Wergedal Jon E, Ackert-Bicknell Cheryl L, Tsaih Shirng-Wern, Sheng Matilda H-C, Li Renhua, Mohan Subburamen, Beamer Wesley G, Churchill Gary A, Baylink David J
Musculoskeletal Disease Center, J. L. Pettis Memorial VA Medical Center, Loma Linda, CA 92357, USA.
J Bone Miner Res. 2006 Aug;21(8):1256-66. doi: 10.1359/jbmr.060510.
Genetic analysis of an NZB/B1NJ x RF/J cross has identified QTLs for femur mechanical, geometric, and densitometric phenotypes. Most mechanical QTLs were associated with geometric QTLs, strongly suggesting common genetic regulation.
Previous studies have shown that bone architecture and BMD are important factors affecting bone strength, and both are genetically regulated. We conducted genetic analyses for loci regulating femur mechanical properties, geometric properties, and BMD in a cohort of F2 mice derived from intercross matings of (NZB/B1NJ x RF/J)F1 parents.
Femurs were isolated from 662 10-week-old females. Mechanical properties were determined for a femur from each animal by three-point bending. Geometric properties and volumetric BMD (vBMD) were determined by pQCT. Genotype data were obtained by PCR assays for polymorphic markers carried in the genomic DNA of each mouse. Genome-wide scans were carried out for co-segregation of genetic marker data with values from 23 different phenotypes. Quantitative trait loci (QTLs) were identified for mechanical, geometric, and mineral density phenotypes.
QTLs for many phenotypes were significantly refined by covariate analyses using body weight and femur length. Major QTLs for mechanical and geometric phenotypes were found on chromosomes 5, 7, 9, 11, and 12. Nine chromosomal locations were identified with mechanical QTLs and 17 locations with one or more geometric QTLs. The significance of five mechanical and nine geometric QTLs was affected by the inclusion of covariates. These changes included both decreases and increases in significance. The QTLs on chromosomes 5 and 12 were decreased by inclusion of the covariates in the analysis, but QTLs on 7 and 11 were unaffected. Mechanical QTLs were almost always associated with geometric QTLs and less commonly (two of six) with vBMD QTLs.
Genetic regulation of mechanical properties in the F(2) mice of this NZB/B1NJ x RF/J cross seems to be caused by genes regulating femur geometry.
对NZB/B1NJ×RF/J杂交后代的遗传分析确定了股骨机械、几何和骨密度表型的数量性状基因座（QTL）。大多数机械QTL与几何QTL相关，强烈提示存在共同的遗传调控。
先前的研究表明，骨结构和骨密度是影响骨强度的重要因素，且二者均受遗传调控。我们对由（NZB/B1NJ×RF/J）F1亲本杂交产生的F2小鼠群体中调控股骨机械性能、几何性能和骨密度的基因座进行了遗传分析。
从662只10周龄雌性小鼠中分离出股骨。通过三点弯曲测定每只动物一根股骨的机械性能。通过外周定量计算机断层扫描（pQCT）测定几何性能和体积骨密度（vBMD）。通过PCR检测每只小鼠基因组DNA中携带的多态性标记获得基因型数据。对遗传标记数据与23种不同表型的值进行全基因组扫描以共分离。确定了机械、几何和矿物质密度表型的数量性状基因座（QTL）。
使用体重和股骨长度进行协变量分析后，许多表型的QTL得到了显著优化。在5号、7号、9号、11号和12号染色体上发现了机械和几何表型的主要QTL。确定了9个存在机械QTL的染色体位置和17个存在一个或多个几何QTL的位置。纳入协变量影响了5个机械QTL和9个几何QTL的显著性。这些变化包括显著性的降低和升高。分析中纳入协变量后，5号和12号染色体上的QTL显著性降低，但7号和11号染色体上的QTL不受影响。机械QTL几乎总是与几何QTL相关，与vBMD QTL的相关性较少（六分之二）。
在这个NZB/B1NJ×RF/J杂交的F2小鼠中，机械性能的遗传调控似乎是由调控股骨几何形状的基因引起的。
