The Project
Exploiting natural and induced genetic variation in the laboratory rat.
Winner
Edwin Cuppen
Netherlands Institute for Developmental Biology
Hubrecht Laboratory
Utrecht, The Netherlands
http://www.niob.knaw.nl/
Dutchman Edwin Cuppen, 35 years old, is Group Leader and Staff Scientist in the Hubrecht Laboratory at the Netherlands Institute for Developmental Biology, Utrecht, The Netherlands. He graduated M.Sc cum laude in 1994 from the Agricultural University of Wageningen, The Netherlands, and obtained his Ph.D from the University of Nijmegen, The Netherlands, in 1998.
Award
€1,199,196
Project Description
The rat model has made enormous contributions to our present understanding of physiology and biology. Due to its size and its well-studied physiology, the rat is now the model of choice in many studies on human health and disease and is currently the most widely studied experimental animal in biomedical research.
Despite the wealth of knowledge that is available on rat physiology, pharmacology, toxicology, and behaviour, genetic tools are only available to a limited extent. Although the primary interest is to study the genetic basis of behaviour in the rat, this project will focus on the development of genetic tools that are essential to facilitate this work. We have recently shown solid proof of principle for making rat knockouts using target-selected mutagenesis: 5 out of the 7 existing knockouts were made in the Award winner's lab. The project intends to improve on this technology by using a mismatch repair-deficient genetic background (MSH6-/-) to enhance ENU-induced mutation frequency. In addition, it will explore emerging mutation discovery technology and massively parallel sequencing approaches to make knockout screening more cost and time efficient. These improvements should make rat knockout technology a routine tool for the whole research community.
To facilitate genetic mapping and cloning and assist in the dissection of the molecular bais and identification of causal polymorphism underlying the currently more than 200 rat models for (complex) human diseases, we will identify and characterize genetic variation between commonly used laboratory rat strains. We will perform shotgun sequencing in wild rat isolates for discovery of single nucleotide polymorphisms (SNPs). Large-scale genotyping of commonly used laboratory rat strains will be done to determine haplotype structure and to design dense SNP-based mapping panels. Finally, bioinformatics tools and web-based interfaces will be developed to assist data mining, management, interpretation, and dissemination of high-throughout data generated in the project.
