A Mouse Model For Complex Human Diseases

复杂人类疾病的小鼠模型

• 批准号: 7237952
• 负责人: JAMES M CHEVERUD
• 金额: $ 37.02万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7237952
• 关键词: A Mouse; Affect; Aftercare; Alleles; Anatomy; Animals; Archives; Back; Backcrossings; Basic Science; Biological Models; Birth; Breeding; Brothers; Caring; Characteristics; Chromosome Mapping; Chromosomes, Human, Pair 2; Chromosomes, Human, Pair 7; Color; Communities; Complement; Complex; Congenic Strain; Cryopreservation; Data; Databases; Decision Making; Development; Disease; Embryo; Fertility; Funding; Generations; Genetic; Genetic Epistasis; Genetic Models; Genetic Recombination; Genetic Variation; Genome; Genome Mappings; Genomics; Genotype; Inbred Mouse; Inbred Strain; Inbred Strains Mice; Inbreeding; Institutes; Internet; LG/J Mouse; Life; Link; Location; Maintenance; Maps; Microsatellite Repeats; Monophenol Monooxygenase; Mus; Mutant Strains Mice; Neurobiology; Numbers; Partner in relationship; Phase; Phenotype; Polymorphic Microsatellite Marker; Population; Positioning Attribute; Preparation; Process; Production; Publications; Quantitative Trait Loci; Recombinants; Recovery; Research; Research Personnel; Research Project Grants; Resources; Score; Series; Shadowing (Histology); Sister; Site; Source; Staging; Structural Genes; Surgical Replantation; Testing; Time; United States National Institutes of Health; Universities; Washington; base; congenic; cost; density; experience; human disease; interest; mouse model; repository; study characteristics; tool; trait

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.

描述（由申请人提供）：我们建议继续开发和维护LGXSM重组近交（RL）应变集，以及由Inbred小鼠菌株LG/J和SM/J形成的相关的高级间变（AL）线。 RI是初步基因映射的工具，之后可以将Al系用于限制定量性状基因座至子CM区域。在先前的支持下，我们已经开发了一组18个RL线，该线路是由LG/J和SM/J的间变成的，并将AL线带到了第32代随机交配中。 RL线的评分超过500个多态性微卫星标记，并且4290多态SNP，每600 kb的多态性SNP。每条RL线的胚胎都是冷冻保存的。由LG/J和SM/J组成的这些线和其他种群允许在NIH机构中绘制与感兴趣的疾病过程相关的大量表型。在这里，我们建议通过使用当前的Al系作为源群来开发50个RL菌株来增强RL应变。这些菌株的添加将大大提高基因映射研究中RL应变的功率。新菌株将比早期集合更有用，因为它们将累积的重组量的16倍于F2生成形成的RL线中预期的重组量。此外，我们将能够利用我们先前的育种经验通过选择特定的基因座来将菌株存活率提高到50％的新菌株，从而单独且结合起来会导致应变损失。新菌株将以500个微卫星和4290个SNP的遗传表征，并通过胚胎冷冻保存存档。应变基因型和表型将通过我们的网站，鼠标现象项目和WebQTL数据库提供。在我们较早的繁殖中，我们发现了SM/J携带的Agouti等位基因的强烈选择，尤其是在这种菌株的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的结构基因进行测序并紧密相连的基因座来检查遗传损失的遗传基础。我们将产生2ble 除Agouti和酪氨酸酶区域外，跨基因组的SM/J的先天性菌株。 使用SM/J进行回串，将用于缩小QTL间隔，以使应变损失并产生新的菌株，并带有SM/J的异常表型，而无需在Agouti基因座上执行杂合性。