Functional genetic evolution of human brain and behavior

人脑和行为的功能遗传进化

• 批准号: 8308543
• 负责人: Eric J. Vallender
• 金额: $ 35.65万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-10 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8308543
• 关键词: 3' Untranslated Regions; 5' Untranslated Regions; Adolescent; Affect; Alcoholism; Alcohols; Animal Disease Models; Animal Model; Anxiety; Autistic Disorder; Behavior; Brain; Candidate Disease Gene; Cataloging; Catalogs; Catecholamines; Cercopithecidae; Cerebrospinal Fluid; Code; Corticotropin; Development; Disease; Dissociation; Enhancers; Frequencies; Funding; Gene Expression; Gene Proteins; Genes; Genetic; Genetic Models; Genetic Polymorphism; Genotype; Goals; Gonadal Steroid Hormones; Grant; Haplotypes; Homeostasis; Human; Hydrocortisone; In Vitro; Incidence; Lead; Macaca mulatta; Measurement; Measures; Mental Depression; Mental disorders; Messenger RNA; Modeling; Molecular Evolution; Monkeys; Monoamine Oxidase; Monoamine Oxidase A; Mutation; Naltrexone; Neurobiology; Neurosciences; Neurosecretory Systems; Organism; Pan Genus; Pharmaceutical Preparations; Pharmacogenetics; Phenotype; Physiological; Plasma; Pongidae; Primates; Reporter; Research Personnel; Scientist; Self Administration; Self-Administered; Serotonin; Substance abuse problem; Symptoms; Testing; Untranslated Regions; Variant; Work; addiction; alcohol use disorder; base; behavior measurement; brain behavior; comparative; early-onset alcoholism; expression vector; genetic evolution; human disease; in vivo; monoamine; neurochemistry; neuropsychiatry; nonhuman primate; promoter; protein function; public health relevance; species difference; vector

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.

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性神经生物学相结合，作为一种更好地理解人类神经精神疾病和成瘾障碍并发展更好动物疾病模型的方法。这最初将集中在单胺氧化酶A（MAOA）上。 MAOA与神经精神病学和成瘾障碍有关，包括酒精中毒，抑郁和自闭症，是广泛处方的抗抑郁和抗焦虑药的目标。自黑猩猩的分歧以来，MAOA也被认为在人类中经历了积极的选择，但携带了一种调节性多态性，在人类，猿类和某些旧世界猴子之间在功能上是同源的。了解人类中MAOA功能的差异可能会更好地理解其相关神经精神疾病的原因，并允许发展非人类灵长类动物中这些疾病的更合适的遗传模型。在这里，我们建议在灵长类动物物种上分类完整的MAOA基因座，包括更常用的生物医学模型物种中的多态性变化。然后，我们建议在体外研究这些差异的后果以及祖先序列的功能。我们还将通过测量血浆中脑脊髓液和神经内分泌作用中的mRNA水平和神经化学浓度来评估非人类灵长类动物和体内多态性变异的影响。最后，我们将将MAOA基因型整合到恒河猕猴中的现有酒精自我管理研究中，以阐明这种基因型/表型关系，并发展出更好的酒精使用障碍遗传模型。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性神经科学的相关性以及人类神经精神病的研究。具体而言，这项工作将阐明特定的精神疾病或症状是由人类特异性遗传变化而引起的人类独有的，以及这些精神疾病及其治疗可以在其他生物体（尤其是非人类灵长类动物）中建模的程度和方式。这将使两个领域更好地整合，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人类疾病的研究中更大。它还将使科学家能够完善候选基因分析，并更好地进入神经精神疾病的动物模型。 公共卫生相关性：这笔赠款的目的是了解人类与单胺氧化酶A基因上的人与其他灵长类动物之间的功能遗传差异，并使用这些信息来了解人类的神经生物学和行为。我们将确定灵长类动物物种之间的差异，并在考虑它们如何影响体内行为和神经化学水平之前测试这些差异对基因表达和蛋白质功能的功能效应。这项工作将使我们能够更好地了解人脑的工作原理，神经精神疾病中的问题以及我们可能开发出更好的动物模型来研究人类疾病的方法。