Dissection of Muscle Weight QTL Via Congenic Strains

描述(由申请人提供)： 利用同源品系分离肌肉重量QTL。虽然众所周知，肌肉质量是可遗传的，但影响它的遗传机制还不完全清楚。这种知识的缺乏限制了开发可用于防止肌肉损失的药物辅助手段的可能性。在小鼠模型中，肌肉重量的遗传结构是多基因的，有许多数量性状基因座(QTL)，每个基因座都解释了一小部分表型差异。我们的目标是启动Skmw11基因座的精细定位，并命名影响肌肉重量的基因(S)。我们在这个建议中的具体假设是，小鼠染色体(Chr)9含有影响肌肉重量的基因(S)。这一假设是基于C57BL/6J和DBA/2J小鼠品系的F2杂交结果，即携带C57BL/6J等位基因的小鼠的后肢肌肉明显大于携带DBA/2J等位基因的小鼠。具体目标是：1)通过利用一组C57BL/6.Psl1dba2同源菌株来精细定位Skmw11基因座，并产生额外的同源菌株以进一步缩小Chr9的相关区域。这将分两个阶段完成：(I)最初将在C57BL/6.Psl1dba2同源菌株和宿主菌株(C57BL/6J)中测量比目鱼肌、胫前肌(TA)、EDL、腓肠肌和二头肌(BB)的重量。(2)通过C57BL/6.Psl1dba2菌株的回交和在感兴趣区域进行重组的杂交后代，将产生更多针对阶段(I)中定义的区域的同源菌株。2)通过比较寄主菌株和同源菌株肌肉中水分、蛋白质和糖原的含量，探讨肌肉重量变化的机制。3)利用生物信息学方法，在同源菌株分析确定的可能影响肌肉重量的Chr 9区域内寻找候选基因。

DESCRIPTION (provided by applicant): Dissection of Muscle Weight QTL via Congenic Strains. Although muscle mass is known to be heritable, the genetic mechanisms influencing it are incompletely understood. This lack of knowledge limits possibilities of developing pharmaceutical aids that could be used to prevent muscle loss. Genetic architecture of muscle weight in a mouse model is polygenic, with many quantitative trait loci (QTL), each accounting for a small fraction of phenotypic variance. Our goal is to initiate fine mapping of the Skmw11 locus and nominate the gene(s) influencing muscle weight. Our specific hypothesis in this proposal is that mouse chromosome (Chr) 9 harbors gene(s) affecting muscle weight. The hypothesis is based on findings from an F2 intercross between C57BL/6J and DBA/2J mouse strains that mice carrying a C57BL/6J allele within a region of 66 - 123 Mb of distal Chr 9 had significantly larger hind limb muscles than those carrying a DBA/2J allele. The specific aims are: 1) to fine map the Skmw11 locus by exploiting the availability of a set of C57BL/6.Psl1dba2 congenic strains and generate additional congenic strains to narrow down further the relevant region of Chr 9. This will be accomplished in two stages: (i) initially the weight of soleus, tibialis anterior (TA), EDL, gastrocnemius and biceps brachii (BB) muscles will be measured in congenic C57BL/6.Psl1dba2 strains and the host strain (C57BL/6J). (ii) Additional congenic strains targeting the region defined in stage (i) will be generated by backcrossing of the C57BL/6.Psl1dba2 strains and intercrossing progeny with recombinations in the region of interest. 2) Explore the mechanisms underlying variation in muscle weight by comparing host and a congenic strain for the muscular content of water, protein and glycogen. 3) Using a bioinformatics approach, search for candidate genes within the region of Chr 9 defined by congenic strain analysis with the potential to influence muscle weight.