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Jumping into chromosome 2
By Bijal P. Trivedi

One of the ultimate goals of gene therapy is to incorporate therapeutic genes into a specific location on a chromosome so that each time a cell divides the new genes are transmitted to the next generation. But designing a piece of DNA that can read a chromosome and find its unique landing site has been unsuccessful until recently. Now a group of scientists has developed a system for inserting new genes into a specific location on human chromosome 2.

Eric Wickstrom and Stephen Cleaver, of Thomas Jefferson University, are delivering genes using a transposon, a naturally nomadic segment of DNA that 'jumps' from chromosome to chromosome. The Tn7 transposon they chose is normally found in the chromosomes of E. coli, a bacterium that resides in the gut. In E. coli Tn7 recognizes a stretch of DNA that lies in a bacterial gene called glmS and inserts itself close by.

chromosome 2 could become a safe location to introduce therapeutic genes

It turns out that the glmS gene has a human counterpart on chromosome 2—fructose-6-phosphate transaminase (GFPT), an essential metabolic enzyme—which looks almost identical. Using a synthesized copy of GFPT, Wickstrom and Cleaver found that Tn7 recognized the DNA sequence of the human gene and predictably inserted itself close by, but outside of the gene. "As far as we can tell the transposon integrates between two genes without disrupting either one of them," says Wickstrom.

Only the ends of the transposon are needed to recognize a specific location along the chromosome, which leaves the middle section available for carrying useful genes. Wickstrom and Cleaver showed that Tn7 carrying a gene for antibiotic resistance could be inserted in the target site next to the GFPT gene. Cells in which the transposon was correctly incorporated were resistant to the antibiotic gentamycin. These results are reported in the August 22 issue of Gene.

More work needs to be done and many more questions need to be answered before this experiment can be tried in humans. Wickstrom plans to test the Tn7 transposon in yeast and mice to see whether it consistently inserts itself next to the yeast and mouse counterpart of glmS without disrupting the functions of other genes. If this work is successful, Wickstrom is hopeful that the Tn7 insertion site on chromosome 2 could become a safe location to introduce therapeutic genes.

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Wickstrom, E. et al. Transposon Tn7 gene insertion into an evolutionarily conserved human homolog of Escherichia coli attTn7. Gene (August 22, 2000).

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