Department of Biology, University of North Carolina at Charlotte, Charlotte, NC 28223, USA.
Bone. 2013 Jul;55(1):222-9. doi: 10.1016/j.bone.2013.02.014. Epub 2013 Feb 26.
Osteoporosis, characterized by low levels of bone mineral density (BMD), is a prevalent medical condition in humans. We investigated its genetic and environmental basis by searching for quantitative trait loci (QTLs) affecting six skeletal (including three BMD) traits in a G10 advanced intercross population produced from crosses of mice from the inbred strain C57BL/6J with mice from a strain selected for high voluntary wheel running. The mice in this population were fed either a high-fat or a matched control diet throughout the study, allowing us to test for QTL by diet interactions for the skeletal traits. Our genome scan uncovered a number of QTLs, the great majority of which were different from QTLs previously found for these same traits in an earlier (G4) generation of the same intercross. Further, the confidence intervals for the skeletal trait QTLs were reduced from an average of 18.5 Mb in the G4 population to an equivalent of about 9 Mb in the G10 population. We uncovered a total of 50 QTLs representing 32 separate genomic sites affecting these traits, with a distal region on chromosome 1 harboring several QTLs with large effects on the BMD traits. One QTL was located on chromosome 5 at 4.0 Mb with a confidence interval spanning from 4.0 to 4.6 Mb. Only three protein coding genes reside in this interval, and one of these, Cyp51, is an attractive candidate as others have shown that developing Cyp51 knockout embryos exhibit shortened and bowed limbs and synotosis of the femur and tibia. Several QTLs showed significant interactions with sex, although only two QTLs interacted with diet, both affecting only mice fed the high-fat diet.
骨质疏松症的特征是骨矿物质密度（BMD）低，是人类常见的医学病症。我们通过在由近交系 C57BL/6J 小鼠与高自愿轮跑选择系小鼠杂交产生的 G10 代高级互交群体中寻找影响六个骨骼（包括三个 BMD）特征的数量性状基因座（QTL）来研究其遗传和环境基础。在这项研究中，该群体中的所有小鼠均在整个研究过程中分别喂食高脂肪或匹配的对照饮食，这使我们能够通过骨骼特征的饮食相互作用来测试 QTL。我们的全基因组扫描发现了许多 QTL，其中绝大多数与之前在同一互交的早期（G4）世代中发现的这些相同特征的 QTL 不同。此外，骨骼特征 QTL 的置信区间从 G4 群体的平均 18.5 Mb 缩小到 G10 群体的大约 9 Mb。我们总共发现了 50 个 QTL，代表了影响这些特征的 32 个独立基因组位点，1 号染色体的远端区域有几个对 BMD 特征有较大影响的 QTL。一个 QTL 位于 5 号染色体上的 4.0 Mb，置信区间从 4.0 到 4.6 Mb。只有三个蛋白编码基因位于该区间内，其中一个是 Cyp51，它是一个有吸引力的候选基因，因为其他人已经表明，Cyp51 敲除胚胎的发育表现出四肢缩短和弯曲，以及股骨和胫骨的 synotosis。几个 QTL 与性别表现出显著的相互作用，尽管只有两个 QTL 与饮食相互作用，这两个 QTL 都仅影响喂食高脂肪饮食的小鼠。
