Ecological Functional Genomics of Cryptic-Phenotype Hox Gene Knockouts

过去十年最令人惊讶的基因之一是，许多基因在被破坏时，没有表现出任何表型变化。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看不见的，直到个体受到压力或以其他方式受到实验室环境中缺失的因素的挑战。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)，但当在竞争性生态条件下进行分析时，雄性显示出500%的影响。HOX基因是指导哺乳动物身体计划发展的转录因子，包括成年特征，如乳腺、行为、神经和免疫系统。靶向突变已经应用于小鼠HOX基因家族的所有39个成员，虽然大多数中断突变都显示出发育缺陷，但令人惊讶的是，发现其中一些没有可检测到的表型变化。半自然家鼠种群社会行为中固有的生态竞争将被用来确定三个隐蔽的表型Hox突变体的表现(适合度)后果。检测到的任何适合性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开发这些敏感的生态学方法来表征小鼠的健康和表现缺陷(表型)。这些方法不仅对于表征基因功能和复杂的表型很重要，而且对于评估潜在的健康风险，如环境毒素、疫苗、治疗剂等的安全性也是重要的。

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.