The genome sequence of the spontaneously hypertensive rat: Analysis and functional significance
- Santosh S. Atanur1,
- İnanç Birol2,
- Victor Guryev3,
- Martin Hirst2,
- Oliver Hummel4,
- Catherine Morrissey1,
- Jacques Behmoaras5,
- Xose M. Fernandez-Suarez6,
- Michelle D. Johnson1,
- William M. McLaren6,
- Giannino Patone4,
- Enrico Petretto7,8,
- Charles Plessy9,
- Kathleen S. Rockland10,
- Charles Rockland11,
- Kathrin Saar4,
- Yongjun Zhao2,
- Piero Carninci9,14,
- Paul Flicek6,14,
- Ted Kurtz12,14,
- Edwin Cuppen3,14,
- Michal Pravenec13,14,
- Norbert Hubner4,14,
- Steven J.M. Jones2,14,
- Ewan Birney6,14 and
- Timothy J. Aitman1,14,15
- 1Physiological Genomics and Medicine Group, Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, United Kingdom;
- 2Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 4S6, Canada;
- 3Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences & University Medical Centre Utrecht, Utrecht 3584 CT, The Netherlands;
- 4Max-Delbrück Center for Molecular Medicine, Berlin D-13092, Germany;
- 5Imperial College London, Division of Investigative Sciences, Hammersmith Hospital, London W12 0NN, United Kingdom;
- 6European Bioinformatics Institute, Hinxton, Cambridge CB10 1SD, United Kingdom;
- 7Integrative Genomics and Medicine Group, Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, United Kingdom;
- 8Department of Epidemiology and Public Health, Faculty of Medicine, Imperial College, London W2 1PG, United Kingdom;
- 9Omics Science Center, RIKEN Yokohama Institute, Yokohama, Kanagawa 230-0045, Japan;
- 10Laboratory for Cortical Organization and Systematics, Brain Science Institute, RIKEN, Wako-shi, Saitama 351-0198, Japan;
- 11Advanced Technology Development Group, Brain Science Institute, RIKEN, Wako-shi, Saitama 351-0198, Japan;
- 12Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California 94107 USA;
- 13Institute of Physiology, Academy of Sciences of the Czech Republic, Prague 14220, Czech Republic
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↵14 These authors contributed equally to this work.
Abstract
The spontaneously hypertensive rat (SHR) is the most widely studied animal model of hypertension. Scores of SHR quantitative loci (QTLs) have been mapped for hypertension and other phenotypes. 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 single nucleotide polymorphisms (SNPs) between the SHR/OlaIpcv and Brown Norway (BN) reference genome, with a high rate of validation (sensitivity 96.3%–98.0% and specificity 99%–100%). We also identified 343,243 short indels between the SHR/OlaIpcv and reference genomes. These SNPs and indels resulted in 161 gain or loss of stop codons and 629 frameshifts compared with the BN reference sequence. We also identified 13,438 larger deletions that result in complete or partial absence of 107 genes in the SHR/OlaIpcv genome compared with 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 localization, providing insights into the likely molecular and cellular basis of hypertension and other phenotypes specific to the SHR strain. This near complete catalog 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.
Footnotes
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↵15 Corresponding author.
E-mail t.aitman{at}imperial.ac.uk; fax 44-20-8383-8577.
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[Supplemental material is available online at http://www.genome.org. The sequence data from this paper have been submitted to the EBI Sequence Read Archive (http://www.ebi.ac.uk/) under accession no. ERA000170. SNPs have been submitted to dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP/) under batch id 2010-1_SHR. The complete set of SNPs is also available on Ensembl (ftp://ftp.ebi.ac.uk/pub/databases/ensembl/snp/rat/shr/). All variants are available in a custom database, SHRbase (http://shr.csc.mrc.ac.uk/) and will be available in the next release of Ensembl. The CGH array data have been submitted to the NCBI Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/) under accession no. GSE20102. The CAGE tag data have been submitted to the DDBJ Read Archive (http://trace.ddbj.nig.ac.jp/registered/) under accession no. DRA000155.]
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Article published online before print. Article and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.103499.109.
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- Received November 23, 2009.
- Accepted March 10, 2010.
- Copyright © 2010 by Cold Spring Harbor Laboratory Press
