New DNA Mapping Tool May Accelerate Human Genome Work

Article originally published in September, 1999

MADISON - A new technology that maps an organism's entire genome from single DNA molecules could ratchet up the race to decipher complex genomes, from food crops to human beings.

Researchers report in the Friday, Sept. 3, issue of the journal Science their completion of the first whole genome assembled by a process called shotgun optical mapping. Scientists developed a physical map of Deinococcus radiodurans, a bacteria with the unusual ability to resist high levels of radiation.

These new types of maps "may become an indispensable resource for large-scale genome sequencing projects," says David Schwartz, a professor of genetics and chemistry at the University of Wisconsin-Madison.

Schwartz joined UW-Madison this summer from New York University in Manhattan, where he spent the past decade as part of a team of scientists developing the system.

Schwartz says his laboratory is currently using optical mapping technology to map at high resolution the human genome, and predicts his process will reduce the amount of time required to achieve that monumental scientific goal.

Optical mapping can be done in a fraction of the time it takes conventional DNA mapping or sequencing, Schwartz says. The usual approach is to decode the chemical base pairs of individual genes and gradually put them all together, one by one. Optical mapping provides an automated process to create a single, complete snapshot of a genome with very small amounts of material.

Its advantages include the ability to analyze differences between individual genomes. By comparing maps of hundreds of individual human genomes, for example, scientists could pinpoint the origin of genetic diseases, understand the complexities of trait inheritance, or examine the dynamic process behind DNA repair.

"The goal is to develop the ultimate data base of genetic information, and a source of analysis that will help us make sense out of the whole thing," Schwartz says. "What's nice about optical mapping is you can look at the whole genome, not just little snippets."

One can think of optical mapping as an entire map of the United States, whereas conventional sequencing would be thousands of detailed maps of every city in the nation, he says. Optical mapping data works in concert with high-resolution DNA sequence data, linking both together in a complete and seamless description of a genome.

Optical mapping begins by preparing DNA molecules on a glass surface. Normally rolled like a ball of yarn, Schwartz uses a flow between two surfaces to straighten the DNA. He then applies an enzyme to the prepared molecules that literally clips the molecular strands into tiny segments, producing landmarks that reveal important features of genome organization.

Next, each segment of a DNA molecule can be measured and defined by an automated scanning technology that uses fluorescence microscopy. The process is repeated roughly 100 times in order to weed out errors and get overlapping results. Those measurements provide the raw material for the optical map.

The laboratory already has completed maps of two other organisms and has another project to map the rice genome, an important milestone since rice is the most relied-upon food crop in the world.

Schwartz says Jie-Yi Lin, his former NYU graduate student, was instrumental in the success of this project. Bud Mishra and Thomas Anantharaman, professors of computer science and mathematics at NYU, developed unique statistical and computational programs that helped overcome errors in the chemical outputs. Their contributions helped automate the process and make it more universally applicable to other genomes, Schwartz says.

Owen White and Craig Venter of the Institute for Genomic Research recognized the value of the optical map and leveraged this data for their own sequencing efforts. Ken Minton and Michael Daly at Uniformed Services University of the Health Sciences used optical mapping data in their studies of how DNA repairs itself after damage.

The D. radiodurans bacteria in Schwartz's study has long interested scientists. It was originally discovered in the 1950s thriving in canned meat that had been irradiated to supposedly kill bacteria. Because of its high resistance to radiation, the Department of Energy is interested in exploring its potential for naturally removing toxins from the environment.

Federal sponsors include the National Institutes of Health, the National Science Foundation and the U.S. Department of Energy.

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Writer: Brian Mattmiller, (608) 262-9772
Contact: David Schwartz, (608) 265-0546