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Consortium completes gene sequencing of laboratory rat

by Ruth SoRelle, MPH

Brown Norway rat

With the announcement of the sequencing of the rat genome, some facts about the Brown Norway rat need to be made clear.

First, it is not from Norway. It is believed to have come from Asia to Europe. It has been best known to the public for its role in spreading diseases such as plague, typhus and hantavirus.

In its role as a laboratory animal model, however, it has speeded understanding of the human organism and the development of drugs. Its value as a laboratory animal has been recognized for nearly 200 years. Most recently it has been crucial in studies of surgery, transplantation, cancer, diabetes, psychiatric disorders, addiction, neural regeneration, wound and bone healing, motion sickness in space and heart disease. It helps scientists understand when a drug is effective and when it is toxic.

Because the understanding of the human organism depends on comparisons to animals used in the laboratory, the announcement the rat genome had been sequenced by a consortium led by the Baylor College of Medicine Human Genome Sequencing Center was met with widespread approval. The primary results are presented in the April 1 issue of Nature, and an additional 30 manuscripts describing further detailed analyses are contained in the April issue of Genome Research. The BCM center directed the project, which was conducted with major funding from the National Heart, Lung and Blood Institute and the National Human Genome Research Institute.

“This is an investment that is destined to yield major payoffs in the fight against human disease,” said NIH Director Elias A. Zerhouni, MD. “For nearly 200 years, the laboratory rat has played a valuable role in efforts to understand human biology and to develop new and better drugs. Now, armed with this sequencing data, a new generation of researchers will be able to greatly improve the utility of rat models and thereby improve human health.”

Major milestone

The Brown Norway rat sequence is the third complete mammalian genome to be sequenced to high quality and described in a major scientific publication. Three-way comparisons with the human and mouse genomes will help to resolve details of mammalian evolution.

“The sequencing of the rat genome constitutes another major milestone in our effort to expand our knowledge of the human genome,” said NHGRI Director Dr. Francis S. Collins. “As we build upon the foundation laid by the Human Genome Project, it’s become clear that comparing the human genome with those of other organisms is the most powerful tool available to understand the complex genomic components involved in human health and disease.”

Peter G.Traber, MD, BCM president and CEO, said, “The genome sequence will further enhance the role of the rat in human medical research, which already has been significant. Scientists have gained a wealth of knowledge in many areas from studies involving the rat, surgery, cancer, cardiovascular disease, diabetes and psychiatric disorders. The genome sequence will boost all of these research efforts.”

The study found the rat genome contains similar numbers of genes to the human and mouse genomes, but at 2.75 billion base pairs is smaller than human (2.9 million base pairs) and slightly larger than mouse (2.6 million base pairs). Almost all human genes known to be associated with diseases have counterparts in the rat genome and appear highly conserved through mammalian evolution. A selected few families of genes have been expanded in the rat, including smell receptors and genes for dealing with toxins, and these give clues to the distinctive physiology of the species.

As the third mammalian genome to be completely sequenced, comparison of the rat genome to human and mouse allows a unique view of mammalian evolution.

“Future work aimed at identifying the genomic differences that contribute to evolution and disease will benefit from analyses such as these, which will become increasingly powerful as the repertoire of mammalian genome sequences expands” said Richard Gibbs, PhD, director of the BCM center and principal investigator of the rat sequencing project.

To ensure a high quality draft, the combined approach used both whole genome shotgun and BAC clone sequencing techniques. The issue of efficacy of whole genome shotgun versus other approaches to the sequencing of large genomes remains a matter of earnest scientific debate, and methodology for producing draft sequences continues to evolve,” said George Weinstock, PhD, co-director of the BCM center.

Future projects

Following the rat project, the BCM center has undertaken the genomes of the honey bee and sea urchin, and is now working on the bovine and Rhesus macaque projects. Like the rat, each will lead to a high quality genome draft sequence. With advances in genome technologies it is likely that genomes from many different species can be analyzed in the next three years.

A network of centers generated data and resources for the project, BCM, Celera Genomics, Genome Therapeutics Corporation, Columbia Cancer Agency Genome Sciences Centre, The Institute for Genomic Research, University of Utah, Medical College of Wisconsin, The Children’s Hospital of Oakland Research Institute, and Max-Delbrück-Center for Molecular Medicine (Berlin). Analysis of the assembled genome was undertaken by 20 groups in six countries.

Funding for the project was largely provided by the National Heart, and Blood Institute and the National Human Genome Research Institute, with additional private funding provided to the BCM Center by the Texas-based Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation.

Nature 428, 493 - 521

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