Indiana University School of Medicine, Indiana University Indianapolis, IN, USA.
Bone. 2011 May 1;48(5):1169-77. doi: 10.1016/j.bone.2011.02.009. Epub 2011 Feb 18.
Previously, we demonstrated that skeletal mass, structure and biomechanical properties vary considerably among 11 different inbred rat strains. Subsequently, we performed quantitative trait loci (QTL) analysis in four inbred rat strains (F344, LEW, COP and DA) for different bone phenotypes and identified several candidate genes influencing various bone traits. The standard approach to narrowing QTL intervals down to a few candidate genes typically employs the generation of congenic lines, which is time consuming and often not successful. A potential alternative approach is to use a highly genetically informative animal model resource capable of delivering very high resolution gene mapping such as Heterogeneous stock (HS) rat. HS rat was derived from eight inbred progenitors: ACI/N, BN/SsN, BUF/N, F344/N, M520/N, MR/N, WKY/N and WN/N. The genetic recombination pattern generated across 50 generations in these rats has been shown to deliver ultra-high even gene-level resolution for complex genetic studies. The purpose of this study is to investigate the usefulness of the HS rat model for fine mapping and identification of genes underlying bone fragility phenotypes. We compared bone geometry, density and strength phenotypes at multiple skeletal sites in HS rats with those obtained from five of the eight progenitor inbred strains. In addition, we estimated the heritability for different bone phenotypes in these rats and employed principal component analysis to explore relationships among bone phenotypes in the HS rats. Our study demonstrates that significant variability exists for different skeletal phenotypes in HS rats compared with their inbred progenitors. In addition, we estimated high heritability for several bone phenotypes and biologically interpretable factors explaining significant overall variability, suggesting that the HS rat model could be a unique genetic resource for rapid and efficient discovery of the genetic determinants of bone fragility.
先前，我们证实了 11 种不同近交系大鼠的骨骼质量、结构和生物力学特性存在显著差异。随后，我们针对四种近交系大鼠（F344、LEW、COP 和 DA）的不同骨骼表型进行了数量性状基因座（QTL）分析，并鉴定出了一些影响多种骨骼特征的候选基因。通常，将 QTL 区间缩小到少数候选基因的标准方法是生成近交系，这既耗时又常常不成功。一种潜在的替代方法是使用能够提供非常高分辨率基因映射的高度遗传信息丰富的动物模型资源，例如异质 stock（HS）大鼠。HS 大鼠源自 8 个近交系祖代：ACI/N、BN/SsN、BUF/N、F344/N、M520/N、MR/N、WKY/N 和 WN/N。这些大鼠经过 50 代的遗传重组，已经显示出能够提供非常高的基因分辨率，用于复杂的遗传研究。本研究的目的是研究 HS 大鼠模型在精细定位和鉴定骨骼脆弱表型相关基因中的作用。我们比较了 HS 大鼠和 8 个祖代近交系大鼠多个骨骼部位的骨骼几何形状、密度和强度表型。此外，我们还估计了这些大鼠不同骨骼表型的遗传力，并采用主成分分析探索了 HS 大鼠骨骼表型之间的关系。我们的研究表明，与它们的近交系祖代相比，HS 大鼠的不同骨骼表型存在显著的变异性。此外，我们还估计了几种骨骼表型的高遗传力，并确定了可解释整体变异性的生物学可解释因素，这表明 HS 大鼠模型可能是一种独特的遗传资源，可用于快速有效地发现骨骼脆弱的遗传决定因素。
