The spontaneously hypertensive rat (SHR) is the most widely used animal model of essential hypertension and associated metabolic disturbances. Multiple quantitative trait loci associated with hemodynamic and metabolic parameters have been mapped in the SHR. Recently, it has become possible to identify some of the specific quantitative trait gene (QTG) variants that underlie quantitative trait loci linked to complex cardiovascular and metabolic traits in SHR related strains. Recombinant inbred strains derived from SHR and Brown Norway progenitors, together with SHR congenic and transgenic strains, have proven useful for establishing the identity of several QTGs in SHR models. It is anticipated that the combined use of linkage analyses and gene expression profiles, together with the recently available genome sequences of both the SHR and Brown Norway strains and new methods for manipulating the rat genome, will soon accelerate progress in identifying QTGs for complex traits in SHR-related strains.

Genome-wide association studies (GWAS) represent the most widely used approach for genetic analyses of common human diseases with multifactorial inheritance [1•]. The identification of genetic variants associated with essential hypertension has turned out to be particularly challenging. The original GWAS (with 14,000 cases and 3000 controls), The Wellcome Trust Case Control Consortium, revealed no statistically significant associations between any of the approximately 500,000 single nucleotide polymorphisms (SNPs) and the dichotomous hypertension trait [2]. Recently, the results of two GWAS were reported, Global Blood Pressure Genetics (Global BP Gen) Consortium [3] and Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium [4], including respective meta-analyses of 34,433 and 29,136 individuals of European ancestry, with measurements of systolic and diastolic blood pressure. Both studies identified several SNPs in the proximity of known genes that were significantly associated with effects on systolic or diastolic blood pressures of less than 1 mm Hg. Notwithstanding the small effect sizes on blood pressure, results of this kind theoretically could point to interesting new candidate genes that may merit further study from both mechanistic and therapeutic perspectives. To date, however, GWAS explain only a small portion of total heritability, and very few publications involving GWAS have gone beyond statistical findings to include direct experimental testing of the SNPs to investigate their functional impact at the cellular level or to confirm putative effects on blood pressure in vivo [5•, 6, 7]. Given the dramatic advances occurring in next-generation sequencing technology [8], together with increasing interest in the rare-variant hypothesis of hypertension [9], it is possible that direct sequence analysis of thousands of hypertensive patients and controls may someday ultimately supplant the use of GWAS in hypertension.

The BN/Mcwi strain, closely related to the BN-Lx progenitor of the BXH/HXB RI strains, was the first completely sequenced rat strain [38]. The other progenitor of the RI strain data set, the SHR/Ola strain, was recently sequenced at 10.7-fold coverage using Illumina high-throughput sequencing technology (Illumina, Inc., San Diego, CA). Comparison of the BN/Mcwi versus SHR/Ola sequences revealed thousands of nonsynonymous SNPs and hundreds of stop codons, frameshift mutations, and copy number variations. All sequence variants are available in the SHRBase database [24••]. Recently, the sequence of the BN-Lx progenitor strain has been determined at greater than 10-fold coverage [39]. The availability of genome sequences of both progenitors of the BXH/HXB RI strains as well as of the SHR.BN-congenic strains that are available for most rat chromosomes or that can be derived within a year using “supersonic“ breeding methods [40] will provide unprecedented opportunities to begin systematically identifying the most promising candidates for in vivo functional analyses and QTG isolation at the molecular level.

The relationship of mitochondrial DNA variants to metabolic risk factors for diabetes and other common diseases has begun to attract increasing attention. However, progress in this area has been limited because the phenotypic effects of variation in the mitochondrial genome are difficult to isolate owing to confounding variation in the nuclear genome, imprinting phenomena, and environmental factors. Substitution of different mitochondrial genomes on the same nuclear genetic background in conplastic strains provides a way to unambiguously isolate effects of the mitochondrial genome on complex traits. The SHR/Ola and SHR/Ola-mt^BN/Crl conplastic strains have identical nuclear genomes but divergent mitochondrial genomes that encode amino acid differences in seven proteins of oxidative phosphorylation, including a unique phenylalanine-to-leucine substitution in mitochondrial cytochrome c oxidase subunit 1 (mt-Co1), as well as variants in five transfer RNA (tRNA) genes [43]. Compared with the SHR, the conplastic strain exhibited impaired glucose tolerance, lower skeletal muscle glycogen and adenosine triphosphate (ATP) levels, as well as decreases in both the activity and content of cytochrome c oxidase in liver mitochondria. Genotyping of 43 rat inbred strains identified four haplotype groups represented by the BN, F344, LEW, and SHR mitochondrial genomes [43]. Additional conplastic strains with these haplotypes of mitochondrial DNA, including SHR/Ola-mt^F344 and SHR/Ola-mt^LEW, also exhibited dyslipidemia and decreased sensitivity of skeletal muscles to insulin action when compared with SHR controls (Pravenec et al., unpublished observations). These findings provide some of the first direct evidence linking naturally occurring variation in the mitochondrial genome (independent of variation in the nuclear genome and other confounding factors) to inherited variation in known risk factors for type 2 diabetes. They also establish that spontaneous variation in the mitochondrial genome per se can promote systemic metabolic disturbances relevant to the pathogenesis of common diseases.

During the past several years, major advances have been made in rat genome technology, and new resources have become available, particularly for studies in the SHR and other rat models of hypertension [44••]. The recent availability of the SHR genome sequence, one of the first nonhuman mammalian genomes sequenced by short-read sequencing, should help to further accelerate analyses of molecular mechanisms underlying spontaneous hypertension and related metabolic phenotypes. It is hoped that these new tools and others will enable investigators to gain better insight into the specific genes and mechanisms that influence blood pressure and other complex phenotypes in the SHR and that such results will ultimately prove relevant to our understanding of hypertension and related cardiovascular and metabolic disorders in humans.