Dissection of blood pressure QTL using substrains of the spontaneously hypertensive rats ans congenic strains

本实验室以前的报道表明，血压的数量性状位点（QTL）位于大鼠1号染色体上。针对该QTL的同源菌株鉴定表明，该基因位于80Mbp区域。这个区域仍然相当大，因此应该把它切成更小的区域，以确定负责的基因。在自发性高血压大鼠（SHR）的发展过程中，几个SHR亚系和卒中易发SHR （SHRSP）已经发展并维持了20多年。由于预计它们彼此共享相同的“高血压”基因，我们假设“高血压”基因周围的染色体片段含有一簇SSR标记，这些标记在SHR亚株和Wistar-Kyoto大鼠（WKY）亚株之间具有多态性；该SSR的一个等位基因为SHR亚株共有，另一个等位基因为WKY亚株共有。在本研究中，我们对270个SSR标记进行了基因分型，更多的标记密集分布在1号染色体QTL区域。结果表明，该区域的2个小片段（3Mbp）含有WKY亚株与SHR/SHRSP亚株之间多态性的SSR标记簇。这些区域是潜在的候选者，具有负责SHR（和SHRSP）和WKY之间血压差异的基因。我们发现了另一个7Mbp的片段，其中包含SHRSP亚株和SHR/WKY亚株之间的SSR标记多态性。该区域可能是SHR和SHRSP之间血压差异的原因，SHRSP和SHR之间的QTL分析也表明了这一点。我们还用遥测系统评估了SHR和SHRSP亚株的血压。结果表明，所有SHR/SHRSP亚株的血压均高于WKY。但不同亚株间血压差异也显著；一些亚株的血压高于其他亚株。根据基因分型结果，QTL中没有任何区域可以解释这种亚种间的血压差异。1号染色体上的qtl之外的qtl可能是造成这种差异的原因。少

Previous reports of our laboratory showed that a quantitative trait locus (QTL) for blood pressure is located on rat chromosome 1.The evaluation of a congenic strain targeting this QTL indicated that the responsible gene(s) was in 80Mbp region. This region was still quite large and therefore it should be cut down into smaller regions to identify the responsible genes. In the process of developing the spontaneously hypertensive rats (SHR), several substrains of SHR and the stroke-prone SHR (SHRSP) have been developed and maintained for more than 20 years. As they are expected to share the same ‘hypertension' genes with each other, we hypothesized that the choromosomal fragment around the ‘hypertension' genes harbored a cluster of SSR markers that are polymorphic between SHR substrains and Wistar-Kyoto rat (WKY) substrains ; one allele of such an SSR was commonly shared in the substrains of SHR while another was observed in WKY substrains.In this study, we therefore genotyped 270 SSR mar … More kers distributed densely in the chromosome-1 QTL region. Results indicated that two small fragments (3Mbp) in the region harbored clusters of SSR markers polymorphic between WKY substrains and SHR/SHRSP substrains. These regions are potential candidates having the genes responsible for the blood pressure difference between SHR (and SHRSP) and WKY. We found another fragment with 7Mbp that harbors SSR markers polymorphic between SHRSP substrains and SHR/WKY substrains. This region may account for the difference of blood pressure between SHR and SHRSP, which was indicated by a QTL analysis between SHRSP and SHR as well. We additionally evaluated blood pressure in SHR and SHRSP substrains with the telemetry system. The result indicated that all of SHR/SHRSP substrains had higher blood pressure than did WKY. However, difference of blood pressure among the substrains was significant as well ; some substrains had greater blood pressure than others. According to the genotyping result, no regions in the QTL could account for this inter-substrain difference of blood pressure. QTLs outside of the one on chromosome-1 may be responsible for this difference. Less