MOUSE GENETIC RESOURCES FOR MULTIGENIC DISEASE ANALYSIS

小鼠的许多遗传特征，包括人类疾病的重要模型，都是许多基因共同作用的结果。目前正在使用几种强大的方法来定位和识别控制这些特征的多基因。然而，这些方法既耗时又昂贵，需要对大型杂交进行广泛的基因分型，通常在精细结构作图和基因克隆之前进行多代育种以构建同源菌株，并且可以进行。我们建议建立专门的遗传资源，称为染色体替代菌株(CSS)，以极大地加强多基因性状的研究。CSS的优势包括无需连锁测试杂交或基因分型的多基因作图，需要表型的小鼠更少，以及可以检测到的较弱的表型。根据重要生物学特性和疾病模型的不同，选择用于这些CS面板的祖细胞株，包括癌症、代谢性疾病、感染易感性、药物成瘾、皮肤病、学习、出生缺陷、听力损失、骨量、寿命等许多其他因素。其中三个小组对检测和表征背景基因也很有用，这些基因调节了带有工程突变的小鼠的表型。我们提出了四个具体目标：具体目标1.构建一个A.B6面板，以补充即将完成的B6面板。具体目的2.用C57BL/6J和129/SVJ两株祖株构建互补嵌合板。具体目标3.测试用近交系、野生来源的祖先CAST/EI制作css面板的可行性。具体目的4.检验利用单核苷酸多态使CSS更加高效的可行性。随着在不太遥远的将来有一个完整的小鼠基因组序列的前景，应该越来越重视以一种容易处理的形式捕获小鼠的表型变异的方法。大规模的突变计划正在启动，以收集具有强烈表型效应的新等位基因。同样，应该构建新类型的菌株，如css面板，以促进重要生理过程的遗传解剖。

Many inherited traits in the mouse, including important models for human diseases, result from the combined action of many genes. Several powerful approaches are currently being used to map and identify the polygenes that control these traits. However, these approaches are time-consuming and expensive, requiring extensive genotyping of large crosses, typically followed by many generations of breeding to construct congenic strains before fine-structure mapping and gene cloning and can be undertaken. We propose making specialized genetic resources, called chromosome substitution strains (CSSs), that greatly enhance the study of polygenic traits. The advantages of CSSs include polygene mapping without linkage testing crosses or genotyping, fewer mice that need to be phenotyped, and weaker phenotypes that can be detected. The choice of progenitor strains for these CSS panels was based on differences in important biological traits and disease models, including cancers, metabolic diseases, susceptibility to infections, drug addiction, skin diseases, learning, birth defects, hearing loss, bone mass, life span, and many others. Three of the panels are also useful for detecting and characterizing background genes that modulate the phenotype of mice with engineered mutations. We propose four Specific Aims: Specific Aim 1. Construct a A.B6 panel to complement the soon to be completed B6.A panel. Specific Aim 2. Construct complementary panels with progenitor strains C57BL/6J and 129/SvJ. Specific Aim 3. Test feasibility of making a CSS panel with an inbred, wild-derived progenitor CAST/Ei. Specific Aim 4. Test feasibility of using single nucleotide polymorphisms for making CSSs more efficiently. With the prospect of a complete sequence of the mouse genome in the not-too-distant future, increasing emphasis should be placed on ways to capture in a tractable form phenotypic variation in the mouse. Large-scale mutagenesis programs are being launched to collect new alleles having strong phenotypic effects. Similarly, new types of strains, such as CSS panels, should be constructed to facilitate the genetic dissection of important physiological processes.