Dissection of Muscle Weight QTL Via Congenic Strains

描述（由申请人提供）： 通过同源品系剖析肌肉重量QTL。 虽然肌肉质量是已知的遗传，影响它的遗传机制是不完全理解。这种知识的缺乏限制了开发可用于预防肌肉损失的药物辅助的可能性。在小鼠模型中，肌肉重量的遗传结构是多基因的，具有许多数量性状基因座（QTL），每个QTL占表型方差的一小部分。我们的目标是启动Skmw 11基因座的精细定位，并提名影响肌肉重量的基因。我们在这一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。该假设基于C57 BL/6 J和DBA/2 J小鼠品系之间F2杂交的发现，即在远端Chr 9的66 - 123 Mb区域内携带C57 BL/6 J等位基因的小鼠比携带DBA/2 J等位基因的小鼠具有显著更大的后肢肌肉。具体目标是：1）通过利用一组C57 BL/6.Psl1dba2同源菌株的可用性来精细定位Skmw 11基因座，并产生额外的同源菌株以进一步缩小Chr 9的相关区域。这将分两个阶段完成：（i）最初，将在同类C57 BL/6.Psl1dba2品系和宿主品系（C57 BL/6 J）中测量比目鱼肌、胫骨前肌（TA）、EDL、腓肠肌和肱二头肌（BB）肌肉的重量。(ii)将通过C57 BL/6.Psl1dba2菌株的回交和与目标区域中的重组的互交后代产生靶向阶段（i）中定义的区域的其他同源菌株。2)通过比较宿主和同源品系的肌肉水分、蛋白质和糖原含量，探讨肌肉重量变化的机制。3)使用生物信息学的方法，搜索候选基因的区域内的Chr 9定义的同源株分析与潜在的影响肌肉重量。

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.