The year of the rat: Improving the utility of the rat as a biomedical model organism through genome and phenome analyses

Amy Lynn Zinski

doi:10.7273/000004214

Interest in genome sequencing exploded after the first DNA sequencings and the launch of the Human Genome Project (HGP) in 1990. It was realized that specific genes and mutations have potential causal relationships with phenotypes and diseases. Thus one year after the HGP was completed (2004), the first rat genome was sequenced, as knowing the genome of a thoroughly researched model organism would hasten new discoveries in genomics such as linkage disequilibriums, population structures, gene discovery, and genome to phenome studies. Sequencing technology and platforms, have produced increasingly greater sequencing depth and accurate reads, leading to significant advancement in the rat genome assembly over the last 20 years. This has led to the discovery of genome variants in rats, which have been widely used to detect quantitative trait loci underlying complex phenotypes based on gene, haplotype, and sweep association analyses. Studies using DNA variants can also yield important information about strain, chromosome and gene functional evolutions. Phenome programs have advanced in parallel resulting in over 10 databases containing genome and/or phenome information. To discover bridges between genomes and phenomes, new approaches in systems genetics and integrative genomics have been developed. Our genome sequencing study along with a behavioral study, literature review, and computational approach to relate the developmental stages of the rat to humans contribute novel genomic and phenotypic data that enhance the utility of the rat as a model organism for human health and diseases. Here, we present new WGS and phenotypic data comparing inbred and outbred rat strains that will serve as foundational knowledge in determining genotype-to-phenotype relations. Our WGS completed on NIH-HS and Wistar rats revealed over 3.6 million genetic variants, including 117,060 that reside within 7,788 genes in pathways related to drug metabolism; muscle development; protein, amino acid, and lipid metabolism; DNA and RNA processing; cell division; and regulation of epigenetic processes. Our phenotypic data highlights behavioral differences between inbred and outbred Wistar rats - such as risk-taking behaviors. With this data, we plan to continue detailing the differences between inbred and outbred rat strains and eventually elucidate cellular mechanisms that describe genotypic differences resulting phenotypic variations.

The year of the rat: Improving the utility of the rat as a biomedical model organism through genome and phenome analyses

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