Although several of them will fit on the head of a pin, the tiny roundworm, known by its scientific name as Caenorhabditis elegans, made it big today as Human Genome Project researchers in the United States and Great Britain announced they have sequenced the animal's 97 million-base genome. It marks the first time scientists have spelled out the instructions for a complete animal, that, like humans, has a nervous system, digests food, and has sex.
The work, carried out at Washington University School of Medicine in St. Louis and the Sanger Centre in Cambridge, England, is published in the December 11 issue of the journal Science.
"This is a tremendously gratifying moment and more of a beginning than an end," said Robert Waterston, leader of the St. Louis group that worked eight years to complete the job. "We have provided biologists with a powerful new tool to experiment with and learn how genomes function. We'll be able to ask-and answer-questions we could never even think about before."
John Sulston, who led the Medical Research Council group at the Sanger Centre, said, "When Bob and I started studying genetics in the worm in the mid-1980s it became clear that the best way to find the genes we were looking for was to sequence the whole genome. Sure enough, what we have now found in that genome far surpasses what we could have imagined."
Though most people have never heard of the short worm with the long name-the animal measures about 1 millimeter from end to end; about 40 of them would span the words Caenorhabditis elegans-they live underfoot daily. C. elegans, as scientists call them, inhabit the dirt in temperate regions. A handful of soil may contain thousands of worms, gliding their way through water droplets trapped between soil particles. Some of its nematode cousins are parasites, but dirt-ranging C. elegans prefer a benign existence among rotting plants. Back at the lab, the creatures live in petri dishes on a steady diet of the bacterium E. coli.
Although it occupies a relatively distant branch on the evolutionary tree, C. elegans nevertheless shares many similarities with humans, which makes it an important organism in which to carry out studies that parallel human biology. Unlike the much smaller microbes sequenced so far, C. elegans begins life as a single, fertilized cell and undergoes a series of cell divisions as it grows into an adult animal. During the process, complex tissues and organ systems form. Some 300 of the 959 cells of the adult worm, for example, constitute a nervous system that can detect odor, taste, and respond to temperature and touch. A digestive tube runs the length of the worm's body. Finding a sex partner is never a problem, since most members of the species bear both male and female sex organs and fertilize themselves. Because the animal is literally transparent, its bodily events can be observed under a microscope.
In its two-to-three week life span, C. elegans carries out many of the same processes that humans do: they undergo embryonic development, eat, reproduce, get old, and die. So researchers have found them particularly useful for studying early development, neurobiology, and aging. In fact, every connection in the worm's nervous system has been mapped, and the lineage of each cell in the adult animal's body has been tracked from the moment of fertilization.
The worm's genetic material is packaged on six chromosomes. According to the Science report, analysis of the worm's genome revealed 19,099 protein-coding genes-about one every 5,000 DNA bases-and 800 or so genes that have other functions. That's several times the number of genes predicted by classical genetics experiments. About 40 percent of the 19,099 genes match those of other organisms, including humans. The other 60 percent represent new mysteries awaiting explanation.
The chromosomes themselves look more like human chromosomes than those of bacteria or yeast. They contain large amounts of repeated DNA that doesn't encode proteins but probably plays some role in chromosome function or organizing genes or regulating their activity.
For almost a decade, teams on both sides of the Atlantic snipped and sequenced millions of bits of worm DNA, pasted it into long stretches of documented sequence, and dumped it into a public database. Slowly and with only a few researchers at first, the project grew in size, output, and funding after about 1993. Besides daily e-mail contact, entire lab staff traveled back and forth from St. Louis to Cambridge yearly until they got too big. The group leaders, Waterston and Sulston, later resorted to regular Sunday phone calls.
"Fortunately," said Waterston, "John is a nightowl."
"Scientists are supposed to be lonely people, but it really has been fun and very rewarding working with the talented bunch of people we have on both sides of the Atlantic," Waterston said, "just to watch the combination of minds and talents go to work on this problem."
The two teams shared information not only with each other, but with any scientist who wanted it. "The commitment of these groups to make their sequence data available to the research community right from the start is admirabled," said Francis Collins, director of the National Human Genome Research Institute, a lead player in the Human Genome Project. "It typifies the spirit of the Human Genome Project and is exactly how we plan to operate our sequencing program on the human genome and other model organisms."
In recent years, as the worm sequencers hit their stride, a few dozen sequencing machines hummed round the clock and most days of the week. The first shift arrived at the lab at 5:30 am, according to Waterston, to unload the previous night's run. The last shift, which left the lab at around midnight, kept the machines whirring until dawn. In all, 2 million "reads" spelled out the worm sequence, 500 bases at a time.
For the Human Genome Project, completing the worm genome is another success in a series of on-rushing milestones. Recently, the project announced it would speed up its effort to complete the 3 billion-base pair human genome sequence two years ahead of time, partly because the worm sequencers had established such successful methods for complex genomes. "Bob and John's work gave us a lot of confidence that we could get the human sequence done sooner than planned," said Collins. "Now we are more eager than ever to get the instruction book for a human being."
The worm group at the Genome Sequencing Center in St. Louis is funded by the National Human Genome Research Institute, part of the National Institutes of Health, the federal government's primary biomedical research institution. The worm group at Sanger Centre is funded by the Medical Research Council of Great Britain.
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