Ecological functional genomics: phenotyping Hox mutants

描述（由申请人提供）：在过去的十年中，一个巨大的遗传惊喜是，许多基因在被破坏时没有显示出表型变化。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。这种生态学方法也被用来揭示Hoxa3D3易位的一个强适应性缺陷，之前被认为与野生型“功能等同”。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。我们将利用存在于半自然小鼠种群中的生态竞争来确定8个隐型Hox突变体的性能（适应性）后果。对于每个Hox突变体，将进行5个群体分析。每个群体将由15个突变型和15个野生型奠基者组成。每测试一个Hox，估计会有1000个后代出生。行为观察和遗传分析可以为每个创始人分配合适的任务。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，而且对评估环境毒素、疫苗和治疗剂等潜在健康风险的安全性也很重要。

DESCRIPTION (provided by applicant): 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. This ecological approach has also been used to reveal a strong fitness defect for the Hoxa3D3 translocation, previously thought to be 'functionally equivalent' to wild type. 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. We will use ecological competition present in seminatural mouse populations to determine the performance (fitness) consequences of eight cryptic-phenotype Hox mutants. For each Hox mutant, 5 populations assays will be conducted. Each population will consist of 15 mutant and 15 wild type founders. An estimated 1000 progeny will be born for each Hox tested. Behavioral observations and genetic parentage analyses allow fitness assignments to each founder. Any fitness differences detected allows 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 and therapeutic agents.