"The results of this project add to the rapidly growing list of pathogenic microbes whose genomes have been sequenced," says Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID), which helped support the research. "This breakthrough will lead to a much better understanding of how U. urealyticum causes disease, and should allow scientists to devise better treatments against it."

"Although this knowledge will not immediately lead to a cure, it will put tools in people's hands," says John Glass, Ph.D., who performed much of the sequencing while a postdoctoral fellow at the University of Alabama at Birmingham (UAB). Dr. Glass, now a researcher at Eli Lilly and Company, is lead author of a paper, published in the current issue of Nature, that describes the genome sequence.

"We know very little about this organism compared with others that cause disease in humans," says senior author Gail H. Cassell, Ph.D., formerly at UAB but now vice president for infectious disease research and clinical investigation at Eli Lilly and Company. The sequence should help clear up several questions scientists want answered about U. urealyticum, she said. For instance, the majority of pregnant women are infected by this bacterium, but in most cases it does no harm. "The enigma surrounding this organism is that it appears to cause disease in only a sub-population of infected people," Dr. Cassell says. "The sequence will help us understand why that is so." It will also help scientists better understand what allows U. urealyticum to invade intact fetal membranes and infect the placenta and amniotic fluid, she notes.

Scientists also want to understand the genetic and molecular mechanisms behind U. urealyticum's propensity to cause disease. Preliminary analyses of its genome did not find certain disease-causing genes known to exist in other bacteria. However, some studies have shown that U. urealyticum causes tissue damage, so Dr. Glass suspects such "virulence" genes exist in the bacterium, but that they're different enough from known genes that scientists will have to look harder to find them. Scientists might even discover a whole new class of such genes, Dr. Glass speculates.

Despite their many questions, the researchers do have some answers. Here are highlights from the initial analysis of the genome:

• The genome of U. urealyticum is the second smallest of any sequenced microbe, consisting of only 751,719 DNA base pairs. (For comparison, a typical bacterium has millions of base pairs of DNA, and the human genome contains about 3 billion.).

• The U. urealyticum genome consists of 652 genes, half of which have unknown functions. Some of these mysterious genes are similar to genes identified in other organisms, but more than half of them have never been seen before.

• This bacterium has a novel metabolic system. Like all bacteria of the genus Ureaplasma, it can "digest" urea, a substance commonly found in urine. But U. urealyticum apparently possesses enzymes that metabolize urea differently than any known bacteria.

The genome sequence of U. urealyticum will be compared with the sequences of other sexually transmitted bacteria in order to search out any commonalities. "The sequence is now available in a relational database designed to make comparisons between organisms that damage the reproductive tract," says project officer Penelope J. Hitchcock, D.V.M., chief of NIAID's Sexually Transmitted Disease branch. To date, the genomes of five STD-causing bacteria have been sequenced with NIAID support, and that information, along with the gene sequences of other STD pathogens, is made widely available to researchers via the STDGEN Web site at http://www.stdgen.lanl.gov .

Finally, the U. urealyticum genome was sequenced with a new technique, developed at PE Biosystems, that allowed just two researchers using one automated sequencing machine to complete the work in 21 months. The effectiveness of such a "micro-sequencing center" may encourage other small, academic labs to take on genome projects of their own.

In addition to NIAID, this effort was supported by the Department of Microbiology of the UAB, PE Biosystems, and Eli Lilly and Company.

NIAID is a component of the National Institutes of Health (NIH). NIAID supports basic and applied research to prevent, diagnose, and treat infectious and immune-mediated illnesses, including HIV/AIDS and other sexually transmitted diseases, tuberculosis, malaria, autoimmune disorders, asthma and allergies.

Press releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov

• For more information on NIAID-supported microbial genome sequencing projects, check http://www.niaid.nih.gov/dmid/genomes/ .

The National Institute of Allergy and Infectious Diseases is a component of the National Institutes of Health, U.S. Department of Health and Human Services.