The genome sequence of the spontaneously hypertensive rat: Analysis and functional significance.
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.
Atanur
Santosh S
SS
Physiological Genomics and Medicine Group, Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, United Kingdom.
Birol
Inanç
I
Guryev
Victor
V
Hirst
Martin
M
Hummel
Oliver
O
Morrissey
Catherine
C
Behmoaras
Jacques
J
Fernandez-Suarez
Xose M
XM
Johnson
Michelle D
MD
McLaren
William M
WM
Patone
Giannino
G
Petretto
Enrico
E
Plessy
Charles
C
Rockland
Kathleen S
KS
Rockland
Charles
C
Saar
Kathrin
K
Zhao
Yongjun
Y
Carninci
Piero
P
Flicek
Paul
P
Kurtz
Ted
T
Cuppen
Edwin
E
Pravenec
Michal
M
Hubner
Norbert
N
Jones
Steven J M
SJ
Birney
Ewan
E
Aitman
Timothy J
TJ
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
D018388:Codon, Terminator