paris. The study's other co-authors work in Jorgensen's Salt Lake City laboratory.

A transposon or jumping gene is a bit of DNA that is somewhat like a virus, except it remains within cells instead of leaving cells to infect other cells. Each type of jumping gene can be activated by an enzyme. When that happens, the transposon is cut out of its normal position on a chromosome, and then hops randomly into a new location in the genome, or genetic blueprint, mutating any gene into which it inserts itself.

Jorgensen said jumping genes have long been used instead of chemicals to cause mutations in genes in fruit flies. Tagging a mutant gene with a jumping gene also allows the mutant gene to be identified immediately. Fruit fly transposons or jumping genes can be put into other organisms to study genes in those species. For example, fruit fly transposons have been transferred into protozoans in the genus Leishmania, while transposons from fish have been transferred to human cells in culture. Jorgensen said the new study is the first to use fruit fly transposons to induce mutations in the nematode worm species C. elegans and identify the mutant genes.

In addition to mice, fruit flies and zebrafish, "C. elegans is one of the few model organisms we have - one of the few organisms we use as a model for all organisms," Jorgensen said. Researchers already know the "sequence" of letters in the worm's genetic code, but not the functions performed by individual genes within the worm genome, he added.

The new method "is a great system for identifying what genes do," Jorgensen said. "Most of the genes in worms are very similar to genes in humans."

Here is how the method would work, for example, to look for a gene related to growth.

Nematode worms have their own transposons or jumping genes, but there are so many that if they were activated, there would be numerous mutations, making it difficult to link a single mutant gene to a particular defect in the worms. So transposons are removed from fruit flies and inserted into nematode worms. Then an enzyme is used to activate the transposons and make them jump.

"You cause transposons to jump in thousands of worms" and induce various mutations, Jorgensen said. "When you look at these plates you see a zoo of different behaviors and morphologies (body forms). You see fat worms. You see long worms. You see worms that are paralyzed. And you see small worms."

The fact the worms grow slowly indicates the jumping gene inserted itself into a gene responsible for growth, mutating it and making it malfunction.

The researchers use PCR - polymerase chain reaction - to recognize the jumping gene that flags a mutant gene. PCR recognizes the genetic code of the jumping gene, latches onto it, and then makes millions of copies of the jumping gene and the attached mutant gene. Machines transform the mutant gene's genetic code into a bar pattern that can be read on film or with a fluorescent detector.

Then the researchers look for that gene on the already decoded genome or genetic blueprint. That would be how they could pinpoint a gene involved in growth.

In the actual study in Nature, the biologists used a fruit fly jumping gene named mariner element Mos1 to mutate and identify genes that help a nematode worm sense the concentration of solutions in which it swims. Strong concentrations of dissolved solids can dry out and kill a worm, so they use the sense to stay in lower concentrations.

Jorgensen said his research group developed the method because they wanted a fast way to look for genes involved in transmission of nerve signals.

Nematodes are unsegmented worms that live in soil and water and often as parasites inside other organisms. Examples include pinworms and roundworms that infest people. Many are tiny, including those in the new study, but one species living inside sperm whales has been reported up to 26 feet long.

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