Functional Neurogenomics / Neurophenomics
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Following the sequencing of the human and mouse genomes, the next major step is to assign a function to each of the identified genes. The currency of gene function is the mutation. The majority of mutations that have been found in humans is single-base pair mutations. Phenotype-driven approaches are important for bridging the gap between gene identification and understanding gene function. Knowledge of the genetics of nervous system function and regulation of behavior will lead to improved understanding of normal and abnormal brain function and behavior, enhanced diagnostics, and more effective therapeutics. Forward genetic strategies are being used to identify genes involved in nervous system function and behavior. Thus, while various genetic engineering strategies provide information about gene function through knockout technologies, to best model human disease mutagenesis programs that employ single-base pair lesions are desirable and often focus on the use of N-ethyl-N-nitrosourea (ENU) to induce single-base pair lesions in the genome and allow for an unbiased approach which involves screening potentially mutant lines for a host of neuro-behavioral, -physiological, and -anatomical phenotypes. For instance, ENU-mutagenized C57BL/6J mice are being used to identify neurobehavioral mutations in five domains (the phenotypic screens focus on neuroendocrine and behavioral responses to stress, learning and memory, psychostimulant response, vision, and circadian rhythm), and a three-generation breeding scheme to produce homozygous mutants to recover both recessive and dominant mutations. Whole-genome and regional approaches as well as large-scale mutagenesis programs are thus being used (see http://www.tnmouse.org/neuromutagenesis/). Furthermore, in this endeavour, issues such as administration, bio-informatics, power of phenotypic screens to detect behavioral outliers, and identifying the mutant gene are important. |
A further interesting contribution in this area concerns a saturation screen of the druggable mouse genome to identify novel drug targets for neuropsychiatric disease. For this, a large-scale phenotypic screen in mice has been undertaken to identify genes that regulate neuropsychiatric behavior. The screen is based on the production and phenotypic analysis of mouse knockouts of all genes that are members of gene families whose protein products are considered to be tractable for drug development (see figure below). The knockout animals are subjected to a behavioral screen that includes tests for anxiety, depression, psychosis, pain, circadian rhythms and cognition. To date more than 1,250 genes have been knocked out and screened with a goal of completing 3,750 additional genes. Another aspect of Neurogenomics is the need for model organisms intermediate between mice and humans that can be investigated using genetic approaches. Genome mapping in non-human primates provides these models, and will be particularly important for the investigation of brain and behavior. Such mapping and sequencing projects are underway in a wide range of primate species, including the vervet monkey. Several decades of studies in well-characterized vervet colonies have demonstrated heritability for a wide range of behavioral phenotypes. These highly inbred colonies are equivalent to human population isolates, and are thus particularly powerful for genome-wide genetic mapping of such phenotypes. Indeed the vervet offers an ideal test for a phenomic approach to the investigation of complex traits; the phenome is the comprehensive representation of phenotypes, and a phenomic approach to genetic mapping involves simultaneous analysis of the whole phenome by performing genome-wide genotyping of an entire study population. For the investigation of brain and behavior, the evaluation of the vervet phenome can include, for example, neuroimaging, gene expression profiling, and pharmacologic interventions, in addition to existing behavioral assessments.
