A Mouse Model For Complex Human Diseases

描述(由申请人提供)：我们建议继续开发和维护LGXSM重组近交系(RL)品系集和由近交系LG/J和SM/J杂交形成的相关高级杂交(Al)系。RIS是一个初步基因定位的工具，之后Al Line可用于将数量性状座位精细定位到亚Cm区域。在前期的支持下，我们培育了一套由LG/J和SM/J杂交形成的18个RL系，并将该Al系引入第32代随机交配。RL品系共检测到500多个多态微卫星标记和4290个多态SNPs，每600kb有1个多态SNPs。对每个RL品系的胚胎都进行了冷冻保存。这些品系和由LG/J和SM/J杂交形成的其他群体，使得NIH研究所能够绘制与感兴趣的疾病过程相关的大量表型图。在这里，我们建议利用目前的Al系作为源群体，通过培育另外50个RL品系来增强RL品系集。这些菌株的加入将极大地提高RL菌株集在基因图谱研究中的能力。新的菌株将比早期的菌株更有用，因为它们积累的重组量是由F2代形成的RL系预期重组量的16倍。此外，我们将能够利用我们以前的育种经验，通过针对单个或组合导致菌株损失的特定位点进行选择，将菌株存活率提高到新菌株生产的50%。这些新菌株将通过500个微卫星和4290个SNPs进行基因特征分析，并通过胚胎冷冻保存进行存档。菌株的基因类型和表型将通过我们的网站、小鼠表型组计划和WebQTL数据库获得。在我们早期的育种中，我们发现了对SM/J携带的刺鼠等位基因的强烈选择，特别是在该菌株存在野生型酪氨酸酶等位基因的情况下。我们将通过对这两个基因座和紧密连锁的基因座的结构基因进行测序，来研究菌株损失的遗传基础。我们将生产2ble 基因组中除刺鼠和酪氨酸酶区域外的SM/J同源菌株。 与SM/J的回交将被用来缩小品系损失的QTL间隔，并产生一个新的品系，该品系携带不寻常的SM/J表型，而不需要在刺鼠座位上强制杂合性。

DESCRIPTION (provided by applicant): We propose to continue the development and maintenance of the LGXSM Recombinant Inbred (Rl) strain set and the associated Advanced Intercross (Al) Line formed by the intercross of inbred mouse strains LG/J and SM/J. The RIs are a tool for preliminary gene mapping, after which the Al Line can be used for finemapping quantitative trait loci to sub-cM regions. Under prior support we have developed a set of 18 Rl lines formed from the intercross of LG/J and SM/J and brought the Al line to the 32nd generation of random mating. The Rl lines have been scored for over 500 polymorphic microsatellite markers and for 4290 polymorphic SNPs, a polymorphic SNPs every 600 kb. Embryos have been cryopreserved for each Rl lines. These lines and other populations formed from the intercross of LG/J and SM/J have allowed the mapping of a large array of phenotypes relevant to disease processes of interest across the NIH Institutes. Here, we propose to enhance the Rl strain set by developing another 50 Rl strains using the present Al line as the source population. The addition of these strains will greatly increase the power of the Rl strain set in gene mapping studies. The new strains will be even more useful than the earlier set in that they will have accumulated 16 times the amount of recombination expected in Rl lines formed from a F2 generation. Furthermore, we will be able to use our prior breeding experience to increase strain survival to 50% in the production of new strains by selecting against specific loci that, singly and in combination, result in strain loss. The new strains will be genetically characterized for 500 microsatellites and 4290 SNPs and archived by embryonic cryopreservation. Strain genotypes and phenotypes will be made available through our web site, the Mouse Phenome Project, and the WebQTL database. In our earlier breeding, we discovered strong selection against the agouti alleles carried by SM/J, especially in the presence of the wild-type tyrosinase allele from that strain. We will examine the genetic basis for strain loss by sequencing the structural genes at these two loci and closely linked loci. We will produce 2ble congenic strains that are SM/J across the genome, except at the agouti and tyrosinase regions. Backcrossing with SM/J will be used to narrow the QTL interval for strain loss and to produce a new strain, carrying the unusual phenotypes of SM/J without requiring enforced heterozygosity at the agouti locus.