Functional genetic evolution of human brain and behavior

描述（由申请人提供）：该提案的重点是将比较遗传学和分子进化与功能神经生物学结合起来，作为更好地理解人类神经精神和成瘾障碍以及开发更好的动物疾病模型的一种手段。这将首先集中在单胺氧化酶A （MAOA）。MAOA与神经精神和成瘾障碍有关，包括酒精中毒、抑郁症和自闭症等，是广泛开具的抗抑郁和抗焦虑药物的靶点。自与黑猩猩分化以来，MAOA也被假设在人类中经历了积极的选择，但在人类、类人猿和某些旧大陆猴子物种之间具有功能同源的调控多态性。了解人类MAOA功能的差异可能会导致更好地了解其相关神经精神疾病的原因，并允许在非人类灵长类动物中开发更合适的这些疾病的遗传模型。在这里，我们建议对灵长类物种的完整MAOA位点进行编目，包括更常用的生物医学模型物种的多态性变异。然后，我们建议在体外功能性地研究这些差异的后果，以及祖先序列的功能。我们还将通过测量脑脊液中的mRNA水平和神经化学物质浓度以及血浆中的神经内分泌效应，评估非人灵长类动物体内和体外多态变异的影响。最后，我们将把MAOA基因型整合到现有的恒河猴酒精自我给药研究中，以阐明这种基因型/表型关系，并建立更好的酒精使用障碍遗传模型。通过这项工作，将更好地了解分子进化和比较遗传学与功能神经科学和人类神经精神疾病研究的相关性。具体来说，这项工作将阐明特定的精神疾病或症状是否是人类特有的，是由人类特有的基因变化引起的，以及这些精神疾病及其治疗可以在其他生物体，特别是非人类灵长类动物中模拟的程度和方式。这将使这两个领域得到更好的整合，并使研究人员能够利用分子进化和比较遗传学的力量，在未来的人类疾病研究中发挥更大的作用。它还将使科学家能够改进候选基因分析，并更好地将其置于神经精神疾病的动物模型中。

DESCRIPTION (provided by applicant): This proposal is focused on integrating comparative genetics and molecular evolution with functional neurobiology as a means of generating a better understanding of human neuropsychiatric and addiction disorders and developing better animal disease models. This will concentrate initially on monoamine oxidase A (MAOA). MAOA has been associated with neuropsychiatric and addiction disorders including alcoholism, depression, and autism among others and is a target for widely prescribed anti-depression and anti-anxiety medications. MAOA is also hypothesized to have undergone positive selection in humans since the divergence from chimpanzees but harbors a regulatory polymorphism that is functionally homologous between humans, apes, and certain old-world monkey species. Understanding differences in MAOA function in humans may lead to better understandings of the causes of its associated neuropsychiatric disorders and allow for the development of more appropriate genetic models of these diseases in non-human primates. Here we propose to catalog the complete MAOA locus across primate species, including polymorphic variation in the more commonly used biomedical model species. We then propose to functionally investigate the consequences of these differences, as well as the functionality of ancestral sequences, in vitro. We will also assess the effects of polymorphic variation from non-human primates ex vivo and in vivo through measurement of mRNA levels and neurochemical concentrations in cerebrospinal fluid and neuroendocrine effects in blood plasma. Finally, we will integrate MAOA genotypes into existing alcohol self-administration studies in rhesus macaques to elucidate this genotype/phenotype relationship and develop better genetic models of alcohol use disorders. Through this work, a better understanding will be gained of the relevance of molecular evolution and comparative genetics to functional neuroscience and the study of human neuropsychiatric disease. Specifically, this work will elucidate if specific psychiatric disorders or symptoms are unique to humans resulting from human-specific genetic changes and the extent to which and ways that these psychiatric disorders and their treatment can be modeled in other organisms, particularly non-human primates. This will allow a better integration of the two fields and allow researchers to leverage the power of molecular evolution and comparative genetics to greater effect in studies of human disease going forward. It will also allow scientists to refine candidate gene analyses and better place into context animal models of neuropsychiatric disease. PUBLIC HEALTH RELEVANCE: The goal of this grant is to understand the functional genetic differences between humans and other primates at the monoamine oxidase a gene and to use this information to understand human neurobiology and behavior. We will identify the differences among primate species and test these differences for functional effects of gene expression and protein function before considering how they affect behaviors and neurochemical levels in the body. This work will allow us to better understand how the human brain works, what goes wrong in neuropsychiatric disorders and ways in which we might develop better animal models for studying human disease.