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Dynamic DNA Segments Don't Stay Put

April 2011--Transposons—jumping genes—were once consigned to the portion of the genome called “junk DNA.” But these prolific parts of the human genome now appear to do much more than simply take up space.

Nobel prize biologist Barbara McClintock named them “controlling elements.” Later, others called them “jumping genes.” Today, they’re usually referred to as transposable elements or transposons—pieces of DNA that can move between different positions in a genome. By whatever name, they now appear to play a larger role in biology than scientists once believed, says Nancy Craig, professor of Molecular Biology and Genetics.

“One of the great revelations of the genomic age was how extensive transposable elements are,” says Craig. “Half the human genome is made of transposons.” Each chromosome is littered with the mobile elements, segments of DNA that emigrated from one part of the genome and took residence in another.

But aside from their sheer volume, transposable elements are significant for other reasons, says Craig, who last year helped launch a new online journal called Mobile DNA dedicated to research on transposition and related mechanisms. Craig is one of the journal’s three editors-in-chief. Transposable elements, she says, are key drivers of evolution. Their movement can also contribute to certain diseases. Moreover, says Craig, geneticists hope that they can exploit these dynamic elements to learn more about the genome and possibly to develop safer forms of gene therapy.

Craig started studying transposable elements about 30 years ago and has focused her research on them ever since. As one of the world’s experts in the field, she is a rich source of interesting transposon facts. For instance, a few species—such as the malaria parasite—have no transposons. Some others—such as corn—have many.

Craig believes that transposition is instrumental to evolutionary change. When a transposon inserts itself into a new position in the genome, it may mutate that gene. Such changes, says Craig, “contribute greatly to genetic diversity, which is the substrate for evolution. “Transposable elements are natural genome engineers,” she says.
 

maize.jpg
The darker kernels result from
moving transposable elements.
Image by Danon Lisch

In the case of corn, transposons make up 85 percent of the genome, which may account for the rapid evolution of the tiny hard-kerneled teosinte form grown thousands of years ago in Mexico, to multi-colored Indian corn, to the larger and sweeter varieties popular today. “Corn has been selected (over thousands of years) to undergo incredible changes,” says Craig. Similarly, transposable elements may also help explain how the dog genome can give rise to both a Chihuahua and a Saint Bernard.

And genome size—the amount of DNA—can vary widely from one species to the next. (The human genome is about 1,000 times larger than a bacterium’s.) That’s due in part to transposition. A transposable element may snip itself out of one part of the genome and paste itself into another; or, more commonly it will perform a copy-and-paste operation, which, over generations, expands the genome.

Most transpositions introduce harmless changes—a different coat color in dogs, or a more mottled kernel of corn—but some can contribute to disease. Researchers have identified about 50 diseases that arise when a transposable element inserts itself into a gene of a gamete or embryo, says Craig. These include some cases of hemophilia, which Johns Hopkins Professor of Human Genetics Haig Kazazian discovered can arise when a transposon inserts itself in a clotting factor gene.
 
On the other hand, Craig believes transposons also hold great promise as tools to fight disease through gene therapy, the effort that involves introducing a healthy gene into cells bearing a defective version of that gene. In some of the past gene therapy trials, researchers employed a virus or retrovirus as a vector to carry the healthy gene into the patient’s cells and integrate the gene into the patient’s DNA. (A retrovirus is a type of transposon.)

One weakness of this approach was that scientists had no control over the gene’s final destination. A virus might integrate in an innocuous spot in the genome, or it might take residence in a place that would trigger more disease. That is what happened in a gene therapy trial begun in 1999 in France involving nine children with severe combined immunodeficiency (SCID). The therapy cured eight of the children of SCID. However, four developed leukemia because the gene-carrying retrovirus inserted itself near an oncogene, or cancer-inducing gene.
 
Some scientists, including Craig, are now studying transposons and fine-tuning retroviruses to find those that can more safely integrate genes into the genome. Craig is studying ways to modify certain transposable elements by amending them with special segments of DNA to create transposons that go only to safe sites in the genome. “We are asking, Can you add new DNA binding domains to transposons that change their specificity and make the transposon bind to one and only one place?” says Craig. “We haven’t been able to do that yet, but we have made some positive first steps.”
 
These “genome engineers” could hold untapped potential for medicine.

–Melissa Hendricks

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