Dmitrieva Renata I, Hinojos Cruz A, Grove Megan L, Bell Rebecca J, Boerwinkle Eric, Fornage Myriam, Doris Peter A
Institute of Molecular Medicine and Human Genetics Center, University of Texas Health Science Center, 2121 Holcombe Blvd., Houston, TX 77030, USA.
Circ Cardiovasc Genet. 2009 Apr;2(2):106-15. doi: 10.1161/CIRCGENETICS.108.809509. Epub 2009 Feb 12.
Identification of genes involved in complex cardiovascular disease traits has proven challenging. Inbred animal models can facilitate genetic studies of disease traits. The spontaneously hypertensive rat (SHR) is an inbred model of hypertension that exists in several closely related but genetically distinct lines.
We used renal gene-expression profiling across 3 distinct SHR lines to identify genes that show different expression in SHR than in the genetically related normotensive control strain, Wistar-Kyoto. To ensure robust discovery of genes showing SHR-specific expression differences, we considered only those genes in which differential expression is replicated in multiple animals of each of multiple hypertensive rat lines at multiple time points during the ontogeny of hypertension. Mutation analysis was performed on the identified genes to uncover allelic variation. We identified those genes in which all SHR lines share a single allele of the gene when normotensive controls (Wistar-Kyoto) have fixed the alternative allele. We then identified which of the differentially expressed genes show expression that is controlled by the alleleic variation present in and around the gene. Allelic expression was demonstrated by observing the effect on gene expression of alleles inherited in the freely segregating F(2) progeny of a cross between SHR and Wistar-Kyoto animals.
The result of these studies is the identification of several genes (Ptprj, Ela1, Dapk-2, and Gstt2) in which each of 4 SHR lines examined have fixed the same allele and in which each of 2 Wistar-Kyoto lines have a contrasting allele for which the inherited allele influences the level of gene expression. We further show that alleles of these genes lie in extensive haplotype blocks that have been inherited identical by descent in the hypertensive lines.
已证明识别参与复杂心血管疾病性状的基因具有挑战性。近交动物模型有助于疾病性状的遗传学研究。自发性高血压大鼠（SHR）是一种高血压近交模型，存在几个密切相关但基因不同的品系。
我们对3个不同的SHR品系进行肾脏基因表达谱分析，以识别在SHR中与遗传相关的正常血压对照品系Wistar-Kyoto相比表现出不同表达的基因。为确保可靠地发现显示SHR特异性表达差异的基因，我们仅考虑那些在高血压发生过程中的多个时间点，在多个高血压大鼠品系的多只动物中均重复出现差异表达的基因。对鉴定出的基因进行突变分析以揭示等位基因变异。我们鉴定出那些当正常血压对照（Wistar-Kyoto）固定了替代等位基因时，所有SHR品系共享该基因单个等位基因的基因。然后，我们确定哪些差异表达基因的表达受该基因及其周围存在的等位基因变异控制。通过观察SHR与Wistar-Kyoto动物杂交的自由分离F(2)后代中遗传的等位基因对基因表达的影响来证明等位基因表达。
这些研究的结果是鉴定出几个基因（Ptprj、Ela1、Dapk-2和Gstt2），在所检测的4个SHR品系中每个品系都固定了相同的等位基因，而在2个Wistar-Kyoto品系中每个品系都有一个对比等位基因，其遗传的等位基因影响基因表达水平。我们进一步表明，这些基因的等位基因位于广泛的单倍型块中，这些单倍型块在高血压品系中通过血统遗传而相同。
