Comprehensive skeletal phenotyping and linkage mapping in an intercross of recombinant congenic mouse strains HcB-8 and HcB-23.
Comprehensive skeletal phenotyping and linkage mapping in an intercross of recombinant congenic mouse strains HcB-8 and HcB-23.
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重组同源小鼠品系 HcB-8 和 HcB-23 杂交中的全面骨骼表型分析和连锁图谱。
DOI：
10.1159/000324774
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Blank,RobertD
中科院分区：
文献类型：
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作者：
Saless,Neema;Litscher,SuzanneJ;Houlihan,MeghanJ;Han,InKyu;Wilson,Derek;Demant,Peter;Blank,RobertD
骨生物力学性能是一个复杂的特征，或者更准确地说，是一个复杂特征的集合。生物力学性能包括载荷下的柔韧性、屈服和破坏载荷以及破坏时的能量，这些都是衡量骨功能的重要指标。到目前为止，绝大多数的工作都集中在屈服和破坏载荷及其替代物--骨密度上。我们对小鼠品系HCB-8和HCB-23进行了反向杂交，以定位并最终确定导致生物力学性能差异的基因。力学测试采用股骨三点弯曲的方法。我们从骨折表面的照片中测量股骨干的横断面解剖。我们使用梁方程来计算材料层的力学性能。我们对标准化的全骨表型(17个输入性状)进行了主成分(PC)分析。我们测量了从校准的数码照片中分离下颌标志物的距离，并进行了连锁分析。通过排列检验建立了实验范围的α=0.0 5显著阈值。在这些研究中发现的三个数量性状基因座(QTL)说明了综合表型方法的优势。4号染色体上的一个多效性QTL影响多种全骨表型，LOD得分高达17.5，包括大小、横截面椭圆度、硬度、屈服和破坏载荷以及骨密度。该基因座与3个PC连锁，但与任何组织水平的表型无关。根据这一模式，我们推断，QTL通过调节对机械负荷的增殖反应来发挥作用。在此基础上，我们成功地预测了该基因座也会影响下颌骨特定区域的长度。10号染色体上LOD得分的多效性基因座对断裂载荷和韧性的影响相反，LOD得分分别为4.5和5.5，因此增加断裂载荷的等位基因降低韧性。PC2的19号染色体QTL的LOD分数为4.8，在整个骨骼或组织水平的表型中均未检测到。我们的结论是，首先，全面的、面向系统的表型分析提供了许多信息，这些信息不能仅通过关注骨密度来获得。其次，机械性能包括强度和脆性之间的内在权衡。第三，考虑到聚合的表型数据，可以预测新的QTL。
Bone biomechanical performance is a complex trait or, more properly, an ensemble of complex traits. Biomechanical performance incorporates flexibility under loading, yield and failure load, and energy to failure; all are important measures of bone function. To date, the vast majority of work has focused on yield and failure load and its surrogate, bone mineral density. We performed a reciprocal intercross of the mouse strains HcB-8 and HcB-23 to map and ultimately identify genes that contribute to differences in biomechanical performance. Mechanical testing was performed by 3-point bending of the femora. We measured femoral diaphysis cross-sectional anatomy from photographs of the fracture surfaces. We used beam equations to calculate material level mechanical properties. We performed a principal component (PC) analysis of normalized whole bone phenotypes (17 input traits). We measured distances separating mandibular landmarks from calibrated digital photographs and performed linkage analysis. Experiment-wide α= 0.05 significance thresholds were established by permutation testing. Three quantitative trait loci (QTLs) identified in these studies illustrate the advantages of the comprehensive phenotyping approach. A pleiotropic QTL on chromosome 4 affected multiple whole bone phenotypes with LOD scores as large as 17.5, encompassing size, cross-sectional ellipticity, stiffness, yield and failure load, and bone mineral density. This locus was linked to 3 of the PCs but unlinked to any of the tissue level phenotypes. From this pattern, we infer that the QTL operates by modulating the proliferative response to mechanical loading. On this basis, we successfully predicted that this locus also affects the length of a specific region of the mandible. A pleiotropic locus on chromosome 10 with LOD scores displays opposite effects on failure load and toughness with LOD scores of 4.5 and 5.5, respectively, so that the allele that increases failure load decreases toughness. A chromosome 19 QTL for PC2 with an LOD score of 4.8 was not detected with either the whole bone or tissue level phenotypes. We conclude that first, comprehensive, system-oriented phenotyping provides much information that could not be obtained by focusing on bone mineral density alone. Second, mechanical performance includes inherent trade-offs between strength and brittleness. Third, considering the aggregate phenotypic data allows prediction of novel QTLs.