Edderkaoui Bouchra, Baylink David J, Beamer Wesley G, Wergedal Jon E, Dunn Nancy R, Shultz Kathryn L, Mohan Subburaman
Musculoskeletal Disease Center, Jerry L. Pettis Memorial VA Medical Center, Loma Linda, California 92357, USA.
J Bone Miner Res. 2006 Jan;21(1):97-104. doi: 10.1359/JBMR.051008. Epub 2005 Oct 17.
Skeletal phenotype analyses of 10 B6.CAST-1 congenic sublines of mice have revealed evidence for the presence of three closely linked QTLs in Chr 1 that influence femoral vBMD both positively and negatively.
BMD is an important component of bone strength and a recognized predictor of risk for osteoporotic fracture. Our goal in this study was to fine map the chromosomal location of volumetric BMD (vBMD) quantitative trait loci (QTLs) in mouse distal chromosome 1 (Chr 1).
After several backcrosses of the B6.CAST-1T congenic strain, which carried the initial BMD QTL in Chr 1 with B6 mice, the N10F1 generation mice were intercrossed to obtain recombinations that yielded different regions of the QTL. Thirty-eight polymorphic markers were used to fine map the initial 1T QTL region (100-192 Mb). Different skeletal parameters were compared between the 10 sublines and B6 female mice at 16 weeks of age. A t-test was used to determine the significant difference between sublines and B6 control mice, whereas one-way ANOVA and posthoc (Newman-Keuls) tests were performed to compare the phenotype between the sublines.
Significantly higher femur vBMD was found in sublines that carried cast alleles from 100 to 169 and 172 to 185 Mb of the centromere compared with the B6 control mice (10-12%, p < 0.001). However, sublines that carried cast alleles from 185 to 192 Mb showed significantly lower femur vBMD compared with the control mice (-6%, p < 0.05). Furthermore, femur vBMD phenotype showed a negative correlation with endosteal circumference (r = -0.8, p = 0.003), and a strong correlation with cortical thickness for combined data from the 10 sublines (r = 0.97, p < 0.001). Moreover, a high correlation was found between body weight and both periosteal and endosteal circumferences for sublines carrying cast alleles from 167 to 175, 168 to 185, and 169 to 185 Mb, whereas no significant correlation was found between these parameters for sublines carrying cast alleles from 172 to 185 Mb.
Genetic analysis using congenic sublines revealed that the initial BMD QTL on Chr 1 is a complex site with multiple loci affecting bone phenotypes, showing the value of the congenic approach in clearly identifying loci that control specific traits.
对10个B6.CAST-1同源近交系小鼠的骨骼表型分析揭示，在1号染色体上存在3个紧密连锁的数量性状基因座（QTL），它们对股骨体积骨密度（vBMD）有正向和负向影响。
骨密度是骨强度的重要组成部分，也是骨质疏松性骨折风险的公认预测指标。本研究的目的是精细定位小鼠1号染色体远端（Chr 1）体积骨密度（vBMD）数量性状基因座（QTL）的染色体位置。
将携带1号染色体上初始骨密度QTL的B6.CAST-1T同源近交系与B6小鼠进行多次回交后，使N10F1代小鼠相互杂交以获得产生QTL不同区域的重组体。使用38个多态性标记精细定位初始1T QTL区域（100-192 Mb）。比较了10个亚系和16周龄B6雌性小鼠之间的不同骨骼参数。采用t检验确定亚系与B6对照小鼠之间的显著差异，而采用单因素方差分析和事后（Newman-Keuls）检验比较亚系之间的表型。
与B6对照小鼠相比，携带着丝粒100至169 Mb和172至185 Mb的CAST等位基因的亚系中，股骨vBMD显著更高（10-12%，p<0.001）。然而，携带185至192 Mb的CAST等位基因的亚系与对照小鼠相比，股骨vBMD显著更低（-6%，p<0.05）。此外，股骨vBMD表型与骨内膜周长呈负相关（r = -0.8，p = 0.003），并且对于来自10个亚系的合并数据，与皮质厚度呈强相关（r = 0.97，p<0.001）。此外，对于携带167至175 Mb、168至185 Mb和169至185 Mb的CAST等位基因的亚系，体重与骨膜和骨内膜周长之间存在高度相关性，而对于携带172至185 Mb的CAST等位基因的亚系，这些参数之间未发现显著相关性。
使用同源近交系进行的遗传分析表明，1号染色体上的初始骨密度QTL是一个复杂位点，有多个影响骨表型的基因座，显示了同源近交系方法在明确识别控制特定性状的基因座方面的价值。
