The emerging role for rat models in gene discovery

Abstract

Rat models have been used for many decades to study physiological and pathophysiological mechanisms. Prior to the release of the rat genome and new technologies for targeting gene manipulation, the rat had been the underdog in the genomics era, despite the abundance of physiological data compared to the mouse. The overarching goal of biomedical research is to improve health and advance medical science. Translating human disease gene discovery and validation in the rat, through the use of emerging technologies and integrated tools and databases, is providing power to understand the genetics, environmental influences, and biology of disease. In this review we briefly outline the rat models, bioinformatics tools, and technologies that are changing the landscape of translational research. The strategies used to translate disease traits to genes to function, and, ultimately, to improve human health is discussed. Finally, our perspective on how rat models will continue to positively impact biomedical research is provided.

Fig. 1

Results from the NCBI PubMed biomedical literature database. 1a: Total number of references by disease (left panel) or organ system (right panel) in mice (open bars) and rats (solid bars); 1b: Left panel: Total publications for rats (solid symbols) and mice (open symbols) by year (1980-2010) with arrows indicate when knockout technologies became available for each species; Right panel: comparison of number of publication between mouse and rat using “genes” and “animals, genetically modified” as search criteria.

Fig. 2

Diagram outlining some of the strategies used to identify candidate genes for disease traits. Left panel depicts the more traditional approach of using F2 crosses for QTL identification or animal breeding strategies to narrow the genomic region containing candidate genes. Right panel illustrates a strategy to use targeted mutation in a rat model to validate GWAS SNPs.

Fig. 3

Diagram highlighting the approaches available for use of animal models for translational biology with the need for bioinformatic tools to integrate gene and phenotype data.

Fig. 4

The Rat Genome Database (RGD) genome browser (GBrowse) allows users to view overlap between human and rat QTLs through synteny. 4a: Browser with Human genome build 36.3 on chromosome 17 with blood pressure QTL shown in red and blue solid lines (first track). The human syntenic blocks are mapped in aqua blue (second track). Corresponding rat syntenic blocks are mapped in yellow (third track). 4b: Detailed information about the corresponding syntenic block in rat can be obtained by mousing over the syntenic block of interest. 4c: View of the overlapping rat blood pressure QTLs for the region on human chromosome 17 shown in 4a.