Functional genomic dissection of rat blood pressure QTL

描述（由申请人提供）：本提案的目的是鉴定控制达尔盐敏感（S）大鼠血压（BP）的数量性状基因座（QTL）。多重连锁分析（每次均使用 S 大鼠作为亲本品系之一）已在 S 大鼠基因组上鉴定出至少 16 个控制血压的不同 QTL。通过构建同系大鼠品系，已证实并明确了大鼠 1、2、3、5、7、9 和 10 号染色体上的 7 个 QTL 的位置。每个同类品系都含有来自相对正常血压品系的基因组片段，该片段渗入到 S 大鼠基因组中，并且与 S 大鼠相比，其血压显着降低。大鼠 1 号和 5 号染色体上含有低 BP QTL 等位基因的同源品系是该提案的主要焦点。这些代表了独特的研究资源，其染色体位置被界定为精确定义的基因组间隔。每个 QTL 的位置克隆虽然是理想的，但却是一个缓慢而费力的过程。该提案的总体策略是将这些 BP QTL 的同源作图与基因表达分析结合起来，从而提供加快 BP QTL 鉴定过程的机会。我们建议使用两种方法解决两个问题： 问题 (1) QTL 内 BP 致病基因的身份是什么？问题（2）它的作用是什么？问题 1 将通过构建并使用同类间隔特异性寡核苷酸阵列来识别 S 大鼠和同类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.