Genetic analysis of mouse chromosome 11

描述(由申请人提供)：既然老鼠和人类的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。单靠核苷酸序列并不能预测基因的功能，因此需要进行功能基因组学研究。揭示基因功能的最有效方法之一是产生突变，并确定它们在活着的有机体中的后果。在这里，我们的目标是通过小鼠突变，为映射到人类17号染色体的基因提供功能信息，人类17号染色体是保存在小鼠11号染色体上的一个连锁群。在这项研究中将研究的近700个基因中，许多将与人类疾病有因果关系。用于该目标区域的功能遗传学研究的遗传资源是先前产生的。R01的目的是利用这些遗传资源来询问1)有多少基因是必不可少的，2)有多大比例的基因可能突变成容易检测到的表型，3)突变后最常见的表型是什么，以及4)哺乳动物的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-亚硝脲(ENU)诱变的正向遗传学是询问哺乳动物基因功能的一种有效方式。我们的具体目标是1)使用高效的ENU突变来查询小鼠11号染色体上的遗传功能，2)识别突变中的分子损伤，3)确定具有血细胞和/或心血管缺陷的突变的分子和细胞基础，以及4)扩展已建立的精子/DNA档案的深度，用于未来的基于基因的筛查。我们产生的突变已经被分享，并将继续通过公共网站www.ouse-genome.bcm.tmc.edu与科学界分享。我们之前的工作改变了我们研究老鼠遗传学的方式，我们拟议的工作将影响我们理解基因在哺乳动物中起什么作用以及它们是如何工作的方式。

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.