Congenic Mouse Strains Harboring Bone Strength Quantitative Trait Loci

描述（由申请人提供）：预防骨折是一项重要的卫生保健挑战，因为脆性骨折已经很常见，并且随着美国人口的持续老龄化，这种情况将变得更加普遍。脆性骨折的易感性变化很大，遗传因素占这种变化的约50%。骨折风险取决于青年期达到的峰值骨量和骨骼形态以及此后骨丢失的速度和程度。小鼠为骨骼遗传学研究提供了一种有价值的动物模型。几个研究小组已经确定了有助于小鼠骨骼强度的遗传位点。利用HcB- 13 × HcB-14和HcB-8 × HcB-23重组同源系小鼠的杂交后代，对生物力学性能进行了QTL定位，QTL位于第1、2、3、4、6、10和X染色体上。我们假设，这些QTL将保留可证明的影响骨架分离后，作为完全同源株窝藏个别捐助者片段最终来自HcB系列的共同C57 BL/10 ScSnA祖先的C3 H/DiSnA背景。我们进一步假设，历史重组事件将有助于我们的努力，以确定潜在的QTL的基因，已经在4号染色体上的情况。该项目包括三个具体目标。首先，我们将构建4个含有C57 BL/10 ScSnA来源的供体片段的同源菌株，靶向具有最稳健的定位QTL的染色体。其次，我们将在N5 F2对早期同类进行表型，并在N10 F2对新建立的同类进行表型。因此，将评估供体区段基因型在C3 H/DiSnA背景背景下对表型的影响。第三，我们将确定亲本菌株HcB/8、HcB/13、HcB/14、HcB/23和早期同源菌株的遗传精细结构，并努力鉴定相关基因。从一个定位的QTL到一个鉴定的基因通常需要几个干预步骤，其中同源菌株是特别有价值的。第一个是确认基因座在隔离时保持其作用。接下来是利用交叉来细分负责基因的候选区间。HcB菌株已经经历了重组事件，这将证明在该分析阶段是有用的。这些努力最终在一组有限的候选基因的功能分析。同源株系在研究QTL间的上位性互作方面也有一定的应用价值。识别影响骨生物力学性能的基因并了解它们的相互作用将为设计更好的预防骨折措施提供可能，无论这些措施是否与衰老、极端负荷条件、其他疾病或药物不良反应有关。公共卫生相关性：我们已经绘制了导致小鼠骨强度和相关特性差异的基因。我们将通过标准的同类育种程序分离含有这些基因的染色体片段。我们将证实，在育种计划之后，骨骼效应仍然存在。我们将进行额外的遗传实验，以确定负责的基因。

DESCRIPTION (provided by applicant): Preventing fractures is an important health care challenge, as fragility fractures are already common and will become more so as the US population continues to age. Susceptibility to fragility fractures varies widely with genetic factors accounting for ~50% of this variation. Fracture risk is determined by peak bone mass and skeletal morphology achieved in young adulthood and the rate and extent of bone loss thereafter. Mice provide a valuable animal model for studying skeletal genetics. Several groups have identified genetic loci that contribute to bone strength in the mouse. We have mapped biomechanical performance quantitative trait loci (QTLs) in intercrosses of HcB- 13 x HcB-14 and HcB-8 x HcB 23 recombinant congenic mice, with QTLs located on chromosomes 1, 2, 3, 4, 6, 10, and X. We hypothesize that these QTLs will retain demonstrable effects on the skeleton following isolation as fully congenic strains harboring individual donor segments ultimately derived from HcB series' common C57BL/10ScSnA ancestor on a C3H/DiSnA background. We further hypothesize that historical recombination events will facilitate our efforts to identify the genes underlying the QTLs, as has been the case on chromosome 4. The project includes 3 specific aims. First, we will construct 4 congenic strains harboring C57BL/10ScSnA-derived donor segments, targeting chromosomes with the most robust mapped QTLs. Second, we will phenotype incipient congenics at N5F2 and newly established congenics at N10F2. The donor segment genotype's effect on phenotype in the context of the C3H/DiSnA background will thus be assessed. Third, we will determine the genetic fine structure of the parental strains HcB/8, HcB/13, HcB/14, HcB/23, and the incipient congenics and work toward identifying the responsible genes. Proceeding from a mapped QTL to an identified gene usually requires several intervening steps, for which congenic strains are particularly valuable. The first is to confirm that the locus retains its effect when isolated. The next is to exploit crossovers to subdivide the candidate interval for the responsible gene(s). The HcB strains have undergone recombination events that will prove useful at this stage of analysis. These efforts culminate in functional analyses of a restricted set of candidate genes. The congenic strains will also prove valuable in studying epistatic interactions between the individual QTLs. Identifying genes that affect bone biomechanical performance and understanding their interactions will offer the potential to design better measures to prevent fracture, regardless of whether these are related to aging, extreme loading conditions, other illnesses, or adverse effects from medications. PUBLIC HEALTH RELEVANCE: We have mapped genes that contribute to differences in bone strength and related properties in mice. We will isolate the chromosome segments that contain these genes by a standard congenic breeding program. We will confirm that the bone effects persist following the breeding program. We will perform additional genetic experiments to identify the responsible genes.