STAR makes rats appealing for genetic research

Rats have been used as laboratory animals for over a century. Over 500 strains of rats have been bred which are particularly susceptible to common diseases such as high blood pressure, arthritis or diabetes. They are used in the examination of the physiology of diseases and the efficacy and tolerability of new medicines. These homogenous strains make it easier to identify genes related to the disease and if the gene has been discovered in rats, it is easier to find in humans.

For this purpose, the variations in the rat strains genomes have to be analysed in as much detail as the physiological variations have already been. Researchers of the international STAR consortium have set themselves this task [STAR is RATS, backwards]. Professor Norbert Hübner, head of a research group at the Max Delbrueck Center in Berlin-Buch and coordinator of the STAR project, explains that their aim was to establish subtle variations in the genome showing differences between the rat strains. Above all, they wanted to map variations in individual sequences of the genome, so-called SNPs. If the SNPs’ relative positions can be established, the genome can be mapped. The SNPs act as milestones. The closer together they are, the more precisely one can orient oneself in the genome. Dr Kathrin Saar of the Buch-based working group and project manager in the STAR consortium says that they have already found about three million new SNPs and have mapped over 20,000 SNPs which are evenly distributed throughout the genome in more than 200 frequently used rat strains. Now they can make statements about the genetic relationships of the strains. This means that detailed genetic maps are now available for the functional analysis of variations in the genome. This gives researchers the chance to start with rat models when they are hunting for genes which are relevant for common human diseases.

Hübner’s working group has used this new tool of rat genetics to find variations in the genome which are connected to cardiac insufficiency. “We chose the rat model because there is a rat strain which reflects the clinical picture of human cardiac insufficiency extremely well. These rats spontaneously develop high blood pressure and later in life they tend to develop cardiac insufficiency. They are known as SHHF rats,” Huber explains. “Animals of a different strain, so-called SHRSP rats, have similar blood pressure levels but tend not to suffer from cardiac insufficiency.” To find the variations in rat genome associated with cardiac insufficiency, the Buchbased research group aim to compare the genomes of rats with high blood pressure and cardiac insufficiency, those with high blood pressure but healthy hearts and those with normal blood pressure.

Rats from the strain with a tendency to cardiac insufficiency have been crossed with rats from other strains. Both cardiovascular and genetic data were analysed in the offspring. From the genetic variations associated with cardiac insufficiency, the Buch researchers were able to identify a gene which favours the development of cardiac insufficiency in rats. It is the gene for the enzyme soluble epoxy-hydrolase.

In rats with a tendency to cardiac insufficiency, a variation in the gene caused an increase in amounts of the enzyme and thus to excessive hydrolase activity. Because the enzyme metabolises substances which protect the heart muscle, excessive activity can lead to cardiac damage. In order to find out if the increased amounts found in the rats also apply to other animals, further experiments were carried out. Tests on mice and on tissue samples from cardiac insufficiency patients confirmed the Buch researchers’ interpretation that the faulty regulation of epoxy-hydrolase increases the likelihood of cardiac insufficiency not only in rats, but also in humans. Hubner believes that this could enable new approaches to treatments for cardiac insufficiency: the findings provide the scientific basis for trials of active ingredients which restrict the epoxy-hydrolase.