Mapping RGC susceptibility alleles

青光眼被认为是一种复杂的遗传性疾病。青光眼的显著特征之一是对普通人群中存在的升高的眼压（IOP）的易感性。有些人在没有视神经病变的情况下患上眼高血压，而另一些人则在正常或低lop的情况下患上严重的疾病。当考虑青光眼的遗传成分时，等位基因变异可能会影响视网膜神经节细胞对凋亡刺激的反应能力和它们执行细胞死亡程序的效率。为了测试这种可能性，我们筛选了15种近交系小鼠，以确定它们的遗传背景是否影响标准化视神经挤压过程后视网膜神经节细胞的损失。筛选出耐药菌株DBA/2J和敏感菌株BALB/cByJ。这些菌株杂交的F1后代获得抗性表型。使用Wright公式分析亲本和F1群体的均值和方差表明，DBA/2J动物对挤压刺激的抗性贡献了一个显性等位基因。我们建议对这一数量性状位点进行分析。我们将从F2小鼠中生成一个定位群体，并使用选择性基因分型方法进行连锁分析，该方法使用信息多态性标记，这些标记以-20 cM的间隔跨越基因组。简单的联系将通过使用间隔映射计算LOD分数来确定，选择的重要区域将进行精细映射。这项研究的相关性在于，它将提供重要的遗传机制信息，涉及响应凋亡刺激的神经节细胞死亡过程，并可能确定影响人类IOP易感性的关键等位基因/基因。

DESCRIPTION: Glaucoma can be considered a complex genetic disease. One of the striking features of glaucoma is the variable susceptibility to elevated intraocular pressure (IOP) that is present in the general population. Some individuals become ocular hypertensive without ever developing an optic neuropathy, while others develop severe disease with normal or low lOPs. When considering the genetic components of glaucoma, it is likely that allelic variation can affect both the ability of retinal ganglion cells to respond to an apoptotic stimulus and their efficiency of executing the cell death program. To test this possibility, we screened 15 lines of inbred mice to determine if their genetic background affected the loss of retinal ganglion cells after a standardized optic nerve crush procedure. This screen led to the identification of a resistant strain (DBA/2J) and susceptible strain (BALB/cByJ). F1 progeny of an intercross of these strains acquire the resistant phenotype. Analysis of the means and variance of the parental and F1 populations using the Wright formula suggests that DBA/2J animals contribute a dominant allele for resistance to the crush stimulus. We propose to conduct an analysis of this quantitative trait locus. We will generate a mapping population from F2 mice and perform linkage analysis using a selective genotyping approach with informative polymorphic markers that span the genome at -20 cM intervals. Simple linkage will be determined by calculating LOD scores using interval mapping and select regions of significance will be subject to fine mapping. The relevance of this study is that it will provide important information on the genetic mechanisms involved in the process of ganglion cell death in response to an apoptotic stimulus and may identify a critical allele/gene that affects susceptibility to IOP in humans.