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，是许多基因共同作用的结果。 目前有几种强有力的方法被用来绘制和鉴定控制这些性状的多基因。然而，这些方法是耗时和昂贵的，需要大量的大杂交的基因分型，通常随后是许多代的育种，以构建同源株之前，精细结构定位和基因克隆，可以进行。 我们建议制作专门的遗传资源，称为染色体替代株（CSS），大大加强了多基因性状的研究。 CSS的优点包括多基因作图而无需连锁测试杂交或基因分型，需要进行表型分型的小鼠更少，并且可以检测到更弱的表型。 这些CSS小组的祖先菌株的选择是基于重要生物学性状和疾病模型的差异，包括癌症，代谢疾病，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。 其中三组也可用于检测和表征调节具有工程突变的小鼠表型的背景基因。我们提出四个具体目标：具体目标1。建造一个A.B6小组，以补充即将完成的B6.A小组。具体目标2。用祖菌株C57 BL/6 J和129/SvJ构建互补组。 具体目标3。测试用近交的、野生衍生的祖细胞CAST/Ei制备CSS板的可行性。 具体目标4。测试使用单核苷酸多态性使CSS更有效的可行性。随着小鼠基因组全序列的前景在不太遥远的将来，越来越多的重点应放在如何捕捉在一个易于处理的形式在小鼠的表型变异。 大规模的诱变计划正在启动，以收集具有强表型效应的新等位基因。同样，应构建新型菌株，如CSS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.