Genetic analysis of mouse chromosome 11

描述（由申请人提供）：现在小鼠和人类基因组序列已经完成，生物学家需要系统的方法来确定每个基因的功能。单核苷酸序列不能预测基因功能，因此需要功能基因组研究。揭示基因功能最有力的方法之一是产生突变并确定它们在生物体中的后果。在这里，我们的目标是通过小鼠诱变，为人类17号染色体上的基因提供功能信息，17号染色体是小鼠11号染色体上保守的连锁组。在这项研究中将调查的近700个基因中，许多将与人类疾病有因果关系。这一目标区域的功能遗传学研究的遗传资源已经产生。这个R01的目的是利用这些遗传资源来问：1)有多少基因是必需的，2)有多大比例的基因可能突变成易于检测的表型，3)突变后最常观察到的表型，以及4)哺乳动物基因可以执行哪些不同的功能？我们的基本假设是，使用n -乙基-n -亚硝基脲（ENU）诱变的正向遗传学是研究哺乳动物基因功能的有效方法。我们的具体目标是1)使用高效的ENU诱变技术查询小鼠11号染色体的遗传功能，2)识别突变中的分子病变，3)确定具有血细胞和/或心血管缺陷的突变体缺陷的分子和细胞基础，以及4)扩展已建立的精子/DNA档案的深度，以用于未来的基因筛选。我们产生的突变已经通过一个公共网站www.mouse-genome.bcm.tmc.edu与科学界共享，并将继续共享。我们之前的工作对我们研究小鼠遗传学的方式产生了影响，我们提出的工作将影响我们理解基因在哺乳动物中的作用和作用方式。

DESCRIPTION (provided by applicant): Now that the mouse and human genome sequences are complete, biologists need systematic approaches to determine the function of each gene. Nucleotide sequence alone does not predict gene function, so functional genomic studies are required. One of the most powerful ways to reveal gene function is to generate mutations and determine their consequence in the living organism. Here, our goal is to provide functional information for genes that map to human chromosome 17, a linkage group that is conserved on mouse chromosome 11, through mouse mutagenesis. Among the nearly 700 genes that will be investigated in this study, many will be causally associated with human disease. Genetic resources for functional genetic studies of this targeted region were generated previously. The purpose of this R01 is to use these genetic resources to ask 1) how many genes are essential, 2) what proportion of genes are likely to mutate to a readily detectable phenotype, 3) what phenotypes are most commonly observed after mutation, and 4) what diverse functions can mammalian genes perform? Our underlying hypothesis is that forward genetics using N-ethyl-N-nitrosourea (ENU) mutagenesis is an efficient way of asking questions about gene function in mammals. Our specific aims are to 1) query genetic function on mouse Chromosome 11 using high- efficiency ENU mutagenesis, 2) identify the molecular lesions in mutations, 3) determine the molecular and cellular basis for the defects in mutants with blood cell and/or cardiovascular defects, and 4) extend the depth of an established sperm/DNA archive for future gene-based screens. The mutations we generate have been shared, and will continue to be shared with the scientific community, through a public website www.mouse-genome.bcm.tmc.edu. Our previous work has made a difference in the way we can approach mouse genetics, and our proposed work will influence the way we understand what genes do and how they work in mammals.