FINE GENETIC MAPPING OF BLOOD PRESSURE QTL

我工作的总体目标是确定数量性状 控制大鼠血压的基因座(QTL)。一种做事情的范例 这包括以下组成部分：(A)识别符合以下条件的遗传标记 与大鼠血压相关；(B)绘制连锁图谱 大鼠染色体区域5-10厘米的分辨率 以获得血压QTL的粗略定位 通过区间作图；(C)为每个低血压者产生同源菌株- 加压QTL等位基因对达尔盐自交系遗传背景的影响 高血压敏感(S)大鼠；d)在一年内建立大鼠连锁图谱 包含QTL的染色体区域的分辨率为1-2厘米；e)细化 逐步替代法定位血压QTL的研究 染色体上越来越小的区域含有低血压性- 加压S遗传背景的QTL等位基因；f)最终准备 至少一个这样的QTL区域的物理图谱和尝试位置 克隆。 目前的建议集中在密集遗传图谱的制作上。 大鼠血压QTL同源品系的获得 染色体1、2和10，以及同源亚株的产生 这些染色体上的血压QTL的精细遗传作图。 血压QTL一级图谱的制备及定位 在9号和13号染色体上也被提出。对一个人的全基因组扫描 取自S和刘易斯大鼠的种群将完成 对这个信息特别丰富的十字的描述，到目前为止 共检测到4个血压QTL，共105 mm Hg。 拟议的研究很重要，因为它们将：(A)提供基因 可用于研究遗传性(本质)高血压的标记物 人类；(B)提供同源菌株，其中一种血液的影响 从所有其他血压QTL中分离出血压QTL，以便 这种菌株可以用来定义病毒的生理功能 QTL；(C)为定位克隆和鉴定 血压QTL，从而大大增加了基本的 了解遗传性高血压的发病机制。

The overall objective of my work is to identify the quantitative trait loci (QTL) controlling blood pressure in the rat. A paradigm for doing this has the following components: (a) identify genetic markers that cosegregate with blood pressure in the rat; (b) develop linkage maps at a resolution of 5-10 centiMorgans (cM) for the rat chromosomal regions involved in order to obtain a crude localization of the blood pressure QTL by interval mapping; (c) produce congenic strains for each low-blood- pressure QTL allele on the genetic background of the inbred Dahl salt- hypertension sensitive (S) rat; d) develop rat linkage maps at a resolution of 1-2 cM for QTL-containing chromosomal regions; e) refine the genetic mapping of blood pressure QTL by substituting progressively smaller and smaller regions of chromosome containing the low-blood- pressure QTL allele on the S genetic background; f) and ultimately prepare physical maps for at least one such QTL region and attempt positional cloning. The present proposal concentrates on the production of dense genetic maps and the production of congenic strains for blood pressure QTL on rat chromosomes 1, 2 and 10, and the production of congenic substrains for fine genetic mapping of the blood pressure QTL on these chromosomes. Preparation of first order maps and localization of the blood pressure QTL on chromosomes 9 and 13 are also proposed. A full genome scan of an population derived from S and Lewis rats will be performed to complete the description of this particularly informative cross which has so far yielded four blood pressure QTL accounting for 105 mmHg. The proposed studies are important because they will: (a) provide genetic markers that can be used to study genetic (essential) hypertension in humans; (b) provide congenic strains in which the effects of one blood pressure QTL are isolated from all other blood pressure QTL in order that such strains can be used to define the physiological function of the QTL;(c) provide the basis for positional cloning and identification of blood pressure QTL, thus adding substantially to the fundamental understanding of the mechanisms of genetic hypertension.