Spontaneously Hypertensive Rat Genome

The spontaneously hypertensive rat (SHR) is the most widely used animal model for the study of hypertension and has been used to map scores of quantitative loci (QTLs) for hypertension and other phenotypes. Progress in identifying the underlying genes has been limited by absence of the SHR genome sequence. We have sequenced the SHR/OlaIpcv genome at 10.7 fold coverage by paired-end sequencing on the Illumina platform. We identified 3.6 million high quality SNPs and 343,243 short indels between the SHR/OlaIpcv and Brown Norway (BN) reference genome, with a very high rate of validation and accuracy. These SNPs and indels resulted in 161 gain or loss of stop codons and 629 frameshifts compared to the BN reference sequence. We also identified 13,438 deletions that result in complete or partial deletion of 107 genes from the SHR/OlaIpcv genome compared to the BN reference and 588 copy number variants (CNVs) that overlap with the gene regions of 688 genes. Genomic regions containing genes whose expression had been previously mapped as cis-regulated expression quantitative trait loci (eQTLs) were significantly enriched with SNPs, short indels and larger deletions, suggesting that some of these variants have functional effects on gene expression. Genes that were affected by major alterations in their coding sequence were highly enriched for genes related to ion transport, transport and plasma membrane localisation, providing insights into the likely molecular and cellular basis of hypertension and other phenotypes specific to the SHR strain. This near complete catalogue of genomic differences between two extensively studied rat strains provides the starting point for complete elucidation, at the molecular level, of the physiological and pathophysiological phenotypic differences between individuals from these strains.