title: The genome sequence of the spontaneously hypertensive rat: Analysis and functional significance.
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.
authors.affiliation: Physiological Genomics and Medicine Group, Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, United Kingdom.
authors.forename: Santosh S
authors.initials: SS
authors.lastname: Atanur
authors.forename: Inanç
authors.initials: I
authors.lastname: Birol
authors.forename: Victor
authors.initials: V
authors.lastname: Guryev
authors.forename: Martin
authors.initials: M
authors.lastname: Hirst
authors.forename: Oliver
authors.initials: O
authors.lastname: Hummel
authors.forename: Catherine
authors.initials: C
authors.lastname: Morrissey
authors.forename: Jacques
authors.initials: J
authors.lastname: Behmoaras
authors.forename: Xose M
authors.initials: XM
authors.lastname: Fernandez-Suarez
authors.forename: Michelle D
authors.initials: MD
authors.lastname: Johnson
authors.forename: William M
authors.initials: WM
authors.lastname: McLaren
authors.forename: Giannino
authors.initials: G
authors.lastname: Patone
authors.forename: Enrico
authors.initials: E
authors.lastname: Petretto
authors.forename: Charles
authors.initials: C
authors.lastname: Plessy
authors.forename: Kathleen S
authors.initials: KS
authors.lastname: Rockland
authors.forename: Charles
authors.initials: C
authors.lastname: Rockland
authors.forename: Kathrin
authors.initials: K
authors.lastname: Saar
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Zhao
authors.forename: Piero
authors.initials: P
authors.lastname: Carninci
authors.forename: Paul
authors.initials: P
authors.lastname: Flicek
authors.forename: Ted
authors.initials: T
authors.lastname: Kurtz
authors.forename: Edwin
authors.initials: E
authors.lastname: Cuppen
authors.forename: Michal
authors.initials: M
authors.lastname: Pravenec
authors.forename: Norbert
authors.initials: N
authors.lastname: Hubner
authors.forename: Steven J M
authors.initials: SJ
authors.lastname: Jones
authors.forename: Ewan
authors.initials: E
authors.lastname: Birney
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Aitman
mesh_terms: D000818:Animals; D018388:Codon, Terminator; D018628:Gene Dosage; D006973:Hypertension / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D051381:Rats; D011918:Rats, Inbred SHR; D014158:Transcription, Genetic
chemical_list: D018388:Codon, Terminator