Ecological functional genomics: phenotyping Hox mutants

描述（由申请人提供）：过去十年中最大的遗传学惊喜之一是，许多基因在被破坏时没有表现出表型变化。这通常被解释为基因之间的功能冗余。或者，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挑战。例如，近亲繁殖对小鼠的有害影响在实验室检测中几乎检测不到（10%的影响），但在竞争性生态条件下分析时，雄性显示出500%的影响。这种生态学方法也被用来揭示Hoxa3D3易位的强烈适应性缺陷，以前被认为与野生型“功能等同”。Hox基因是指导哺乳动物身体计划发育的转录因子，包括成年性状，如乳腺，行为，神经和免疫系统。靶向诱变已应用于小鼠Hox基因家族的所有39个成员，虽然大多数破坏突变体显示发育缺陷，但令人惊讶的是发现有些突变体没有可检测的表型变化。我们将使用生态竞争中存在的自然小鼠种群，以确定性能（健身）的后果，8个神秘的表型Hox突变体。对于每种Hox突变体，将进行5次群体试验。每个群体将由15个突变体和15个野生型创始人组成。估计每一个Hox测试将产生1000个后代。行为观察和遗传亲子关系分析允许健身分配给每个创始人。检测到的任何适合度差异允许进行遗传缺陷的生理和分子基础的表征。这项研究计划的长期目标是继续开发这些敏感的生态学方法，用于表征小鼠的健康和表现缺陷（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、疫苗和治疗剂）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.