Team Including Penn State Researchers Announces Completed Gene Sequencing of Laboratory Rat

The Rat Genome Sequencing Project Consortium, in conjunction with the National Heart, Lung, and Blood Institute and the National Human Genome Research Institute at the National Institutes of Health, has announced the generation and analysis of the genome sequence of the Brown Norway (BN) rat. The consortium’s primary report of a high-quality “draft” sequence that covers over 90% of the rat genome was published in the journal Nature. An additional 30 manuscripts describing further detailed analyses were featured in Genome Research.

Ross Hardison, professor of biochemistry and director of the Penn State Center for Comparative Genomics and Bioinformatics, participated in the press conference at the headquarters at the National Press Club in Washington, D.C. Researchers in the Penn State center, which is part of the Huck Institutes of the Life Sciences, are using the rat genome, along with the previously published mouse genome, to learn how the human genome functions. The Penn State group is part of an international team with over 20 groups in 6 countries that are performing analyses of the newly sequenced rat genome.

“The consortium knows that the laboratory rat is an indispensable tool in research on experimental medicine and drug development," Hardison says. “We are using comparative approaches to help translate these genome sequences into applications that improve human health." Along with the human and the mouse genomes, the rat sequence is the third mammalian genome to be sequenced to a high degree of quality and to be described in a major scientific publication. Almost all human genes known to be associated with diseases have counterparts in the rat genome and appear to be highly conserved throughout the evolution of mammals. The new data expand and consolidate the role of the rat as a resource in medical research. In addition, Hardison explains, three-way comparisons of the rat genome with the human and mouse genomes will help to resolve details of the evolution of mammals. “What we learn about the mechanisms of evolution help us to predict the function of DNA sequences,” he says.

In a collaborative effort between research groups headed by Hardison and Webb Miller, professor of biology and computer science and engineering, Penn State has been developing software for aligning long genomic sequences and analyzing the results since about 1989. The specific pattern of such sequences—the DNA building blocks that make up a genome—records all the information needed for an organism to develop from a fertilized egg to an adult. However, some sections of the DNA structure have important functions and others do not. “It is a particularly difficult challenge to learn all the functional DNA sequences for any organism—especially for the human genome because of its large size,” Hardison says. “Because functional sequences should not change as much during evolution as nonfunctional sequences, the best way, currently, to find a large proportion of these important sequences is by comparison with genome sequences of related species,” he explains.

Hardison’s and Miller’s groups, along with Francesca Chiaromonte, assistant professor of statistics, joined the Mouse Genome Sequencing Consortium in 2001 to meet the challenging but important goal of aligning the entire human genome—almost 3 billion nucleotides—with the entire mouse genome—about 2.5 billion nucleotides—at high sensitivity and specificity in order to find the likely functional DNA sequences. By working with collaborators at the University of California at Santa Cruz, headed by David Haussler and Jim Kent, the team computed and made public whole-genome alignments shortly after the mouse genome was assembled in 2002. In 2003, the team—which now included Anton Nekrutenko, assistant professor of biochemistry and molecular biology, and Kateryna Makova, assistant professor of biology—joined the Rat Genome Sequencing Project Consortium to compute and analyze alignments among human, mouse, and rat genomes. “The 3-way alignments are even more challenging to compute, but we were able to do it with the software and methods our team developed shortly after the rat assemblies were available,” Hardison says. The results have been made public on the web, both at the Penn State Genome Alignment and Annotation Database (GALA) and at the UCSC Genome Browser.

“The rat data show that about 40% of the modern mammalian genome derives from the last common mammalian ancestor and that these ‘core’ one-billion bases encode nearly all the genes and their regulatory signals, accounting for the similarities among mammals,” Hardison reports. These parts of the genome will be of particular focus in other mammals as new genomes are explored, and the events leading to the current species are unraveled.

“This work is an investment that is destined to yield major payoffs in the fight against human disease,” said NIH Director Elias A. Zerhouni. “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.”

Current examples of use of the rat in human medical research include surgery, transplantation, cancer, diabetes, psychiatric disorders such as behavioral intervention and addiction, neural regeneration, wound and bone healing, space motion sickness, and cardiovascular disease. In drug development, the rat is routinely employed both to demonstrate therapeutic efficacy and to assess toxicity of novel therapeutic compounds prior to human clinical trials. The high-quality genome sequence of the rat will facilitate all of these studies.

“The sequencing of the rat genome constitutes another major milestone in our effort to expand our knowledge of the human genome,” said National Human Genome Research Institute Director Francis S. Collins. “As we build upon the foundation laid by the Human Genome Project, it has 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.”

Barbara K. Kennedy and Ross Hardison (Penn State)
and Heather Bonham (Baylor College of Medicine)