MOUSE GENETIC RESOURCES FOR MULTIGENIC DISEASE ANALYSIS

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。描述(由申请人提供)：许多常见人类疾病的模型和许多具有重大生物学意义的特征在近亲交配的实验室小鼠品系中有所不同。剖析它们的多基因控制和识别负责基因一直是出了名的困难。染色体置换菌株(CSSs)是在特定的近亲交配的遗传背景上进行的单染色体置换，代表了一种新颖而强大的范式。用其他来源的资金进行的概念验证研究表明，这些菌株在检测用任何其他作图方法都无法检测到的遗传变异方面非常强大。在上一个资助期间，我们完成了B6.A-CHR面板中的22个CSS的建造工作。这些菌株被提供给杰克逊实验室保存和分发，作为生物医学研究社区的资源。此外，1个A.B6-Chr CS，以及8个129.B6和B6.129 CSSS已经完成，其余的面板正在建造中。我们提出了两个具体目标：具体目标1：完成129.B6和B6.129 CSSS的建设。8个品系已完成，其余品系处于回交的不同阶段。这些CSS可以用来剖析这些菌株之间不同性状的遗传控制，它们可以用来表征修饰基因，这些修饰基因调节由来自129/Sv小鼠的ES(胚胎干细胞)细胞产生的工程突变小鼠的表型，它们可以用来识别对建立ES细胞系至关重要的蛋白质。具体目标2：完成10个129个MOLF CSS的建设。这些品系对于研究这些品系之间的不同特征将是有价值的，这些品系来自10万多年前分化的小鼠。这些菌株还可以用来表征调节这些小鼠表型的修饰基因。这些css面板将通过促进QTL的检测和发现，使复杂性状的研究发生革命性变化。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. DESCRIPTION (provided by applicant): Many models of common human diseases and numerous traits of great biological interest vary among inbred strains of laboratory mice. Dissecting their multigenic control and identifying the responsible genes has been notoriously difficult. Chromosome substitution strains (CSSs), single chromosome substitutions on a defined and inbred genetic background, represent a novel and powerful paradigm. Proof-of-concept studies, with funds from other sources, demonstrated that these strains are remarkably powerful for detecting genetic variants that eluded detection with any other mapping method. During the previous funding period, we completed construction of the 22 CSSs in the B6.A-Chr panel. These strains were provided to the Jackson Laboratory for preservation and distribution as a resource for the biomedical research community. In addition, one A.B6-Chr CSS, and eight 129.B6 and B6.129 CSSs were completed and the remainder of these panels is under construction. We propose two Specific Aims: Specific Aim 1: Complete construction of the 129.B6 and B6.129 CSSs. Eight strains are complete and the remainder is at various stages of backcrossing. These CSSs can be used to dissect the genetic control of traits that differ between these strains, they can be used to characterize modifier genes that modulate phenotypes of mice with engineered mutations that are made with ES (embryonic stem) cells that are derived from 129/Sv mice, and they can be used to identify proteins that are critical to establish ES cell lines. Specific Aim 2: Complete construction of 10 129.MOLF CSSs. These strains will be valuable for studying traits that differ between these strains that are derived from mice that diverged more than 100,000 years ago. These strains can also be used to characterize modifier genes that modulate phenotypes in these mice. These CSS panels will revolutionize studies of complex traits by facilitating detection and discovery of QTLs.