GENETIC ANALYSIS OF BONE MASS IN MICE

数量性状基因座（QTL）是染色体区域，含有影响数量（或复杂）性状的基因，如峰值骨量。 在过去的三年中，目前RO 1的资金，我们已经绘制了几个QTL，共同有一个重大影响的峰值骨密度的人口来自C57 BL/6（B6）和DBA/2（D2）近交系小鼠品系。 4个最大的QTL（LOD大于6）位于第1、2、4和11染色体上。 基于小鼠-人连锁同源性，将4个小鼠QTL的人对应位点分别定位在人类染色体1 q41 -43、11号、1 p36和5 q23 -31的近着丝粒区。 这些区域中的每一个都在最近的人类遗传学研究中被确定，表明这些是高度相关的QTL，显然值得进一步评估。使用同源株系，其中这四个QTL中的每一个都已被分离出一个统一的（近交）遗传背景，我们建议继续这些研究，最终确定的基因（S），每个QTL的基础。 为了实现这一点，我们建议开发小供体片段同源株，只有1-2 cM的渗入片段含有QTL。 我们还将开始通过在全基因组范围内搜索上位相互作用位点来研究QTL与基因组中影响或控制QTL表达的其他位点之间的相互作用。 将检索小鼠和人基因数据库，以查找在每个SDS同源菌株的1cM渗入区域内定位的候选基因。 在人类数据库的情况下，这将涉及已知小鼠-人连锁同源性的区域。将检测存在于这些狭窄染色体区域内的有希望的候选基因的基因型依赖性表达和/或序列差异。使用这些强大的动物模型，我们很有可能在这四个染色体区域中的每一个区域中分离出参与骨量调节的推定靶基因。 潜在候选基因的鉴定将代表我们对骨骼发育的理解向前迈出了一大步，并对骨质疏松症高危个体的检测具有重要意义。

Quantitative trait loci (QTLs) are chromosomal regions containing genes that influence a quantitative (or complex) trait such as peak bone mass. During the last three years of present RO1 funding, we have mapped several QTLs that jointly have a major influence on the attainment of peak bone mineral density in populations derived from C57BL/6 (B6) and DBA/2 (D2) inbred mouse strains. The four largest QTLs (LOD greater than 6) are on chromosomes 1, 2, 4, and 11. Based on mouse-human linkage homology the human counterparts of the four mouse QTLs map of human chromosomes 1q41-43, the pericentromeric region of 11, 1p36 and 5q23-31, respectively. Each of these regions have been identified in recent human genetic studies suggesting that these are highly relevant QTLs, clearly deserving further evaluation. Using congenic strains in which each of these four QTLs have been isolated against a uniform (inbred) genetic background, we propose to continue these studies toward the eventual identification of the gene(s) that underlie each QTL. To accomplish this, we propose to develop small donor segment congenic strains with only a 1-2 cM introgressed segment containing the QTL. We will also begin to examine the interplay among QTLs and other loci in the genome that influence or control QTL expression by conducting a genome- wide search for epistatically-interacting loci. Mouse and human gene databases will be searched to find candidate genes that map within the 1cM introgressed region in each SDS congenic strain. In the case of human databases, this will involve regions of known mouse-human linkage homology. Promising candidate genes that reside within these narrow chromosomal regions will be tested for genotype-dependent expression and/or sequence differences. Using these powerful animal models, we have a high likelihood of isolating putative target genes within each of these four chromosomal regions that participate in the regulation of bone mass. The identification of potential candidate genes would represent a huge step forward in our understanding of skeletal development and should have important implications for the detection of individuals at high risk for osteoporosis.