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The Rat Genome Unveiled

By Kate Ruder

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Scientists have sequenced the Brown Norway rat, a popular laboratory rat that is also a pet and a pest worldwide.
Scientists have sequenced the genome of the laboratory rat. Although the rat is a nuisance to most people, it is beloved by researchers who study human diseases such as heart disease, diabetes, and addiction, and also by those who develop drugs to treat these disorders.

Today, the Rat Genome Sequencing Project Consortium, an international group of scientists, published an analysis of the rat genome in Nature. In the study, they found that rats have versions of many of the genes that are known to cause disease in humans.

The findings were announced today, but the raw sequence of the rat genome has been available online to scientists worldwide for about 18 months.

“We’re using the rat sequence day in and day out, day after day,” says Michael Gould, a cancer researcher at the University of Wisconsin-Madison, who studies the breast cancer genes BRCA1 and BRCA2.

Last May, Gould and his colleagues were the first to make “knockout” rats, a genetic trick that allows scientists to disrupt specific genes to study how the genes function in rats. The insights can then be applied to humans. Although knockout mice have been a staple of research for some time, the knockout rat is sometimes a better model for human diseases.

Another rat aficionado is Paul Lombroso of Yale University School of Medicine in New Haven, Connecticut, who studies a rat model of Tourette’s syndrome. He also uses rats to investigate how the brain adapts to stimulant drugs taken by some children with Attention Deficit Disorder. For this research, Lombroso prefers rats to mice because their brains are larger and easier to work with.

Led by Baylor College of Medicine in Houston, Texas, the rat sequencing consortium includes 20 groups of scientists from six countries. Among them are Celera Genomics of Rockville, Maryland, the British Columbia Cancer Agency Genome Sciences Centre in Vancouver, and The Institute for Genomic Research (TIGR), also in Rockville.

The researchers sequenced the Brown Norway rat, the most popular rat for laboratory studies, and one that can be found worldwide as a pet and a pest. Most of the rat DNA for the project came from two females, and the rest from a male.

The rat genome was sequenced for close to $120 million. Most of the money came from the U.S. National Human Genome Research Institute (NHGRI) and U.S. National Heart, Lung and Blood Institute.

The rat genome is what scientists call a “draft” sequence, because it is only 90 percent complete. To sequence the remaining 10 percent of the genome—stretches of DNA that are difficult to decipher—would cost more than government agencies are prepared to spend at the moment.

Richard Gibbs of the Human Genome Sequencing Center at Baylor College of Medicine said today at a press conference that there are no immediate plans to complete a final version of the rat genome, but he wouldn’t rule out the possibility.

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Meanwhile, Gould says that he is thrilled about the rat genome sequence, but would like to see it in a more finished form.

“It would be unlucky, but what if a gene that gives resistance to breast cancer is not in the 90 percent they sequenced?” asks Gould. “It’s worth investing the extra money necessary to complete the sequence. That’s a high priority to the [rat research] community.”

The rat genome is smaller than the human genome, but larger than the mouse genome, and all three organisms probably have a similar number of genes, roughly 25,000 to 30,000.

Scientists interested in evolution now have genomes of three mammals to compare and contrast (the human sequence was completed in April 2003 and a draft of the mouse genome was published in December 2002). Having three genomes should help scientists learn more about how we evolved from a common ancestor about 80 million years ago.

Gibbs, R. et al. Genome sequence of the Brown Norway rat yields insights into mammalian evolution. Nature 428, 493-521 (April 1, 2004).
Zan, Y. et al. Production of knockout rats using ENU mutagenesis and yeast-based screening assay. Published online in Nature Biotechnology (May 18, 2003).

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