The Rat Genome Sequencing Project Consortium (RGSPC), led by the Human Genome Sequencing Center at Baylor College of Medicine (BCM-HGSC) in Houston, in conjunction with the National Heart, Lung and Blood Institute (NHLBI) and the National Human Genome Research Institute (NHGRI), announced today the generation and analysis of the genome sequence of the Brown Norway (BN) rat. The high quality 'draft' sequence covers over 90 percent of the genome. The primary results are presented in the April 1 issue of Nature, and an additional thirty manuscripts describing further detailed analyses are contained in the April issue of Genome Research.
A network of centers generated data and resources for the RGSPC, including the BC Cancer Agency's Michael Smith Genome Sciences Centre. Dr. Robert Holt, head of sequencing at the Genome Sciences Centre, was a principal investigator on the project while working for Celera. He became introduced to the Genome Sciences Centre, and subsequently joined the GSC, because of the rat genome project.
"The laboratory rat is an indispensable tool for investigation of common human diseases, including cancer, cardiovascular and neurological disorders," says Dr. Holt. "The full sequence of the rat genome will dramatically accelerate research by facilitating the design of studies to probe these disorders in rats, and facilitate translation of data into an understanding of the equivalent human conditions."
The Genome Sciences Centre has been a key consortium member, and has generated a bacterial artificial chromosome (BAC) fingerprint map of the rat genome, as also accomplished for the mouse genome. For the rat genome effort, the BAC fingerprint map offers an independent view of the genome, and was extremely important in guiding the assembly process – that is, defining the correct order and orientation of the millions of sequence fragments that comprise the raw data set. Drs. Jaquie Schein, Marco Marra, and Steven Jones led the mapping effort at the GSC. The manuscript describing it was accepted for publication in Genome Research. The Genome Sciences Centre receives core funding from the BC Cancer Foundation.
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. The BN 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 study found the rat genome contains similar numbers of genes to the human and mouse genomes but at 2.75 Gb is smaller than human (2.9 Gb) and slightly larger than mouse (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.
Current 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, space motion sickness, and cardiovascular disease. In drug development, the rat is routinely employed both to demonstrate therapeutic efficacy and assess toxicity of novel therapeutic compounds prior to human clinical trials. The genome sequence will facilitate all of these studies.
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. The rat data shows about 40 percent of the modern mammalian genome derives from the last common mammalian ancestor. These 'core' one billion bases encode nearly all the genes and their regulatory signals, accounting for the similarities among mammals. 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.
To ensure a high quality draft, the combined approach used both whole genome shotgun (WGS) and BAC clone sequencing techniques. To merge these into the final draft sequence, the BCM-HGSC developed the Atlas software package for genome assembly. The resulting genome sequence was contained in 291 large segments, with a typical length of 19 Mb. Moreover, the structure of the 3 percent of the genome containing recent duplications, where genes are born, was accurately determined by the Atlas assembler. These statistics match or exceed other draft genome sequences. Overall, the combined approach takes advantage of strengths of previous methods, either pure WGS or pure BAC sequencing, with few of the disadvantages.
The Genome Sciences Centre's vision is to minimize the burden of cancer on individuals and society through genomics research, and the application of genomics technologies. The GSC includes 135 staff, and is home to Canada's largest DNA sequencing, BAC fingerprint mapping and bioinformatics facilities. The GSC was the first lab in the world to sequence the coronavirus associated with SARS.
The BC Cancer Agency, a part of the Provincial Health Services Authority, is committed to reducing the incidence of cancer, reducing the mortality from cancer, and improving the quality of life of those living with cancer. It provides a comprehensive cancer control program for the people of British Columbia by working with community partners to deliver a range of oncology services, including prevention, early detection, diagnosis and treatment, research, education, supportive care, rehabilitation and palliative care. The BC Cancer Research Centre conducts research into the causes and cures for cancer. The Genome Sciences Centre operates with support from the BC Cancer Foundation, Western Economic Diversification, Genome Canada,Genome British Columbia, and the National Institutes of Health (USA).