IDENTIFYING POLYMORPHISMS IN THE LRP5 GENE IN BABOONS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 人类低密度脂蛋白受体相关蛋白5(LRP5)的突变是导致高和低骨密度(BMD)的骨骼疾病的原因。近交系小鼠的研究证实了LRP5突变对骨骼质量的几个方面的影响。在普通人群中，LRP5基因的变异在多大程度上导致了骨密度(BMD)的正常变化，目前是深入研究的主题，因为有大量的人受到骨质疏松症等骨脆性疾病的影响。最近的研究表明，LRP5基因的多态性可能确实导致了人群水平的骨密度差异。小鼠的研究正在帮助确定LRP5对骨骼影响的潜在机制，但将这种远亲物种的研究结果外推到人类可能是有问题的。它与人类在系统发育上的相似性以及由此导致的骨骼生理学和新陈代谢的相似性，使其成为研究人类骨骼维持遗传学的极佳模式。先前的一项研究表明，染色体11q12-13(LRP5区域)上的一个基因影响狒狒骨密度的正常变异，这是重要的证据。我们建议对狒狒的LRP5基因的相关部分进行测序，以表征这一人类骨骼维持和转换的灵长类动物模型中的遗传变异。LRP5的第2、3、4、6、7、8、9和10号外显子与骨量紊乱有关，我们将对120只狒狒进行测序，我们已经有了它们的骨密度数据。本研究的具体目的是：1)已知影响BMD的LRP5外显子序列，2)在SNPRC狒狒中发现这些外显子中的单核苷酸多态(SNPs)，3)在最初的狒狒样本中对观察到的SNPs与BMD之间的关联进行初步证据的分析。这一测序和SNP的发现将为NIH未来的应用提供必要的先导数据，为本研究中确定的SNP对另外556只动物进行基因分型，从而使大规模的关联研究能够确定是否有任何发现的SNP与BMD变异有关。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Mutations in the Low-density-lipoprotein-receptor-related protein 5 (Lrp5) in humans are responsible for skeletal disorders of both high and low bone mineral density (BMD). Inbred mouse studies have confirmed the effect of Lrp5 mutations on several aspects of bone quality. The extent to which variation in the Lrp5 gene contributes to normal variation in bone mineral density (BMD) in the general human population is currently the subject of intense investigation because of the large numbers of people affected by bone fragility diseases such as osteoporosis. Recent studies suggest that Lrp5 polymorphisms may indeed contribute to population level BMD variation. Mouse studies are serving to identify potential mechanisms of Lrp5 influence on bone, but extrapolation to humans of results from studies of such distantly related species can be problematic. The phylogenetic proximity of the baboon to humans and consequent similarities in skeletal physiology and metabolism make it an excellent model for studies of the genetics of human skeletal maintenance. A previous study shows significant evidence for a gene on chromosome 11q12-13 (the area of Lrp5) that affects normal variation in BMD in the baboon. We propose to sequence relevant portions of the Lrp5 gene in baboons to characterize genetic variation in this primate model for human bone maintenance and turnover. Exons 2,3,4,6,7,8, 9 and 10 of Lrp5 have been implicated in bone mass disorders and will be sequenced in 120 baboons for which we have existing data on BMD. The specific aims of this study are to: 1) sequence exons in Lrp5 known to affect BMD, 2) discover single nucleotide polymorphisms (SNPs) in these exons in SNPRC baboons, and 3) conduct analyses for tentative evidence of association between observed SNPs and BMD in the initial sample of baboons. This sequencing and SNP discovery will provide essential pilot data for a future application to the NIH to genotype another 556 animals for the SNPs identified in this study, thereby enabling a large scale association study to determine whether or not any of the discovered SNPs are associated with BMD variation.