March 24, 2000
Drosophila Genome Sequence Completed
The common fruit fly, Drosophila melanogaster, has been the
workhorse of biology and genetics laboratories for the past 90 years.
Now the entire Drosophila genome has been sequenced through the
collaborative effort of researchers from the Drosophila Genome
Project Group, led by Howard Hughes Medical Institute (HHMI) vice
president Gerald Rubin at the University of California Berkeley, and
researchers led by J. Craig Venter at the Celera Genomics
Corporation.
The Drosophila genome sequence was published in the March 24,
2000, issue of Science. The researchers report that they have
sequenced 97 to 98 percent of the genome and perhaps 99 percent of the
estimated 13,600 genes. The sequence data will be accessible to
scientists worldwide through Genbank, the National Institutes of Health
genetic sequence database.
“If you give people very efficient tools for figuring out the functions of genes, you can do it in a massively parallel way.”
Gerald M. Rubin
In an accompanying editorial in Science, Thomas Kornberg at
the University of California, San Francisco, and HHMI investigator Mark
Krasnow at Stanford University, report that the Drosophila
sequence will be a "critical resource" for research in genetics,
biology and medicine.
Over the years, Drosophila has been one of the most
influential model systems for geneticists. "The conservation of
biological processes from flies to mammals extends the influence of
Drosophila to human health," write Kornberg and Krasnow. "When a
Drosophila homology of an important but poorly understood
mammalian gene is isolated, the arsenal of genetic techniques in the
Drosophila system can be applied to its characterization."
The Drosophila sequencing project was launched in 1991 when
Rubin and HHMI investigator Allan
Spradling at the Carnegie Institution decided, says Rubin,
that the time was right to begin a fly genome project. In May
1998, the Berkeley Drosophila Genome Project was one year into a
three-year NIH grant and had finished 20 percent of the sequencing,
when Rubin was approached by Venter with what Rubin calls "an offer
that was too good to turn down."
Venter proposed that his newly-formed company, Celera, would
sequence the Drosophila genome free-of-charge using a
controversial technique known as whole genome shotgunning. The
technique requires shearing the Drosophila DNA into three
million random clones with overlapping ends. These clones are then
sequenced by automated DNA sequencing machines—at Celera, some
300 sequencers, each costing $300,000—and then massive computing
power is put to work to assemble the complete genome sequence in a
process similar to reconstructing a jigsaw puzzle.
Venter formed Celera with backing from PE Corporation (formerly
known as Perkin-Elmer Corporation), which makes the DNA sequencing
machines, as a commercial venture to sequence the human genome by 2001,
several years before the date projected for completion by the
international Human Genome Project. While promising the data would be
made available to researchers, Venter was also betting that Celera
could make money by licensing early looks at the sequencing data to the
pharmaceutical industry.
The Drosophila genome, says Mark Adams, Celera's vice
president for genome programs, would be "a proof-of-principle" for the
whole genome shotgun strategy. "It seemed like a good idea to do a
medium-sized organism in which there was extensive scientific
interest," he says, "and in which there was already a lot of good
information available in terms of map and sequence data that we could
use to validate the strategy."
While Rubin says he had some concern about working with Celera, he
was delighted by the offer nonetheless. "Anyone who would help me get
the Drosophila sequence done and out of the way was my friend,"
says Rubin. "They were offering to do all this work in a collaborative
way and not expecting any money for it."
Celera started the sequencing last April and finished collecting the
raw data in early September. "Since then," says Rubin, "we've been
putting all the pieces together, which is not trivial. It's the big
challenge of the whole genome shotgun approach."
The finished genome already seems to be remarkably revealing. Of the
289 genetic flaws known to cause disease in humans, says Rubin, they
have found Drosophila homologues for 60 percent and for 70
percent of the genes involved in human cancers. Among the genes that
have already been identified are Drosophila homologues of genes
involved in Parkinson's disease, and the long-sought Drosophila
homologue of the p53 tumor suppressor gene, which is implicated
in a host of human cancers.
The biggest surprise to come out of the Drosophila sequencing
project, says Rubin, is that flies have only twice as many genes as
yeast. "Yeast is a simple, single-cell fungus, " says Rubin, "and yet
flies only need twice as many genes to make an animal that can fly
around without crashing into walls, has tissues, nerves, muscles,
memories and other kinds of complicated behaviors like circadian
rhythms. The take-home message is that the higher complexity in animals
like flies and humans comes without needing a lot of new parts. You can
build them with the same parts list—with more of the same parts
organized together—in much the same way a supercomputer can be
built from a bunch of desktop PCs hooked together in parallel."
Rubin sees the genome drastically changing the pace of his research.
With less than 15,000 genes in Drosophila, and some 5,000
researchers worldwide working on the organism, he says, "that's one
human being for every three genes. If you give those people very
efficient tools for figuring out the functions of genes, you can do it
in a massively parallel way." Moreover, the full Drosophila
sequence allows researchers to look at multiple genes simultaneously to
understand the complex signal transduction pathways that regulate
cellular processes. "That is where the genome project really comes into
play," he says. "It enables us to know all the genes so we can look at
all of them at once and see what they're doing. "
At the Princess Margaret Hospital in Toronto, researcher Tak Mak
says he has been working to understand the signal transduction pathways
involved in cancer formation. "The easiest way to understand that would
be some kind of a genetic screen." As a result he has recently
dedicated one-third of his laboratory to Drosophila genetics in
anticipation of the publication of the sequence. "It will make
Drosophila genetics relatively easy," he says.
Whether the whole genome shotgun technique will work as impressively
for the human genome is now the next question. Celera's Adams says the
Drosophila work is obviously encouraging, and that Celera's
human sequencing work has already begun and should "start to look like
a genome" toward the end of the year. Rubin says, "It worked better in
Drosophila than most people expected it would. I think it will
work for humans. But the problems are more complex for humans, so we'll
have to wait and see."
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