Ecological functional genomics: phenotyping Hox mutants

University Of Utah, Salt Lake City UT

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Abstract

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.