SPECIAL MOUSE STRAINS RESOURCE

许多常见的人类遗传性疾病在遗传上是复杂的；也就是说，它们是由多个基因相互作用的结果。例如糖尿病、心血管疾病、癌症、肥胖症和哮喘。即使是遗传上“简单”的单突变疾病，其严重程度也常常受到次级基因的影响。在位置克隆和候选基因分析方面的进展使得相对快速地确定了由单基因突变引起的许多人类和小鼠疾病的潜在基因。同样，基因复杂疾病的遗传分析的目标是发现潜在的基因，最终目的是预防或治疗。复杂性状的遗传分析需要模型系统，在模型系统中可以进行遗传操作。小鼠和人类之间的代谢、器官/组织和遗传相似之处，以及小鼠可以很容易地被基因操纵，使小鼠成为许多这些复杂的人类疾病的明显模型。然而，用于复杂性状分析的连锁杂交既耗时又昂贵。我们建议用这笔赠款资助一种特殊的小鼠品系资源，这些品系是复杂性状分析的宝贵工具，使用这些品系将提高在人类多基因疾病小鼠模型中识别基因的效率。特殊小鼠品系资源(SMSR)将包含6个重组近交系(RI)品系群，一组21个染色体替代(CSS)品系，以及多个同源品系。RI和同源菌株已经在杰克逊实验室，但需要部分支持才能继续在繁殖群体中保持它们。Css毒株将从凯斯西储大学的J.Nadeau博士那里进口。为了提高菌株的价值，我们将1)增加RI菌株集合中的DNA标记的基因分型数量，以提高其遗传图谱的价值；2)更准确地定义同源菌株中差异片段的程度，以提高其遗传图谱的价值；以及3)对css菌株进行表型，以改善其基线特征。我们还将开发一个关于RI、CS和同源菌株的表型信息的数据库，以及同源菌株集合中差异片段的分布和范围的图形地图。

Many common inherited human diseases are genetically complex; that is, they result from the interaction of more than one gene. Examples are diabetes, cardiovascular diseases, cancer, obesity, and asthma. Even genetically "simple" single mutation diseases are frequently modulated in severity by secondary genes. The advances in positional cloning and candidate gene analysis have led to relatively rapid identification of the genes underlying many human and mouse disorders caused by single gene mutations. Similarly, the goal of genetic analysis of genetically complex diseases is to discover the underlying genes with the ultimate goal of prevention or therapy. Genetic analysis of complex traits requires model systems in which genetic manipulations can be carried out. The metabolic, organ/tissue, and genetic similarities between mice and humans and the ease with which the mouse can be genetically manipulated make mice the obvious model for many of these complex human diseases. Linkage crosses for complex trait analysis, however, are time-consuming and expensive. We propose to fund with this grant a resource of special mouse strains that are valuable tools for complex trait analysis and whose use will improve the efficiency of identifying genes in mouse models of human multigenic diseases. The Special Mouse Strains Resource (SMSR) will contain six Recombinant Inbred (RI) strain panels, a set of 21 Chromosome Substitution (CSS) strains, and multiple Congenic strains. The RI and congenic strains are already at The Jackson Laboratory but are in need of partial support to continue to maintain them in breeding colonies. The CSS strains will be imported from Dr. J. Nadeau, Case Western Reserve University. To enhance the value of the strains we will 1) increase the number of DNA markers genotyped in the RI strain sets to improve their value for genetic mapping, 2) define more precisely the extent of differential segments in the congenic strains to improve their value for genetic mapping, and 3) phenotype the CSS strains to improve their baseline characterization. We will also develop a database of phenotypic information on the RI, CS, and congenic strains covered by this grant and a graphic map of the distribution and extent of differential segments in the congenic strain set.