August 9th, 2002
University Of Michigan Health System (http://www.med.umich.edu/)
ANN ARBOR, MI – Results of a new University of Michigan study suggest that junk DNA – dismissed by many scientists as mere strings of meaningless genetic code – could have a darker side.
In a paper published in the Aug. 9 issue of Cell, scientists from the U-M Medical School report that, in cultured human cancer cells, segments of junk DNA called LINE-1 elements can delete DNA when they jump to a new location – possibly knocking out genes or creating devastating mutations in the process.
"The value of this study is the unexpected knowledge that LINE-1 elements have the potential to cause broad-spectrum mutations in individual tumor cells," says John V. Moran, Ph.D., an assistant professor of human genetics and internal medicine in the U-M Medical School.
Transposable LINE-1 or L1 elements make up 17 percent of human DNA, according to Moran, who developed the first assay to identify mobile L1s in the human and mouse genome. L1s "reproduce" by using RNA and a process called reverse transcription to make complementary DNA copies of themselves, as they integrate into other DNA sequences.
"Of 37 transposable events in our study, four resulted in deletions of genetic material," says Nicolas Gilbert, Ph.D., a U-M post-doctoral fellow in human genetics. "One of the deletions was more than 24 Kb in length [24,000 individual units of DNA called nucleotides] and potentially as large as 71 Kb. That's roughly equivalent to the size of BRCA1, a well-known gene that helps prevent the development of breast cancer."
"In cultured cells, we know that L1s can add to the genome by increasing its size, and now we've learned that they can decrease genome size by deleting genetic material," says Sheila Lutz-Prigge, a U-M research associate and co-author of the study. "But we have no control over the size or location of the deletion, and we don't yet know how often it occurs in humans."
Moran and his research team are part of a small group of scientists who study L1s in the human genome. "My personal feeling is that L1s built our genome and have continued to co-evolve with us for millions of years in sort of a host-parasite relationship," Moran says. "The more we learn about L1s, the more we'll learn about the evolution of the human genome."
When the project began, Gilbert and Lutz-Prigge were simply looking for a faster, more efficient way to figure out where L1s land when they jump and what changes L1s make in the original DNA sequence. Instead of using time-consuming, traditional molecular cloning techniques, they developed a new plasmid cassette technology and used E. coli bacteria to churn out multiple copies of DNA at the insertion site.
"Before Nico and Sheila developed this technique, we could jump L1s into cells, but we could never get them out efficiently," Moran explains. "Now we can see where L1s integrate and what they change. Access to the draft human genome lets us isolate the original site prior to L1 integration, and compare it with the post-integration sequence. We have gone from characterizing four events over a six-year period to about 50 events within the last 18 months."
Moran says one of the more intriguing results of the study is that L1s use different mechanisms to create new breaks, or take advantage of existing breaks, in DNA. He suspects L1s interact in multiple ways with host enzymes in the cell.
"The L1 is always the same, no matter what cell it's in, so if you end up with different rearrangements, that implies interaction between host factors and the L1 retrotransposition machinery," he says. "The more we study L1s, the more we realize how little we know about them. In biology, the stories are always simple until somebody delves deeper into them."
The research project was supported by the W.M. Keck Foundation, the National Institutes of Health, the March of Dimes, and the U-M Comprehensive Cancer Center.
The original news release can be found at http://www.med.umich.edu/opm/newspage/2002/junkdel.htm
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