Phenotype-Genotype Studies in Non-Human Primate Model of Social Behavior

非人类灵长类动物社会行为模型的表型基因型研究

• 批准号: 10914594
• 负责人: Christie Gunter
• 金额: $ 17.36万
• 依托单位: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10914594
• 关键词: Adolescent; Animal Model; Behavior; Behavioral; Child; Competence; Copy Number Polymorphism; DNA; Data; Development; Exhibits; Factor Analysis; Genes; Genetic; Genetic study; Genomics; Genotype; Heritability; Housing; Human; Individual; Intrinsic factor; Macaca; Macaca mulatta; Measures; Modeling; Modification; Motivation; Neurobiology; Neurosciences; Phenotype; Primates; Risk; Risk Factors; Sampling; Single Nucleotide Polymorphism; Social Behavior; Social Development; Social Interaction; Study Subject; Study models; Variant; autism spectrum disorder; behavior measurement; behavior observation; behavioral phenotyping; developmental psychology; exome sequencing; genetic association; genetic variant; genome sequencing; genomic variation; individual variation; interest; nonhuman primate; sex; social; social group; trait

Nonhuman primates and especially rhesus macaques (Macaca mulatta) have been indispensable animal models for studies of various aspects of neurobiology, developmental psychology, and other aspects of neuroscience. While remarkable progress has been made in our understanding of the causes of autism spectrum disorders (ASD), many significant questions remain and access to a tractable and highly translational animal model would benefit efforts to investigate risk factors, developmental mechanisms, and potential therapies for ASD. To study genetic influences on key aspects of the ASD phenotype individual competence and/or motivation for specific aspects of social behavior we analyzed individual variation in social interactions among juvenile rhesus macaques. All study subjects were housed in species-typical mixed-sex matrilineal social groups, providing opportunities for normal social development among these juveniles. We quantified individual variation in social behavior using both a standard macaque ethogram and a macaque-relevant modification of the human Social Responsiveness Scale. Our analyses demonstrate that various aspects of juvenile social behavior exhibit significant genetic heritability, including similar levels to those described for ASD in humans. We also performed whole exome sequencing and analyzed variants in 143 genes previously suggested to influence risk for human ASD. We find preliminary evidence for genetic association between specific variants and both individual behaviors and multi-behavioral factor scores. To our knowledge, this is the first demonstration that spontaneous social behaviors performed by free-ranging juvenile rhesus macaques display significant genetic heritability and that some variation may be associated with genes known to influence risk of ASD in children. Based on these data, we are moving forward with genome sequencing of the same macaque genomic samples, with plans to analyze the data for copy number variants (CNVs). These data will be crucial because CNVs have been shown in humans to contribute at least 1.4 times the risk for development of ASD phenotypes when compared to single nucleotide variants (SNVs), such as those we identified through exome sequencing. The combination of SNVs, CNVs, and detailed behavioral observation in the macaque samples will generate a powerful new picture of the relationships between genomic variation and social behavior in free-ranging juvenile rhesus macaques.

非人类灵长类动物，尤其是恒河猕猴（Macaca Mulatta）是必不可少的动物模型，用于研究神经生物学，发育心理学和神经科学的其他方面的各个方面。尽管我们对自闭症谱系障碍的原因（ASD）的理解取得了显着进展，但仍然存在许多重要的问题，并获得了可聊天且高度转化的动物模型的机会，这将有益于调查ASD的风险因素，发育机制和潜在的ASD疗法。为了研究遗传影响社会行为特定方面的ASD表型个人能力和/或动机的关键方面，我们分析了少年恒河猕猴之间社交互动中的个体变异。所有研究对象均位于物种类典型的混合性基质社会群体中，为这些少年的正常社会发展提供了机会。我们使用标准猕猴的伦理图和与人类社会响应量表的猕猴的修改一起量化了社会行为的个体变化。我们的分析表明，青少年社会行为的各个方面表现出重要的遗传遗传力，包括与人类中ASD所描述的相似水平。我们还进行了整个外显子组测序，并分析了先前建议影响人ASD风险的143个基因中的变体。我们发现特定变异与个体行为和多行为因素得分之间的遗传关联的初步证据。据我们所知，这是第一次证明，自由放养的幼稚猕猴表现出显着的遗传遗传力，并且可能与已知会影响儿童ASD风险的基因有关。 基于这些数据，我们正在使用相同猕猴基因组样本进行基因组测序，并计划分析拷贝数变体（CNV）的数据。这些数据将是至关重要的，因为与单核苷酸变体（SNV）相比，人类已经显示了CNV至少有助于ASD表型发育风险的1.4倍，例如我们通过外显子组测序所识别的。猕猴样品中SNV，CNV和详细的行为观察的结合将产生有力的新图片，说明基因组变异与自由放映的少年恒河猕猴之间的关系之间的关系。