The genome sequence of the spontaneously hypertensive rat: Analysis and functional significance
The genome sequence of the spontaneously hypertensive rat: Analysis and functional significance
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DOI：
10.1101/gr.103499.109
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发表时间：
2010-06-01
期刊：
影响因子：
7
通讯作者：
Aitman, Timothy J.
中科院分区：
文献类型：
--
作者：
Atanur, Santosh S.;Birol, Inanc;Aitman, Timothy J.
自发性高血压大鼠（SHR）是研究最为广泛的高血压动物模型。已经针对高血压及其他表型绘制了大量的SHR数量性状基因座（QTL）图谱。我们通过在Illumina平台上进行双端测序，以10.7倍的覆盖度对SHR/OlaIpcv基因组进行了测序。我们在SHR/OlaIpcv和布朗挪威（BN）参考基因组之间鉴定出360万个高质量的单核苷酸多态性（SNP），验证率很高（灵敏度为96.3% - 98.0%，特异性为99% - 100%）。我们还在SHR/OlaIpcv和参考基因组之间鉴定出343243个短插入缺失（indel）。与BN参考序列相比，这些SNP和indel导致161个终止密码子的获得或缺失以及629个移码突变。我们还鉴定出13438个较大的缺失，与BN参考基因组相比，这些缺失导致SHR/OlaIpcv基因组中107个基因完全或部分缺失，以及588个拷贝数变异（CNV），它们与688个基因的基因区域重叠。包含先前被定位为顺式调控表达数量性状基因座（eQTL）的基因的基因组区域显著富集SNP、短indel和较大缺失，这表明这些变异中的一些对基因表达具有功能影响。编码序列发生重大改变的基因在与离子转运、运输和质膜定位相关的基因中高度富集，这为了解SHR品系特有的高血压及其他表型的可能分子和细胞基础提供了见解。这两个被广泛研究的大鼠品系之间近乎完整的基因组差异目录为在分子水平上完全阐明这些品系个体之间的生理和病理生理表型差异提供了起点。
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.