Functional genomic dissection of rat blood pressure QTL

描述（由申请人提供）：本提案的目的是确定达尔盐敏感(S)大鼠控制血压（BP）的数量性状位点（QTL）。多重连锁分析，每一个都使用S大鼠作为亲本菌株之一，已经在S大鼠基因组上鉴定出至少16个控制血压的不同QTL。其中7个QTL在大鼠1、2、3、5、7、9和10号染色体上的位置已通过构建同源大鼠菌株得到确认和明确。每个同源菌株都包含一个基因组片段，来自于一个渗透到S大鼠基因组中的相对正常的菌株，与S大鼠相比，其血压显著降低。在大鼠1号和5号染色体上含有低BP QTL等位基因的同源菌株是本研究的重点。这些代表了一个独特的研究资源，通过他们的染色体位置划定精确定义的基因组间隔。这些QTL的定位克隆虽然是可取的，但却是一个缓慢而费力的过程。本文的总体策略是将这些BP QTL的同源定位与基因表达分析结合起来，从而为BP QTL的鉴定提供机会。我们建议使用两种方法来解决两个问题：问题(1)QTL中BP致病基因的身份是什么？问题(2)它的作用是什么？问题1将通过构建和使用同源间隔特异性寡核苷酸阵列来识别S大鼠和同源大鼠之间的差异表达基因来解决。问题2将通过使用现有的大鼠基因组芯片来解决，以确定其mRNA表达水平受致病基因影响的基因。

DESCRIPTION (provided by applicant): The purpose of this proposal is to identify the quantitative trait loci (QTL) that control blood pressure (BP) in the Dahl salt sensitive (S) rat. Multiple linkage analyses, each using the S rat as one of the parental strains, has resulted in the identification of at least 16 different QTL on the S rat genome that control blood pressure. The locations of 7 of these QTL on rat chromosomes 1, 2, 3, 5, 7, 9 and 10 have been confirmed and well defined by the construction of congenic rat strains. Each congenic strain contains a genomic segment from a relatively normotensive strain introgressed into the S rat genome and has significantly lower BP compared to the S rat. Congenic strains containing low BP QTL alleles on rat chromosomes 1 and 5 are the major focus for this proposal. These represent a unique research resource, by having their chromosomal locations delimited to precisely defined genomic intervals. Positional cloning of each of these QTL, while desirable, is a slow and laborious process. The overall strategy of this proposal is to couple congenic mapping of these BP QTL with gene expression analysis, thus providing the opportunity to expedite the process of BP QTL identification. We propose to address two questions using two approaches: Question (1) What is the identity of the BP causative gene within a QTL? Question (2) What is its action? Question 1 will be addressed by constructing and using a congenic-interval specific oligonucleotide array to identify differentially expressed genes between S rats and congenic rats. Question 2 will be addressed by using an already available rat genome chip, to identify the genes whose mRNA expression levels are affected by the causative gene.