Functional genetic evolution of human brain and behavior

描述(申请人提供)：这项建议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，作为一种更好地理解人类神经精神和成瘾障碍的手段，并开发更好的动物疾病模型。这将首先集中在单胺氧化酶A(MAOA)上。MAOA与神经精神障碍和成瘾障碍有关，包括酒精中毒、抑郁症和自闭症等，是广泛开出的抗抑郁和抗焦虑药物的靶点。MAOA也被假设为自与黑猩猩的分化以来在人类中经历了正向选择，但拥有一种在人类、猿类和某些东半球猴子物种之间在功能上同源的调节多态。了解MAOA在人类中的功能差异可能有助于更好地理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基因座进行分类，包括在更常用的生物医学模式物种中的多态变异。然后，我们建议在体外从功能上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水平和神经化学浓度以及血浆中神经内分泌的影响来评估非人类灵长类动物体内和体外的多态变异的影响。最后，我们将把MAOA基因分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/表型的关系，并开发更好的酒精使用障碍的遗传模型。通过这项工作，将更好地理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。具体地说，这项工作将阐明特定的精神障碍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，以及这些精神障碍及其治疗可以在多大程度上和以何种方式在其他生物，特别是非人类灵长类动物中模拟。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。它还将允许科学家改进候选基因分析，并更好地结合神经精神疾病的动物模型。 与公共健康相关：这笔赠款的目标是了解人类和其他灵长类动物在单胺氧化酶基因上的功能遗传差异，并利用这些信息来了解人类的神经生物学和行为。我们将确定灵长类物种之间的差异，并测试这些差异对基因表达和蛋白质功能的功能影响，然后再考虑它们如何影响体内的行为和神经化学水平。这项工作将使我们更好地了解人脑是如何工作的，神经精神障碍中出了什么问题，以及我们可能会以何种方式开发出更好的动物模型来研究人类疾病。

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.