Hofstetter J R, Hitzemann R J, Belknap J K, Walter N A R, McWeeney S K, Mayeda A R
Department of Veterans Affairs, Richard L. Roudebush Medical Center, Indianapolis, IN 46202, USA.
Genes Brain Behav. 2008 Mar;7(2):214-23. doi: 10.1111/j.1601-183X.2007.00340.x. Epub 2007 Aug 13.
We report here the confirmation of the quantitative trait locus for haloperidol-induced catalepsy on distal chromosome (Chr) 1. We determined that this quantitative trait locus was captured in the B6.D2-Mtv7a/Ty congenic mouse strain, whose introgressed genomic interval extends from approximately 169.1 to 191.3 Mb. We then constructed a group of overlapping interval-specific congenic strains to further break up the interval and remapped the locus between 177.5 and 183.4 Mb. We next queried single nucleotide polymorphism (SNP) data sets and identified three genes with nonsynonymous coding SNPs in the quantitative trait locus. We also queried two brain gene expression data sets and found five known genes in this 5.9-Mb interval that are differentially expressed in both whole brain and striatum. Three of the candidate quantitative trait genes were differentially expressed using quantitative real-time polymerase chain reaction analyses. Overall, the current study illustrates how multiple approaches, including congenic fine mapping, SNP analysis and microarray gene expression screens, can be integrated both to reduce the quantitative trait locus interval significantly and to detect promising candidate quantitative trait genes.
我们在此报告了位于1号染色体远端的氟哌啶醇诱导僵住症数量性状基因座的确认情况。我们确定该数量性状基因座在B6.D2-Mtv7a/Ty同源近交系小鼠中被捕获，其渐渗基因组区间从大约169.1兆碱基延伸至191.3兆碱基。然后我们构建了一组重叠的区间特异性同源近交系，以进一步细分该区间，并将该基因座重新定位在177.5至183.4兆碱基之间。接下来，我们查询了单核苷酸多态性（SNP）数据集，并在数量性状基因座中鉴定出三个具有非同义编码SNP的基因。我们还查询了两个脑基因表达数据集，发现在这个5.9兆碱基区间内有五个已知基因在全脑和纹状体中均有差异表达。使用定量实时聚合酶链反应分析，其中三个候选数量性状基因存在差异表达。总体而言，当前研究说明了如何整合多种方法，包括同源近交系精细定位、SNP分析和微阵列基因表达筛选，既能显著缩小数量性状基因座区间，又能检测出有前景的候选数量性状基因。
