HIGH EFFICIENCY ENU MUTAGENESIS TO ISOLATE MOUSE MODELS OF HUMAN DISEASE

小鼠Chr 11远端部分的基因也存在于人类Chr 17.这种极端的连锁保守性使我们能够利用 小鼠和人类在生理、病理和分子方面的相似性， 利用小鼠实验遗传优势的研究。的 这项研究的主要目标是获得新的突变， 反映了小鼠Chr 11远端区域的单基因功能。 通过诱变在特定区域中建立基因型/表型可以 提供了一种确定基因功能的成本有效的方法， 特别是在基因丰富的地区。小鼠与 人类将为预测基因功能提供直接联系， 人类 我们将加强小鼠11号染色体的遗传分析， 用化学诱变剂N-乙基-N-亚硝基脲进行突变。适当 遗传标记将用于分离隐性胚胎和幼鱼 第二代（G/2）动物中的致死和可见表型。我们 将通过筛选多种医学上的 相关的隐性表型包括：a）神经，行为， 和感觉器官缺陷，B）造血缺陷，c）自身免疫 疾病，d）肥胖，e）不育，和f）形态异常。 纯合隐性胚胎致死表型将被归类为a 胚胎死亡的特定阶段，以了解独特的方面， 哺乳动物的发育选定的新突变将被映射到更高的 使用缺失子区间和互补分析的分辨率。一些 成对互补测试将在突变上进行，如 表型类我们将确定基因涉及din选择 突变，并将分子病变与生物学 表型。突变将提供给社区和可用性 将在万维网上发布。突变小鼠的库存将被冻结 作为胚胎和/或精子用于存档目的。 我们的工作将产生许多新的人类疾病模型， 并了解各种各样的疾病，如行为疾病，生育， 缺陷，不育，衰老和肥胖，这将是有益的成员， 生物医学界。

Genes on the distal portion of mouse Chr 11 are also found on human Chr 17. This extreme linkage conservation allows us to utilize the physiologic, pathologic, and molecular similarities of mouse and human in studies that exploit the experimental genetic advantages of the mouse. The primary goal of the proposed research is to obtain new mutations that reflect single gene function on the distal region of mouse Chr 11. Establishing genotype/phenotype in a specific region by mutagenesis can provide a cost effective approach to determining gene function, particularly in gene rich regions. The conserved synteny between mouse and human will provide a direct link to predications of gene function in humans. We will enhance the genetic analysis of mouse Chromosome 11 by inducing mutations with the chemical mutagen N-ethyl-N-nitrosourea. Appropriate genetic markers will be used to isolate recessive embryo and juvenile lethal and visible phenotypes in the second generation (G/2) animals. We will extend the mutational analysis by screening for multiple medically relevant recessive phenotypes that include: a) neurological, behavioral, and sensory organ defects, b) hematopoietic defects, c) autoimmune disease, d) obesity, e) infertility, and f) morphological abnormalities. Homozygous recessive embryos lethal phenotypes will be classified to a particular stage of embryonic death to understand unique aspects of mammalian development. Selected new mutations will be mapped to a higher resolution using deletion sub-intervals and complementation analysis. Some pairwise complementation tests will be performed on mutations like phenotypic classes. We will identify the genes involve din selected mutations, and correlate the molecular lesion with the biological phenotype. Mutations will be provided to the community and availability will be posted on the World Wide Web. Mutant mouse stocks will be frozen as embryos and/or sperm for archival purposes. Our work will generate many new models of human diseases, to help treat and understand diverse disorders such as behavioral maladies, birth defects, infertility, aging, and obesity that will be useful to members of the biomedical community.