Functional characterisation of the genomes of rat models of human diseases

Abstract

Large numbers of inbred laboratory rat strains have been developed in the past 100 years by phenotype-driven selective breeding for the study of a range of disease phenotypes. The spontaneously hypertensive rat (SHR) is the most widely studied animal model of hypertension. The SHR Genome was sequenced with 10.7X coverage, and ~4 million genomic variants between SHR and the BN reference genome were identified. Analysis of the SHR genome revealed that cis expression quantitative trait locus genes were significantly enriched for genomic variants and that the genes harboring major mutations were enriched for ion transport and plasma membrane localization. To gain insights into the evolutionary pressures acting on inbred rat strains during phenotype driven selective breeding and, in turn, the molecular basis underlying disease phenotypes, the genomes of an additional 27 rat strains were sequenced, including 11 models of hypertension, diabetes and insulin resistance along with their respective control strains. A total of 9,665,340 single nucleotide variants (SNVs), 3,502,117 indels and 555,419 structural variants and 897,217 copy number variants were identified across the 28 rat strains. Using SNVs, 96 distinct artificial selective sweeps were identified in the disease models, a significant proportion of which were co-localised with physiological quantitative trait loci mapped previously in respective rat strains. Further, clusters of genes that had co-evolved in the disease models were identified, human orthologous of which were enriched for the genes implicated in the human genome wide association studies for cardiovascular and metabolic phenotypes. These analyses identified both known and new genes involved in the renin-angiotensin pathway, in ion transport and in regulation of oxidative stress. These genes may underlie disease phenotypes manifested by the rat strains thus providing novel insights into molecular mechanisms underlying complex traits in these rat strains.