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UC Berkeley collaboration with Celera Genomics concludes with publication of nearly complete sequence of the genome of the fruit fly
24 Mar 2000

By Robert Sanders, Public Affairs

BERKELEY -- In a unique collaboration between industry and university scientists, researchers this week reported the complete sequence of nearly all the genes on all the chromosomes of the fruit fly, Drosophila melanogaster.

The feat, achieved in record time with new techniques pioneered by Celera Genomics Corp. of Rockville, Md., is reported in three articles in this week's issue of Science magazine by Celera and the Berkeley Drosophila Genome Project (BDGP), based at the University of California, Berkeley, and Lawrence Berkeley National Laboratory. The BDGP, directed by Gerry Rubin, professor of genetics in the College of Letters & Science, teamed up with Celera last February in an attempt to speed up sequencing of the fruit fly genome.

"This should accelerate things quite a lot, allowing us to finish in a year rather than another three years, which was the original plan," Rubin said last year. The scientists met their goal, depositing most of the sequence of the fruit fly genome in a public database, GenBank, by the end of last year, for use free of charge by researchers around the world.

The sequencing of the fruit fly genome is an important milestone on the road to sequencing the entire human genome, Rubin said.

"Because the fruit fly is more similar to humans than any other animal sequenced so far, its genetic information can be directly related to humans in many cases," he said. As one of the most popular research animals for geneticists, he added, "the animal has provided an extraordinarily deep and broad understanding of the function of genes in disease."

Principal authors of the papers are Rubin and Suzanna Lewis, leader of the informatics group in the BDGP; Sue Celniker, leader of the LBNL team; and Mark D. Adams, PhD, vice president, genome programs; Eugene Myers, PhD, vice president, informatics research, and J. Craig Venter, PhD, president and chief scientific officer of Celera.

The Science papers, one with 192 authors, outline the sequencing, assembly and analysis of the fruit fly genome, which the scientists declare is "substantially complete." Celera estimates that the sequences published today containing the fruit fly's genetic information have an accuracy of greater than 99.99 percent. The first insect and the largest organism sequenced to date with 120 million base pairs, the fruit fly is also the first organism with a central nervous system to be sequenced.

"This unique collaboration between Celera and the publicly funded researchers at BDGP has been one of the most successful academic collaborations that I have been involved in during my 30-year scientific career. It should serve as a model for future collaborations," Rubin said. "We now have a complete Drosophila genome 18 months sooner and millions of dollars cheaper than anyone expected."

Rubin said that because of this cost and time savings, researchers could now move forward sooner in delving deeper into the fly genome, possibly uncovering the functions of many of the genes.

Using a technique called "whole-genome shotgun sequencing," the team at Celera and BDGP identified 13,601 genes on the four chromosomes of the fly. The accuracy and degree of completeness was confirmed by analysis using data supplied by BGDP. Of the 289 genes known to cause diseases in humans, researchers discovered about 175 of them in Drosophila melanogaster. These genes cover a wide range of diseases including cancer, neurological and cardiovascular disorders, and malformation syndromes.

"One of the advantages of the whole-genome shotgun technique in sequencing genomes is that gene discovery is an immediate by-product," said Celera's Mark Adams. "The discovery of approximately 60 percent of the genes known to cause human disease is an example of how Drosophila research and the whole shotgun sequencing technique can speed gene discovery and could aid researchers in more efficient and cost effective drug development."

One article published this week in Science compares the genomes of three organisms sequenced to date: the fruit fly, the roundworm Caenorhabditis elegans and common bakers yeast, Saccharomyces cerevisiae.

That paper, authored principally by Lewis and Rubin of UC Berkeley, notes that the worm and fruit fly have very nearly the same number of proteins, despite the evolutionary gap between them. The number is only twice that of yeast, which is even more removed from the others.

"This is perhaps counterintuitive, because the fly, a multicellular animal with specialized cell types, complex development and a sophisticated nervous system looks more than twice as complicated as single-celled yeast," the researchers write. "The lesson is that the complexity apparent in the metazoans (multicellular animals) is not achieved by sheer number of genes."

Rather, they say, animals got more complex by using existing proteins in new ways, including segregating proteins in different places and using them at different times to achieve a new function.

The new fruit fly genome sequences are bound to help scientists attack problems of human disease and development much more effectively, and open new areas of research, they conclude.

"The availability of the annotated sequence of the Drosophila genome enhances the fly's usefulness as an experimental organism," they wrote, adding, "the relative simplicity and manipulability of the fly genome means that we can address some of these biological questions much more readily than in vertebrates."

The fruit fly has been an important animal in genetics studies for most of this century, since Thomas Hunt Morgan chose it for study in 1910. Genetic experiments in the fly have revealed many important features, including the signals - those, for example, that make the head form at one end of the body and the tail at the other - that establish body regions. Genes that control organization of the fly's body also have counterparts in humans and can help explain developmental problems that result in birth defects.

The fruit fly sequencing project was first funded in 1992 by the Human Genome Project, with UC Berkeley as the base of operations and Rubin as head of a consortium of universities and federal labs. The plan was to sequence the fruit fly's 150 million base-pair genome by 2001. By the time BDGP teamed up with Celera, researchers at UC Berkeley had already produced about 20 percent of the fly's DNA sequence in high-quality form.

Researchers at Celera, a business unit of The Perkin-Elmer Corporation, employed their shotgun sequencing strategy to attack the fruit fly genome. The whole-genome shotgun method produces sequences from many small, random DNA fragments, using high-throughput machines. By combining sequences with map information and additional sequences provided by the UC Berkeley group, the team assembled the data into long stretches of correctly ordered, continuous genomic sequence.

To date Venter has wielded the whole-genome shotgun method to sequence the much smaller genomes of nearly a dozen bacteria, including Hemophilus influenzae, the cause of various respiratory and neurologic infections. Celera is now hard at work on the much larger human genome.

"This is an exciting day for Celera. Not only has the whole genome shotgun technique been proven in the very large and complicated Drosophila genome, but we have done it in the context of an extremely successful collaboration with Dr. Rubin and researchers at the Berkeley Drosophila Genome Project and Baylor University," said Dr. Venter. "This bodes well for our ability to assemble the human genome."

The BDGP is a consortium of research groups working at UC Berkeley, Lawrence Berkeley National Laboratory, Baylor College of Medicine and Carnegie Institution of Washington. It is funded by the National Institutes of Health, the Department of Energy and the Howard Hughes Medical Institute.


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