| The zebrafish is a unique vertebrate model system, it combines excellent embryology with genetics. The latter means that it is possible to identify genes purely on the basis of their function in the intact organism. This function is defined though a mutation. If a mutant lacks eyes it can be deduced that the "broken gene" was required for eye formation. Since in this situation, genes are identified by their function and their sequence is not known, the challenge lies in the molecular identification of the gene. This requires the knowledge of the position of the mutation within the genome and knowledge of the genes, which are located in the same region. Then it has to be figured out which of these genes is the real culprit. For this reason genomics is extremely important in the zebrafish, we need to know where genes are located and we must be able to locate mutations efficiently. This proposal will add to the international effort to identify all genes in the zebrafish genome, and identify their structure and function more precisely. Our approach will also create a toolbox of ready-to-use genes for functional experiments. For some of them we will identify variations that can be used to place them precisely on the genome and to position them relative to mutations. We will work out the most efficient procedure for cloning mutants, basically we have to test different methods for locating the mutants on the genome and for finding the culprit, and subsequently implement this technology at our institute for routine use. Although zebrafish was chosen as a model system to identify genes by their function, it will be necessary and interesting to integrate knowledge that has been gained on genes known by sequence in other organisms, for instance human disease genes. The best way to study their function in the zebrafish will be inactivating them, using this knowledge of their sequence. Inactivating sequenced genes has so far only been possible in mouse and in invertebrate organisms, but we have developed a method that can be used in the zebrafish. We will make a resource available that will allow researchers to inactivate his/her gene of choice and to compare their phenotype in the embryo with known mutants. In conclusion, we will strive to create a vertebrate model system in which functions can be linked to genes and genes can be linked to function in an efficient way. |
