Progress and prospects in rat genetics: a community view

The rat is an important system for modeling human disease. Four years ago, the rich 150-year history of rat research was transformed by the sequencing of the rat genome, ushering in an era of exceptional opportunity for identifying genes and pathways underlying disease phenotypes. Genome-wide association studies in human populations have recently provided a direct approach for finding robust genetic associations in common diseases, but identifying the precise genes and their mechanisms of action remains problematic. In the context of significant progress in rat genomic resources over the past decade, we outline achievements in rat gene discovery to date, show how these findings have been translated to human disease, and document an increasing pace of discovery of new disease genes, pathways and mechanisms. Finally, we present a set of principles that justify continuing and strengthening genetic studies in the rat model, and further development of genomic infrastructure for rat research.     

Physiogenomic resources for rat models of heart, lung and blood disorders

Cardiovascular disorders are influenced by genetic and environmental factors. The TIGR rodent expression web-based resource (TREX) contains over 2,200 microarray hybridizations, involving over 800 animals from 18 different rat strains. These strains comprise genetically diverse parental animals and a panel of chromosomal substitution strains derived by introgressing individual chromosomes from normotensive Brown Norway (BN/NHsdMcwi) rats into the background of Dahl salt sensitive (SS/JrHsdMcwi) rats. The profiles document gene-expression changes in both genders, four tissues (heart, lung, liver, kidney) and two environmental conditions (normoxia, hypoxia). This translates into almost 400 high-quality direct comparisons (not including replicates) and over 100,000 pairwise comparisons. As each individual chromosomal substitution strain represents on average less than a 5% change from the parental genome, consomic strains provide a useful mechanism to dissect complex traits and identify causative genes. We performed a variety of data-mining manipulations on the profiles and used complementary physiological data from the PhysGen resource to demonstrate how TREX can be used by the cardiovascular community for hypothesis generation.     

Linkage of Rieger syndrome to the region of the epidermal growth factor gene on chromosome 4.

Rieger syndrome is an autosomal dominant disorder of morphogenesis in which previous cytogenetic arrangements have suggested chromosome 4 as a candidate chromosome. Using a group of highly polymorphic short tandem repeat polymorphisms (STRP), including a new tetranucleotide repeat for epidermal growth factor (EGF), significant linkage of Rieger syndrome to 4q markers has been identified. Tight linkage to EGF supports its role as a candidate gene, although a recombinant in an unaffected individual has been identified. This study demonstrates the utility of using polymorphic STRP markers when only a limited number of small families are available for study.