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重组自交系（Rl）和由自交系LG/J和SM/J杂交形成的相关高级杂交（Al）系。RIs是初步基因定位的工具，之后可以使用Al Line将数量性状位点精细定位到亚cm区域。在前期的支持下，通过LG/J和SM/J的杂交，我们培育出了18个Rl系，并将Al系随机杂交到第32代。对Rl系进行了500多个多态性微卫星标记和4290个多态性snp的标记，每600 kb有一个多态性snp。每个Rl系的胚胎都已冷冻保存。这些系和其他由LG/J和SM/J交叉形成的种群已经允许绘制与NIH研究所感兴趣的疾病过程相关的大量表型。在此，我们建议以现有的Al系为源群体，开发另外50个Rl菌株来增强Rl菌株集。这些菌株的加入将大大提高Rl菌株集在基因定位研究中的能力。新菌株将比之前的菌株更有用，因为它们将积累16倍于F2代形成的Rl系的重组量。此外，我们将能够利用我们之前的育种经验，通过选择单独或组合导致菌株损失的特定位点，将菌株存活率提高到新菌株生产的50%。新菌株将获得500个微卫星和4290个snp的遗传特征，并通过胚胎冷冻保存存档。菌株基因型和表型将通过我们的网站、小鼠表型计划和WebQTL数据库提供。在早期的育种中，我们发现对SM/J携带的刺鼠等位基因有很强的选择，特别是在该菌株的野生型酪氨酸酶等位基因存在的情况下。我们将通过对这两个位点和紧密相连的位点的结构基因测序来研究菌株损失的遗传基础。我们将生产2ble

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.