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Biological Chemistry

Bacterial Genome Made From Scratch

Study is milestone in assembling large DNA segments

by Stu Borman
January 28, 2008 | A version of this story appeared in Volume 86, Issue 4

Credit: J. Craig Venter Institute
Credit: J. Craig Venter Institute

IN SCIENTIFIC RESEARCH, it's often best to think big. That's what researchers at the J. Craig Venter Institute in Rockville, Md., were doing when they synthesized what is by far the largest DNA sequence ever made (Science, DOI: 10.1126/science.1151721). The sequence is the entire genome of Mycoplasma genitalium, one of the smallest bacterial genomes.

The methods 1978 Nobelist Hamilton O. Smith and coworkers devised to create this genomic DNA "will be generally useful for constructing large DNA molecules from chemically synthesized pieces and also from combinations of natural and synthetic DNA segments," the researchers write.

One of their goals has been to create a synthetic "minimal" organism, having as few genes as possible, and they created the bacterial sequence from scratch as a key step toward that objective.

The synthetic genome is like the native one, but one gene was replaced to block infectivity and several nongene areas were modified as markers. The genome is 583 kb (kilobase pairs)-much larger than the longest synthetic DNA reported previously, a 32-kb polyketide gene sequence. To create it, Smith and coworkers purchased 101 DNA sequences, combined them into quarter-genome pieces in vitro, and assembled the pieces in yeast cells.

Last year, a Venter Institute group converted one type of bacterium into another by replacing its genome with the other bacterium's genome. The new synthetic genome has not yet been transplanted in the same way into a cell to see whether it can be "booted up" into a living M. genitalium, but Smith's group plans to do that next.

Geneticist George M. Church of Harvard Medical School says the study "seems like a milestone worth celebrating" but notes that it also raises questions, such as whether the methods will scale well and whether total synthesis is cost-effective relative to conventional genetic engineering.

"The work provides a good cookbook for people who want to manipulate large chunks of DNA," says Eckard Wimmer of the State University of New York, Stony Brook, whose group synthesized a 7.5-kb poliovirus in 2002.



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