To identify genes involved in cerebral infarction, we have employed a forward genetic approach in inbred mouse strains, using quantitative trait loci (QTL) mapping for cerebral infarct volume after middle cerebral artery occlusion. We had previously observed that infarct volume is inversely correlated with cerebral collateral vessel density in most strains. In this study, we expanded the pool of allelic variation among classical inbred mouse strains by utilizing the eight founder strains of the Collaborative Cross and found a wild-derived strain, WSB/EiJ, that breaks this general rule that collateral vessel density inversely correlates with infarct volume. WSB/EiJ and another wild-derived strain, CAST/EiJ, show the highest collateral vessel densities of any inbred strain, but infarct volume of WSB/EiJ mice is 8.7-fold larger than that of CAST/EiJ mice. QTL mapping between these strains identified four new neuroprotective loci modulating cerebral infarct volume while not affecting collateral vessel phenotypes. To identify causative variants in genes, we surveyed nonsynonymous coding SNPs between CAST/EiJ and WSB/EiJ and found 96 genes harboring coding SNPs predicted to be damaging and mapping within one of the four intervals. In addition, we performed RNA-sequencing for brain tissue of CAST/EiJ and WSB/EiJ mice and identified 79 candidate genes mapping in one of the four intervals showing strain-specific differences in expression. The identification of the genes underlying these neuroprotective loci will provide new understanding of genetic risk factors of ischemic stroke, which may provide novel targets for future therapeutic intervention of human ischemic stroke.

中文翻译：

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野生近交系小鼠品系中调节缺血性中风量的新型神经保护位点。


为了鉴定与脑梗塞相关的基因，我们在近交系小鼠品系中采用了正向遗传方法，利用数量性状位点（QTL）作图来确定大脑中动脉闭塞后的脑梗塞体积。我们之前观察到，在大多数菌株中，梗塞体积与脑侧支血管密度呈负相关。在这项研究中，我们利用协作杂交的八个创始品系扩大了经典近交小鼠品系中的等位基因变异库，并发现了一种野生衍生品系 WSB/EiJ，它打破了侧支血管密度与侧支血管密度成反比的这一一般规则。梗塞体积。 WSB/EiJ 和另一种野生品系 CAST/EiJ 表现出所有近交系小鼠中最高的侧支血管密度，但 WSB/EiJ 小鼠的梗塞体积比 CAST/EiJ 小鼠大 8.7 倍。这些菌株之间的 QTL 作图确定了四个新的神经保护位点，可调节脑梗塞体积，同时不影响侧支血管表型。为了识别基因中的致病变异，我们调查了 CAST/EiJ 和 WSB/EiJ 之间的非同义编码 SNP，发现 96 个基因含有预计会造成损害的编码 SNP，并定位在四个区间之一内。此外，我们对 CAST/EiJ 和 WSB/EiJ 小鼠的脑组织进行了 RNA 测序，并在四个间隔之一中鉴定了 79 个候选基因，显示了品系特异性表达差异。这些神经保护位点基因的鉴定将为缺血性中风的遗传危险因素提供新的认识，这可能为未来人类缺血性中风的治疗干预提供新的靶点。