Ecological Functional Genomics of Cryptic-Phenotype Hox Gene Knockouts

隐性表型 Hox 基因敲除的生态功能基因组学

• 批准号: 0344907
• 负责人: Wayne Potts
• 金额: $ 28万
• 依托单位: University of Utah
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0344907&HistoricalAwards=false
• 关键词: Ecological; Functional; Genomics; Cryptic; Phenotype

One of the great genetic surprises of the last decade is that many genes when disrupted, reveal no phenotypic change. This is usually interpreted as functional redundancy among genes. Alternatively, many phenotypes are largely invisible until the individual is stressed or otherwise challenged by factors absent from the lab environment. For example, the deleterious effects of inbreeding in mice are barely detectable using lab assays (10% effect), but when analyzed under competitive ecological conditions, males show a 500% effect. Hox genes are transcription factors that direct development of the mammalian body plan, including adult traits such as mammary glands, behavior, nervous and immune systems. Targeted mutagenesis has been applied to all 39 members of the mouse Hox gene family and while most disruption mutants show developmental defects, it was surprising to discover that some have no detectable phenotypic change. The ecological competition inherent in the social behavior of seminatural house mouse populations will be used to determine the performance (fitness) consequences of three cryptic-phenotype Hox mutants. Any fitness differences detected allow characterization of the physiological and molecular basis of the genetic defect to proceed. The long-term goal of this research program is to continue developing these sensitive ecological methods for characterizing health and performance defects (phenotypes) in mice. These methods are important not only for characterizing gene function and complex phenotypes, but also for evaluating the safety of potential health risks such as environmental toxins, vaccines, therapeutic agents, among others.

在过去的十年里，一个巨大的遗传惊喜是，许多基因被破坏后，并没有显示出表型的变化。这通常被解释为基因之间的功能冗余。另外，许多表型在很大程度上是不可见的，直到个体受到实验室环境中不存在的因素的压力或其他挑战。例如，使用实验室分析几乎无法检测到小鼠近亲繁殖的有害影响（10%的影响），但在竞争生态条件下分析时，雄性显示出500%的影响。Hox基因是指导哺乳动物身体发育的转录因子，包括乳腺、行为、神经和免疫系统等成年特征。靶向诱变已应用于小鼠Hox基因家族的所有39个成员，虽然大多数中断突变表现出发育缺陷，但令人惊讶的是，发现一些没有可检测到的表型变化。半自然家鼠群体社会行为中固有的生态竞争将被用来确定三种隐型Hox突变体的表现（适应度）后果。检测到的任何适应度差异都允许对遗传缺陷的生理和分子基础进行表征。这项研究计划的长期目标是继续发展这些敏感的生态方法，以表征小鼠的健康和性能缺陷（表型）。这些方法不仅对表征基因功能和复杂表型很重要，而且对评估潜在健康风险（如环境毒素、疫苗、治疗剂等）的安全性也很重要。