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International Team Sequences Genome of Rat Hypertension Model

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – In the early, online edition of Genome Research today, an international research team reported that they have sequenced the genome of the rat model of human hypertension.

The researchers used paired-end Illumina sequencing to tackle the genome of a so-called spontaneously hypertensive rat strain using genomic DNA isolated from two female SHR rats. In so doing, the team found millions of SNPs not present in the rat reference genome, along with a host of insertion, deletion, inversion, and copy number changes.

"So many major differences in protein sequence were unexpected because of the previous belief that differences in a small number of genes and proteins would be responsible for the phenotypic differences between such rat strains," co-senior author Timothy Aitman, a clinical and molecular genetics researcher at the Imperial College London, said in a statement.

By cataloguing these changes and looking at the genes affected by them, researchers hope to learn more about the genetic diversity in rat strains and track down genetic changes in the hypertensive strain that can inform future studies of human hypertension.

The SHR line is a commonly used model for human hypertension and related conditions, the researchers explained, and has been developed through more than 100 generations of inbreeding.

For the current study, Aitman and his colleagues used paired-end sequencing with the Illumina Genome Analyzer II platform to sequence genomic DNA from two female rats belonging to a spontaneously hypertensive rat strain called SHR/O1aIpcv to around 10.7 times coverage.

When they compared this sequence with the Brown Norway rat reference genome, published in 2004, the researchers identified more than 3.6 million high-quality SNPs, including 27,340 SNPs in coding regions. Of these, 11,542 SNPs appear to be non-synonymous.

Overall, these SNPs weren't equally distributed across the genome. Instead, the team found three large areas on chromosomes 2, 13, and 15 — dubbed "SNP deserts" — with exceptionally low SNP density.

Their analysis also turned up 343,243 small insertions and deletions, 835 apparent insertions, 366 inversions, 588 potential CNVs, and 13,438 larger deletions in the hypertensive rat genome. More than 100 genes were affected by deletions and 60 were completely missing in the hypertensive rat. These included genes coding for ribosomal proteins, olfactory receptors, yet-uncharacterized genes, and more.

Meanwhile, many of the 788 genes that appear to be mutated in the hypertensive rat genome belonged to pathways involved in ion transport as well as immunological, neurological, and mechanical processes.

When the researchers focused in on variants that appear to influence expression, they found more than 3,000 cis-eQTLs — expression quantitative trait loci acting in or around the affected genes. These eQTLs tend to coincide with parts of the hypertensive rat genome that are also rich in SNPs, indels, and structural variants, the team noted.

By cataloguing the differences between the hypertensive and Brown Norway rat strains, the researchers noted, they hope to eventually get what they call a "complete elucidation, at the molecular level, of the physiological and pathophysiological phenotypic differences between individuals from these strains."

Moreover, the data is expected to yield genetic clues to human hypertension. "This in turn will pave the way for greater understanding of the genetic basis of hypertension in humans," Aitman said in a statement, "a problem that has proved remarkably difficult to study in humans directly."

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