Recessive Mutations that Disrupt Develop of Mouse Embryo

描述(申请人提供)：基因组技术的最新进展使应用基于表型的筛选来识别在哺乳动物发育过程中发挥基本重要作用的基因成为可能。在斯隆-凯特琳研究所已经进行的ENU突变筛选中，已经鉴定出41个隐性致命突变，这些突变破坏了胚胎发生的特定方面。在映射到基因组特定区域的30个突变中，有3个被发现是先前定义的基因的等位基因。大多数新的突变会影响以前不知道在哺乳动物发育中发挥作用的基因。现有的41个突变将被定性，以提供足够的信息，使其他对发展的特定方面感兴趣的研究人员能够识别这些突变，这些突变将推动他们的研究。对于每个突变，将获得三种信息：发育停止时的形态；图谱位置；以及信息性分子标记的表达。将开发一个网站，向社区提供有关这些突变的信息，并向感兴趣的调查人员提供来自突变系的冷冻精子。 五名研究人员将结合他们的专业知识进行新的筛查，以确定在怀孕的三个阶段，即e9.5、e12.5和e18.5的特定发育过程中导致缺陷的隐性突变。E9.5屏幕将根据外部形态异常和基因沉默中的异常(基因组印迹、反转录病毒沉默和雄性Xist表达)来识别突变体。E12.5屏幕将根据神经模式的外部形态异常和分子标记的不适当表达来识别突变体。E18.5筛查将根据异常的外部形态、泌尿生殖道的异常形态和肾脏的异常组织学来识别突变。有关新突变体的信息将在网站上输入，并向感兴趣的调查人员提供冷冻精子。对于该联盟感兴趣的少数基因，将使用基于图谱的方法来识别与突变表型有关的基因。所有新的多态地图标记和新方法将作为电子资源提供给社区。

DESCRIPTION (provided by applicant): Recent advances in genome technology have made it possible to apply phenotype-based screens to identify genes that perform roles of fundamental importance during mammalian development. In ENU mutagenesis screens already carried out at Sloan-Kettering Institute, 41 recessive lethal mutations that disrupt specific aspects of embryogenesis have been identified. Of 30 mutations mapped to specific regions of the genome, three were found to be alleles of previously defined genes. Most of the new mutations affect genes that were not previously known to play a role in mammalian development. The 41 existing mutations will be characterized to provide enough information that other investigators interested in specific aspects of development will be able to identify those mutations that will advance their research. Three kinds of information will be obtained for each mutation: the morphology at the time of developmental arrest; map position; and expression of informative molecular markers. A website will be developed to make the information about these mutations available to the community and frozen sperm from mutant lines will be made available to interested investigators. Five investigators will combine their expertise to perform new screens to identify recessive mutations that cause defects in specific developmental processes at three stages of gestation, e9.5, e12.5, and e18.5. The e9.5 screen will identify mutants based on abnormal external morphology and abnormalities in gene silencing (genomic imprinting, retroposon silencing, and Xist expression in males). The e12.5 screen will identify mutants based on abnormal external morphology and inappropriate expression of molecular markers of neural patterning. The e18.5 screen will identify mutants based on abnormal external morphology, abnormal morphology of the genitourinary tract, and abnormal histology of the kidney. Information about the new mutants will be entered on website, and frozen sperm made available to interested investigators. For a small number of genes of interest to the consortium, map-based approaches will be used to identify the genes responsible for the mutant phenotype. All new polymorphic mapping markers and new methods will be made available to the community as electronic resources.