A large team of researchers, including a University computer scientist, has effectively completed the genome sequence of the common laboratory brown rat, Rattus norvegicus.
This will make the third mammal to be sequenced, following the human and mouse.
The Rat Genome Sequencing Project Consortium was led by the Human Genome Sequencing Center at the Baylor College of Medicine, in conjunction with the National Heart, Lung, and Blood Institute and the National Human Genome Research Institute (NHGRI).
Michael R. Brent, Ph.D., associate professor of computer science and engineering, contributed to the analysis of the gene set.
The consortium announced March 31 the generation and analysis of the genome sequence of the Brown Norway rat. The high quality ‘draft’ sequence covers more than 90 percent of the genome.
The primary results were presented in the April 1 issue of Nature, and an additional 30 manuscripts describing further detailed analyses are in the April issue of Genome Research.
“This is an investment that is destined to yield major payoffs in the fight against human disease,” said National Institutes of Health Director Elias A. Zerhouni, M.D. “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.”
The laboratory rat is an indispensable tool in experimental medicine and drug development and has made inestimable contributions to human health. The new data expand and consolidate its role as a research resource.
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 Francis S. Collins, M.D., Ph.D. “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.”
According to Brent, results from the study show that the change from the last common ancestor of rodents and humans has occurred much faster along the rodent branch than change along the human branch. Also, the study finds that approximately one-fourth of the human genome is shared with both rats and mice.
That’s approximately 825 non-repetitive megabases of DNA shared by all three animals.
“It’s surprising that the amount of shared DNA is so small,” Brent said.
Relative to their last common ancestor, the rodent lineage has mutated more than the human lineage, Brent pointed out, while analysis of the human genome reveals significantly more segmental duplication — a biological process whereby a large piece of the genome is copied in small numbers. Segmental duplications are one of the key things that differentiate the human genome from that of chimpanzees, and may contribute to the physical and behavioral difference between the two species.
Rodent mutation is due to various different factors, an obvious one being generation time — they reproduce faster than humans. The results of the analysis show that the rat has mutated slightly more frequently than the mouse from the last common ancestor.
“It’s not clear how to explain that, because they both have the same generation time,” Brent said.
Results also show there is nearly two times more mutation in the brown rat male germ line than the female germ line, perhaps because there are more cell divisions along the path to making a sperm than the path to making an egg, and thus more chance for error.
Females carry two X chromosomes and males one. The study finds less mutation in the X chromosome than in chromosomes equally divided between males and females.
The study found the rat genome contains similar numbers of genes to the human and mouse genomes, but at 2.75 gigabases (Gb) is smaller than the human’s (2.9 Gb) and slightly larger than the mouse’s (2.6 Gb).
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.
Examples of use of the rat in human medical research include surgery, transplantation, cancer, diabetes, psychiatric disorders (including behavioral intervention and addiction), neural regeneration, wound and bone healing, motion sickness and cardiovascular disease.
Researchers at Baylor have now undertaken the genomes of the honeybee and sea urchin and are working on 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.