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| ONE LITTLE MOUSE, ONE GIGANTIC GENETIC LEAP FOR MANKIND |
- Eran Karmon
Of The Post-Dispatch - St. Louis Post-Dispatch (MO)
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- December 8, 2002
- Section: NEWSWATCH
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- Edition: FIVE STAR LIFT
- Page B4
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In the army of medical research, mice are the privates. Each year about 25 million of the rodents are used to provide insight into disease and develop treatments for ailments ranging from cancer to epilepsy to obesity. On Wednesday, more than 200 researchers from Washington University and elsewhere released a draft of the mouse's complete genetic blueprint in the journal Nature. Some scientists say this discovery furthers medical research in ways more profound than the mapping of the human genome. "The mouse has ended up being the ideal model for human disease because they reproduce very rapidly and we have the ability to routinely alter their genetics," said Perren Cobb, director of the Cellular Injury and Adaptation Laboratory at the Washington University School of Medicine. And because we now know that about 99 percent of mice genes have counterparts thought to perform similar biological functions in humans, the ubiquitous lab animal is poised to tell us even more about what the 30,000 or so genes in our own DNA do. "It's really amazing mice turn out the way they are and we turn out the way we are because we are so similar genetically," said Mark Sands, associate professor of medicine and genetics at Washington University. "Because it's so similar to the human genome, much of what we discover in the mouse will be applicable to the human condition as well," he said. "It's not exact, but it's very, very close." For about 20 years, scientists have been able to remove (or "knockout"), insert, or alter particular mouse genes with dead-on accuracy. Over the past five years, the process has become so routine that making a new breed of mouse doesn't even warrant scientific publication. "Making a mouse knockout model is itself no longer a publishable event. It has to be something that tells you a story. In the early days one could get into a reasonable scientific journal just by making a mouse model," says William Sly, chair of Biochemistry and Molecular Biology at Saint Louis University School of Medicine. But the process of identifying which human genes are involved in a certain disease, finding their counterpart genes in the mouse genome, altering or removing those genes, and then breeding several generations of lab mice to make a "mouse model" - a breed of mouse that has the disease or symptoms -was painstakingly slow, taking two to three or more years for each gene. It took from five to 10 years to identify the gene responsible for causing cystic fibrosis in humans, and an additional three years until for the debut of a mouse model for the disease in 1992, Sands said. In the mid-1990s, researchers worked for six years just to identify the defective gene in a mouse model for one form of epilepsy. The completion of the mouse genome makes much of that work a thing of the past because researchers don't have to chemically comb through the mouse genome any more. They can now search computer databases with complete lists of all the mouse genes. "Now that the genome is sequenced, in many cases it could be as simple as making a phone call or searching a computer database to actually get the gene you're looking for," Sands said. "Virtually all the genes are now there for you to ask which ones could be defective in your particular mouse," said Wayne Frankel, senior staff scientist at the Jackson Laboratory in Bar Harbor, Maine, which has developed a number of commonly used mouse disease models. "Before you had to go and find what genes were there and then ask which of those is defective," he said. "What's going to happen is people will now be able to do their gene discovery much faster than they did before." It'll still take a bit of work to identify a gene responsible for a disease, though. Current computer and database technology isn't up to the voluminous task of searching through all 30,000 genes in the mouse database. Old-fashioned biology and chemistry must still be used to first narrow down the general region of the complete genome where the gene of interest may lie, Frankel said. "If there was a way to look at all 30,000 genes at once, it would be faster," he said. "And that'll happen. Probably sooner than we think." Only about five percent of both the mouse and human genomes hold instructions for making proteins, pieces of biological machinery in our cells. These are the 30,000 or so genes. Two categories of DNA make up the remaining 95 percent: Junk DNA, whose function is still a mystery and that changes a lot from generation to generation, and also long stretches of DNA, which don't code for proteins but tell a cell when to make more or less of a particular protein. And even though the entire sequence of DNA for both man and mouse is mapped out, we only know what a tiny amount of it actually does - about a third of the genes. "We don't even know what many of those new genes are, what they do, how they work," says Sands. "On a more global scale, we certainly don't understand how genes interact with each other." "We're still at a rudimentary stage of understanding." Comparing and contrasting the two genomes should help scientists zero in on regions of the genome that perform important biological functions. Even though mice and humans diverged on the evolutionary tree about 75 million years ago, in the grand scheme of things we're pretty close cousins with mice. Because natural selection only acts on pieces of the genome that are biologically important - those that actually control traits in the grown animal - these pieces have over the past 75 million years remained pretty much unchanged. But the pieces of junk DNA in mouse and man have over the years become different through random mutations. So it follows that stretches of DNA that are similar in the two animals are probably the ones that are biologically functional. "So you say, 'Aha! Since they're similar they must be important,'" said Mark Johnston, a genetics professor at Washington University. Now that the most important mammal model's genome is sequenced, we're that much closer to deciphering our own code of life. "It's going to take many, many, many years to decipher all the information," said Sands. "But certainly having that data in front of us is an enormous start towards that goal." === THE NEWS: Last week, scientists released a draft of the complete genetic blueprint of the mouse. THE IMPACT: Because mice and humans are so genetically similar, the discovery promises to lay the groundwork for great strides in medicine.
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