The laboratory rat has made invaluable contributions to the cardiovascular medicine, neural regeneration, wound healing, diabetes, transplantation, behavioural studies and space motion sickness research. Rats have also been widely used to test drug efficacy and safety. Improved models in all these areas of research should result from our new knowledge of the rat genome.
The genome sequence of the Brown Norway rat was unveiled on 1 April 2004.transgenic rats were announced last year, allowing powerful models of human diseases to be developed.
The rodent's DNA was deciphered and analysed by a collaborative network of researchers, known as the Rat Genome Sequencing Project Consortium, led by the US Baylor College of Medicine. To achieve its goal of producing a high-quality draft sequence, the Consortium developed a new, "combined" approach that used both whole genome shotgun (WGS) and bacterial artificial chromosome (BAC) clone sequencing techniques. To merge these into the final draft sequence, they developed a software package for genome assembly.
The sequence is a high-quality draft of 2.75 billion bases that covers 90% of the genome. It is the third mammalian genome to be decoded, allowing three-way comparisons to be made with the human and mouse genomes. The rat genome is smaller than its human equivalent, but larger than that of the mouse. All three encode a similar number of genes - between 25,000 and 30,000. The new information should enable researchers to determine which characteristics are specific to rodents and which are shared by all mammals.
Around 10% of the rat's genes are both shared with the mouse and absent in humans, including some that code for olfactory proteins. This may explain rodents' exceptional sense of smell. Rats have more genes for breaking down toxins than man. This means that rats may be better at removing toxins from their bodies than humans, so it may be possible to refine the use of rats in toxicology. There are significant distinctions, also, in the genes of the immune system.
Almost all disease-linked human genes have counterparts in the rat. Pinpointing these should help researchers to develop rat genetic models of human disease. Better rat models are likely to decrease drug failure in clinical trials - currently standing at about 90% - which will decrease development costs and time to market. The genome will also throw up new targets for drug intervention.
Recent research in rats may offer a new way of protecting people from cardiac ischaemia, a reduction of blood flow to the heart which can be life-threatening. Researchers at Stanford University in California found that rats with increased activity of the enzyme aldehyde dehyrogenase 2 (ALDH2) have reduced damage following cardiac ischaemia, and have isolated a compound, Alda-1, which activates the enzyme.
A mutation in the ALDH2 gene, which is particularly common in East Asian populations, leads to reduced enzyme activity, and therefore increases the risk of serious damage due to cardiac ischaemia. Giving Alda-1 can activate the mutant enzyme, restoring its activity to normal levels.
- Rat Genome Sequencing Project Consortium. 2004. Genome sequence of the Brown Norway rat yields insights into mammalian evolution, Nature, 428, 493