Garrett Norman E, Grainger Andrew T, Li Jing, Chen Mei-Hua, Shi Weibin
Departments of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA, USA.
Biochemistry & Molecular Genetics, University of Virginia, Charlottesville, VA, USA.
Mamm Genome. 2017 Apr;28(3-4):90-99. doi: 10.1007/s00335-016-9677-0. Epub 2017 Jan 23.
Nearly all genetic crosses generated from Apoe or Lldlr mice for genetic analysis of atherosclerosis have used C57BL/6 J (B6) mice as one parental strain, thus limiting their mapping power and coverage of allelic diversity. SM/J-Apoe and BALB/cJ-Apoe mice differ significantly in atherosclerosis susceptibility. 224 male F mice were generated from the two Apoe strains to perform quantitative trait locus (QTL) analysis of atherosclerosis. F mice were fed 5 weeks of Western diet and analyzed for atherosclerotic lesions in the aortic root. Genome-wide scans with 144 informative SNP markers identified a significant locus near 20.2 Mb on chromosome 10 (LOD score: 6.03), named Ath48, and a suggestive locus near 49.5 Mb on chromosome 9 (LOD: 2.29; Ath29) affecting atherosclerotic lesion sizes. Using bioinformatics tools, we prioritized 12 candidate genes for Ath48. Of them, Tnfaip3, an anti-inflammatory gene, is located precisely underneath the linkage peak and contains two non-synonymous SNPs leading to conservative amino acid substitutions. Thus, this study demonstrates the power of forward genetics involving the use of a different susceptible strain and bioinformatics tools in finding atherosclerosis susceptibility genes.
几乎所有为进行动脉粥样硬化遗传分析而由载脂蛋白E（Apoe）或低密度脂蛋白受体（Lldlr）基因敲除小鼠产生的遗传杂交实验，都使用C57BL/6 J（B6）小鼠作为亲本之一，从而限制了它们的定位能力和等位基因多样性的覆盖范围。SM/J-Apoe和BALB/cJ-Apoe小鼠在动脉粥样硬化易感性方面存在显著差异。从这两种Apoe基因敲除品系中培育出224只雄性F1小鼠，以进行动脉粥样硬化的数量性状基因座（QTL）分析。给F1小鼠喂食5周西方饮食，然后分析主动脉根部的动脉粥样硬化病变。使用144个信息丰富的单核苷酸多态性（SNP）标记进行全基因组扫描，在10号染色体上20.2 Mb附近发现了一个显著基因座（LOD评分：6.03），命名为Ath48，在9号染色体上49.5 Mb附近发现了一个提示性基因座（LOD：2.29；Ath29），影响动脉粥样硬化病变大小。使用生物信息学工具，我们为Ath48确定了12个候选基因。其中，抗炎基因Tnfaip3恰好位于连锁峰下方，包含两个导致保守氨基酸替换的非同义SNP。因此，本研究证明了正向遗传学在寻找动脉粥样硬化易感基因方面的作用，该方法涉及使用不同的易感品系和生物信息学工具。
