Mapping RGC susceptibility alleles

描述：青光眼可以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存在于一般人群中的对升高的眼内压（IOP）的可变易感性。 一些个体变得高眼压而从未发展成视神经病变，而另一些个体发展成具有正常或低IOP的严重疾病。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及其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个近交系小鼠，以确定它们的遗传背景是否会影响标准化视神经挤压手术后视网膜神经节细胞的丢失。该筛选导致鉴定了抗性菌株（DBA/2 J）和敏感菌株（BALB/cByJ）。这些菌株互交的F1后代获得抗性表型。使用Wright公式对亲本和F1群体的均值和方差进行分析表明，DBA/2 J动物对挤压刺激的抗性具有显性等位基因。 我们建议对这个数量性状位点进行分析。我们将从F2小鼠中产生作图群体，并使用选择性基因分型方法进行连锁分析，该方法具有以约20 cM间隔跨越基因组的信息多态性标记。将通过使用区间作图计算LOD评分来确定简单连锁，并将对选择的显著区域进行精细作图。本研究的相关性在于，它将提供有关神经节细胞响应于凋亡刺激而死亡的过程中所涉及的遗传机制的重要信息，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.