Science / Medicine : Genetic Mapping Charts New World : Cells: Research projects are demonstrating that humans are not as different from other species as they have long imagined themselves to be.
Many people have heard about the Human Genome Project, the $3-billion, 15-year effort to map the 50,000 to 100,000 genes that make up the blueprint for human life. It’s one of the federal government’s “Big Science” projects, along with the $6-billion Superconducting Supercollider and the $1.4-billion Hubble Space Telescope.
But how many know about the Mouse Genome Project? Or the Rice Genome Project? How about the efforts to map the genes of worms, tomatoes, yeast, fruit flies, wheat, onions, lettuce, bacteria, or a tiny weed called Arabodopsis?
The projects have a functional purpose: Mapping the genes of fruit flies and the tiny nematode worm, Caenorhabditis elegans, for example, will help scientists understand similar biochemical functions in humans, such as how vision works and how cell death occurs. Tracking rice and wheat genomes may keep the world’s burgeoning population from famine. The mouse project, among other things, will help those tackling the enormous human genome project by validating mapping techniques.
But the projects are also contributing to an overriding theme: that humans are not as different and separate from other species as they have long imagined themselves to be.
“The real message is that all of life is extremely similar,” said Tom Roderick, senior staff scientist at the Jackson Laboratory in Bar Harbor, Me. “We’re all humming and moving along together--our cells are behaving very similarly.”
Mapping various plant and animal species’ genomes is the key to unraveling the chemical blueprint that determines the characteristics of all living organisms, such as resistance to a particular disease in lettuce, or the cause of a disease such as Alzheimer’s in humans.
Mapping a genome consists of locating landmarks or identified genes on a chromosome. Genetic mapping links a particular gene to a chromosome by studying the expression of that gene through successive generations.
This type of mapping has been going on since 1911, when the gene for human color blindness was traced through several generations of families. It was linked to the gene that determines female gender, and thus determined to be on the X chromosome.
With the advent of recombinant technologies in the 1970s, scientists began to isolate a piece of DNA--the genetic blueprint of life--with restriction enzymes that cut a specific sequence along the chain, then clone it and make more detailed physical maps. Physical maps use these molecular techniques to locate genes or identified sequences of DNA associated with genes on a particular part of a chromosome.
Humans have 3 billion chemical-letter steps, or base pairs, arranged into 23 pairs of chromosomes. On them are 50,000 to 100,000 genes. The most definitive mapping--sequencing--will identify all the base pairs in the genome in order, from one end of each chromosome to the other.
The physical maps for two single-cell organisms--baker’s yeast and the bacteria Escherichia coli are essentially complete. In the animal kingdom, the nematode worm, C. elegans , is close behind, and is one of the more amazing projects to come out of biology.
The story of the nematode began with Sydney Brenner, an English scientist at the Medical Research Council’s Laboratory of Medical Biology in Cambridge, who set a goal in 1963 to know all there was to know about a many-celled animal. He chose a tiny transparent worm no longer than a millimeter. Three hundred can fit in a biologist’s petri dish. Their life span is only three days.
After nearly three decades of research, Brenner and his graduate students, who continued the project at their own labs, now know that this little worm has 959 cells. Like constructing a family tree, the scientists have traced the lineage of each cell to the original egg cell. They have also completed a wiring diagram of the 302 neurons (humans have 100 billion neurons) and connections that make up the worm’s nervous system.
Now that the physical map is nearly complete, scientists have decided to sequence the worm’s 100 million base pairs, with its 3,000 to 8,000 genes. When that is done, a project estimated to last 10 years, they will know more about this tiny worm than any other multi-celled animal.
Having that coding information will help scientists study biological mechanisms in other organisms, said Robert Horvitz, professor of biology at the Massachusetts Institute of Technology in Cambridge, Mass., who researches cell death.
By identifying the series of genes involved in cell death in the worm, he will have more information for studying cell death in humans. “Clinically, it’s very important,” he said. “There are lots of neurodegenerative diseases where cell death is involved: Alzheimer’s, Parkinson’s. It’s a very basic component of stroke, trauma and heart attack.”
The fruit fly, the mainstay in the study of genetics, also can provide clues to human functions, and the effort to map its genome began three years ago. For example, said Dan Hartl, head of the genetics department at Washington University School of Medicine in St. Louis, some components of the fruit fly’s visual system are the same in humans. “We can identify what receives light, how that protein signals the next protein, and how it changes to tell the organism that it’s seen something,” he said.
The physical map of the fruit fly should be completed in two or three years, and then, Hartl said, it’s on to sequencing. “I want to identify and sequence all the genes in (the fruit fly),” Hartl said. “I’m still young enough--47--that it will be done in my professional lifetime.”
For years, the model species for the plant world has been a weed called Arabodopsis, “a miserable little beast,” said Richard Michelmore, a UC Davis lettuce researcher. “It’s the green thing you see between the cracks in the pavement.”
But its relatively small number of base pairs--70 million--and the ability to grow eight to 12 life cycles a year, prompted the founding of a cooperative genome project this year. It is funded by the U.S. Department of Agriculture, the U.S. Department of Energy, the National Institutes of Health and the National Science Foundation.
A separate project--the Plant Genome Project--has scientists scrambling for the $11 million that the USDA will spread among those mapping rice, wheat, barley onion, corn, wheat, soybean, tomato, lettuce and “some of the smaller veggies,” according to project director Jerome Miksche of the U.S. Department of Agriculture.
But some scientists are not relying only on the USDA. Michelmore, who completed a map of lettuce’s nine chromosomes (consisting of 2 billion base pairs), receives part of his funding from California lettuce growers. He does not care about sequencing the entire genome. Instead, he is focusing on isolating genes for disease resistance, with the goal of incorporating them into lettuce crops.
“Disease resistance is a hot topic,” he said. “We don’t know how it works in any organism.”
Ray Rodriguez, a UC Davis genetics professor, began coordinating a U.S.-Japanese effort to map the rice genome two years ago, after he learned that Japan had started its own rice genome project. His primary concern in pushing the project is to ward off world famine.
In the 1970s, the worldwide production of rice, which is a primary source of nutrition for 60% of the world’s population and is 80% of the caloric intake of 2 billion Asians, accelerated as a result of the Green Revolution that spread the results of classical plant breeding to other countries. “Now we’re in a race to keep up with population demand,” Rodriguez said. “We’re looking for some way to create a second Green Revolution.” With the acceptance of the Human Genome Project, he decided the time was ripe for rice.
Although genetic engineering of plants has been touted as a solution to feeding the world’s future millions, it is a long-term solution, Rodriguez said, at least 20 years away. But the demand for rice will double within the next 20 years.
A short-cut is to map the genes on rice chromosomes, enabling plant breeders to use genetic probes to determine if desired genes, such as those for salt tolerance or drought resistance, have survived in offspring of cross breeding.
The genome project most closely linked to the Human Genome Project is that of the mouse, which officially began on Sept. 1, although scientists have been mapping parts of mouse chromosomes for years. So much of mouse and human DNA is alike--more than 90%--that some scientists suggest that the mouse genome be mapped before the human one.
Since mice can be inbred to track genes--something that cannot be done in humans--it will be easier to develop the genetic maps more quickly. “But, for political reasons, the interest is in getting the human genome done,” said Joe Nadeau, a Jackson Laboratory scientist working on the project.
Early medical benefits from the human genome project will come from identifying genetic diseases and devising tests to detect those diseases in people.
The quintessential laboratory animal model, the mouse has 20 chromosomes, with about the same number of base pairs and genes as humans. Many scientists study the mouse and the human genome together.
That approach provides clues to molecular evolution by determining what parts of the DNA sequence were conserved in humans when the human and mouse trees separated 65 million to 70 million years ago. It also helps those looking for human disease genes by finding the same disease genes in the mouse first to figure out where to look on the human genome.
So far, of the 2,720 loci--genes and DNA markers associated with genes--located on the mouse map and 1,884 located on the human map, 535 are the same. “I know there are going to be lots more,” said Roderick.
“It’s healthy for human beings to know that we aren’t somehow different and apart and special,” Roderick said. “If you take the origin of life on Earth and make it the height of the Washington Monument, human beings are a postage stamp on top, proving we’re still an experiment. To think that our special brain is going to keep us going isn’t necessarily true. Evolution is trying out intelligence. It may not work.”
Simple Combinations Make Up Complex Ladder of DNA
All genes--whether in plants or animals--are made up of DNA--deoxyribonucleic acid. DNA is made up of four chemical bases: adenine (A), thymine (T), cytosine (C) and guanine (G). These bases, arranged in pairs (A bonds with T, C bonds with G), form the steps of DNA’s twisting ladder, known as the double helix.
Genes are chains, or sequences, of these chemical-letter steps along the DNA. They code for particular proteins that perform the functions necessary for cells to function. In between the genes are long stretches of “junk” DNA, described as such because scientists don’t yet know its function. The DNA in a cell is divided into long, thin strands called chromosomes that wind throughout the nucleus of a cell. During cell division, these chromosomes constrict into short, fat segments resembling rice grains and can be seen under a microscope. All the DNA in a cell’s chromosomes is called a genome.
Humans have 3 billion chemical-letter steps, or base pairs, arranged in 23 pairs of chromosomes. On them are 50,000 to 100,000 genes. (An average gene is made up of about 30,000 base pairs.) Fruit flies, on the other hand, have about 10,000 genes on 165 million base pairs arranged into four chromosomes. One would expect that humans, being so complex, would have more genetic material than any other species. They don’t. Wheat has 4 billion base pairs. Pine trees have 5 billion. Salamanders have 90 billion. But all have fewer genes than humans.
