Recessive Mutations that Disrupt Develop of Mouse Embryo

破坏小鼠胚胎发育的隐性突变

• 批准号: 6575086
• 负责人: Kathryn V Anderson
• 金额: $ 84.3万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-25 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6575086
• 关键词: animal breeding; autosomal recessive trait; biomarker; biotechnology; cooperative study; cryopreservation; developmental genetics; embryogenesis; ethanol; genetic mapping; genetic screening; information dissemination; laboratory mouse; lethal genes; morphometry

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.

描述（由申请人提供）：基因组技术的最新进展使得应用基于表型的筛选来鉴定在哺乳动物发育过程中发挥重要作用的基因成为可能。 在 Sloan-Kettering 研究所已经进行的 ENU 诱变筛选中，已经鉴定出 41 种破坏胚胎发生特定方面的隐性致死突变。 在映射到基因组特定区域的 30 个突变中，发现 3 个突变是先前定义的基因的等位基因。 大多数新突变影响的基因此前并不知道在哺乳动物发育中发挥作用。 将对 41 个现有突变进行表征，以提供足够的信息，使对发育特定方面感兴趣的其他研究人员能够识别那些将推进其研究的突变。 每个突变都会获得三种信息：发育停滞时的形态；地图位置；和信息分子标记的表达。 将开发一个网站，向社区提供有关这些突变的信息，并将向感兴趣的研究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，以识别导致妊娠三个阶段（e9.5、e12.5 和 e18.5）特定发育过程缺陷的隐性突变。 e9.5 筛选将根据异常的外部形态和基因沉默的异常（基因组印记、逆转录子沉默和雄性中的 Xist 表达）来识别突变体。 e12.5 筛选将根据异常的外部形态和神经模式分子标记的不适当表达来识别突变体。 e18.5筛选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体。 有关新突变体的信息将输入网站，冷冻精子将提供给感兴趣的研究人员。 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导致突变表型的基因。 所有新的多态性作图标记和新方法都将作为电子资源提供给社区。