PRIMATE COMPARATIVE NEUROGENETICS AND MOLECULAR EVOLUTION

灵长类动物比较神经遗传学和分子进化

• 批准号: 8357962
• 负责人: Eric J. Vallender
• 金额: $ 1.38万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357962
• 关键词: Animal Model; Callithrix jacchus jacchus; Candidate Disease Gene; Cataloging; Catalogs; Disease; Evolution; Funding; Genes; Genetic; Genetic Polymorphism; Genomics; Goals; Grant; Human; In Vitro; Macaca mulatta; Mammals; Measurement; Measures; Mental disorders; Messenger RNA; Modeling; Molecular; Molecular Evolution; Mutation; National Center for Research Resources; New England; Organism; Physiological; Primates; Principal Investigator; Research; Research Infrastructure; Research Personnel; Resources; Source; Symptoms; United States National Institutes of Health; Variant; Work; base; comparative; cost; human disease; in vivo; neurogenetics; neuropsychiatry; nonhuman primate

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The goal of this proposal is to systematically explore the molecular and genomic evolution of mammals focused on humans and non-human primates in order to better understand the context of human disease. First we will catalog the differences between species with a focus on regions showing evidence for positive selection or genes demonstrated to be associated with disease. This effort will make use of all major primate lineages but will in particular focus on the more commonly used biomedical model species (notably rhesus macaques and common marmosets). It will also include both differences between (divergence) and within (polymorphism) species. We will then 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 through correlation with physiological measures. 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 researchers to leverage the power of molecular evolution and comparative genetics to greater effect in studies of human disease going forward and to refine candidate gene analyses and better place into context animal models of neuropsychiatric disease.The goal of this proposal is to systematically explore the molecular and genomic evolution of mammals focused on humans and non-human primates in order to better understand the context of human disease. First we will catalog the differences between species with a focus on regions showing evidence for positive selection or genes demonstrated to be associated with disease. This effort will make use of all major primate lineages but will in particular focus on the more commonly used biomedical model species (notably rhesus macaques and common marmosets). It will also include both differences between (divergence) and within (polymorphism) species. We will then 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 through correlation with physiological measures. 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 researchers to leverage the power of molecular evolution and comparative genetics to greater effect in studies of human disease going forward and to refine candidate gene analyses and better place into context animal models of neuropsychiatric disease.

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 这项建议的目标是系统地探索以人类和非人类灵长类为重点的哺乳动物的分子和基因组进化，以更好地了解人类疾病的背景。首先，我们将对物种之间的差异进行分类，重点放在显示正向选择证据的区域或被证明与疾病相关的基因。这项工作将利用所有主要灵长类动物谱系，但将特别侧重于更常用的生物医学模式物种(特别是恒河猴和普通绒猴)。它还将包括物种之间(差异)和物种内(多态)的差异。然后，我们将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mRNA水平并通过与生理指标的相关性来评估非人类灵长类动物在体外和体内的多态变异的影响。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体，特别是非人类灵长类动物中模拟。这将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，完善候选基因分析，并更好地结合神经精神疾病的动物模型。这项建议的目标是系统地探索以人类和非人类灵长类动物为重点的哺乳动物的分子和基因组进化，以更好地了解人类疾病的背景。首先，我们将对物种之间的差异进行分类，重点放在显示正向选择证据的区域或被证明与疾病相关的基因。这项工作将利用所有主要灵长类动物谱系，但将特别侧重于更常用的生物医学模式物种(特别是恒河猴和普通绒猴)。它还将包括物种之间(差异)和物种内(多态)的差异。然后，我们将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mRNA水平并通过与生理指标的相关性来评估非人类灵长类动物在体外和体内的多态变异的影响。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体，特别是非人类灵长类动物中模拟。这将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，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。