Genetic basis of behavior in Macaca mulatta

猕猴行为的遗传基础

• 批准号: 7963840
• 负责人: David Goldman
• 金额: $ 31.45万
• 依托单位: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
• 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/7963840
• 关键词: Aggressive behavior; Alcohol consumption; Amino Acids; Animal Model; Animals; Autoreceptors; Base Pairing; Behavior; Behavioral; Behavioral Genetics; Behavioral Model; Brain; CRH gene; Candidate Disease Gene; Cell Line; Cercopithecus aethiops; Cercopithecus tantalus; Chromatin Structure; Clinical; Code; Collection; DNA; Data; Environment; Fibroblasts; Fostering; Frequencies; GTP-Binding Proteins; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Polymorphism; Genotype; Haplotypes; Heritability; Histones; Human; Hydrocortisone; Island; Laboratories; Life Stress; Macaca; Macaca fascicularis; Macaca mulatta; Macaca nemestrina; Maternal Deprivation; Methaqualone; Methylation; Mothers; Mutation; National Institute of Child Health and Human Development; Nerve; Neurosciences Research; Phylogeny; Population; Preparation; Primates; Research; Research Personnel; Role; Serotonin; Single Nucleotide Polymorphism; Stress; Temperament; Universities; Utah; Variant; Work; base; biological adaptation to stress; father role; genome-wide; maternal separation; neurochemistry; neurogenetics; next generation; nonhuman primate; novel; peer; response; serotonin receptor; serotonin transporter; translational study; vocalization

Nonhuman primate behavioral models offer a unique opportunity for understanding the role of gene x environment interactions in behavior. Christina Barr in the Lab of Clinical and Translational Studies (M. Heilig) has been principal collaborator together with Dee Higley, now at University of Utah and Steven Suomi (NICHD). They have collected dense neurochemical and behavioral data on animals raised by their mothers, cross-fostered and peer reared. We have established over 200 fibroblast cell lines and assisted with collections of DNA from the Poolesville and Morgan Island colonies. Heritability of aspects of macaque behavior e.g aggression, alcohol consumption and neurochemistry e,g. CSF 5HIAA levels were established. They detected effects of rearing environment on alcohol consumption and demonstrated interaction with serotonin transporter and MAOA genotype. These investigators have worked directly in LNG towards the studies on the relationship of candidate genes to behavior. We have detected both interspecific and intraspecific sequence variations in HTR1A in macaques and other nonhuman primates. HTR1A is the intronless coding locus (1266 base pair - 422 amino acids) for a 5HT1A, a G protein-coupled serotonin receptor which serves as the autoreceptor on serotonin nerve terminals. Previous work in this laboratory discovered two variants (Biochem Biophys Res Commun 1995;210(2):530-6), characterized their frequency and distribution in human populations (Human Mutation 1996;7:135-43) and investigated their functional effects (Neuropsychopharmacology 1997; 17:18-26). In order to assess the polymorphic spectrum of this locus in a primate animal model heavily used in neuroscience research, we cloned and sequenced the highly conserved 5HT1A gene from four macaque species (Macaca fascicularis , Macaca maura, Macaca mulatta and Macaca nemestrina) and from the vervet monkey (Cercopithecus aethiops). The interspecific variation supports the known phylogeny of Macaca. The relationships of these sequence variants to behavior is being studied. An STR panel was developed by T. Newman to determine paternity relationships in macaques. In addition to HTR1A, several other neurogenetic candidate genes e.g. COMT, DAT, OPRM1, and CRH are being sequenced and studied in parallel fashion in various primate species. Remarkably, functional polymorphisms similar to the human MAOA and HTTLPR loci are found in the macaque. These are being followed for linkage to behavior, including G x E interactions. The macaque HTTLPR variant was shown to predispose to increased alcohol consumption and enhanced stress-induced cortisol response only in the context of early life stress (peer rearing) (Spinelli et al, 2007). OPRM1 predicts alcohol consumption (Barr et al, 2007) and stress-induced behaviors, including vocalization associated with maternal separation Barr et al, PNAS, 2008). Also in the domain of stress response, a CRH haplotype predicted CSF CRH, HPA activity, temperament and alcohol consumption (Barr et al, 2008). In a genome-wide, integrative approach we have used next generation sequencing to discover 167,000 novel macaque single-nucleotide polymorphisms and to define differences in brain histone methylation and transcriptome changes resulting from early maternal deprivation (Barr et al, in Preparation).

非人类灵长类动物行为模型为理解基因X环境相互作用在行为中的作用提供了独特的机会。克里斯蒂娜·巴尔（Christina Barr）在临床和转化研究实验室（M. Heilig）与现任犹他大学和史蒂文·苏米（Steven Suomi）（NICHD）的迪·希格利（Dee Higley）一起担任首席合作者。他们已经收集了对母亲饲养的动物，交叉养育和同伴养育的动物的密集神经化学和行为数据。我们已经建立了200多个成纤维细胞系，并协助了来自Poolesville和Morgan Island殖民地的DNA收集。猕猴行为方面的遗传力，例如侵略，饮酒和神经化学e，g。建立了CSF 5HIAA水平。他们检测到饲养环境对饮酒的影响，并证明了与5-羟色胺转运蛋白和MAOA基因型的相互作用。这些研究者直接致力于液化天然气研究候选基因与行为的关系的研究。我们已经检测到猕猴和其他非人类灵长类动物中HTR1A的种间和种内序列变化。 HTR1A是5HT1A的无内膜编码基因座（1266碱基对-422氨基酸），G蛋白偶联的5-羟色胺受体，可作为5-羟色胺神经末端的自感受器。该实验室的先前工作发现了两种变体（Biochem Biophys Res Commun 1995; 210（2）：530-6），表征了它们在人类人群中的频率和分布（Human Stutation 1996; 7：135-43），并研究了其功能效应（Neuropsychopharmacology 1997; 17：18-26）。为了评估在神经科学研究中广泛使用的灵长动物模型中，我们从四个猕猴（Macaca fascicularis，Macaca Maura，Macaca Maura，Macaca Mulatta和Macaca Nemertrina）和Vervetiencith（V​​erverveterius）（corcecopith）（corcecopith）（corcecopith）（corcopith）（corcopith）（corcopith）（corcopith）（corcopith）（corcopith）（corcopith）（corcopithiencithi）（Macaca Maura）（Macaca fascicularis），我们对该基因座的多态性谱进行了。种间变异支持已知的Macaca系统发育。这些序列变体与行为的关系正在研究。 T. Newman开发了Str面板，以确定猕猴中的亲子关系关系。除HTR1A外，其他几个神经遗传候选基因，例如COMT，DAT，OPRM1和CRH正在以各种灵长类动物的方式进行测序和研究。值得注意的是，在猕猴中发现了类似于人MAOA和HTTLPR基因座的功能多态性。遵循这些与行为的联系，包括g x e相互作用。猕猴的HTTLPR变体仅在早期生命应力的背景下（Spinelli等，2007），才显示出增加饮酒量并增强压力引起的皮质醇反应的易感性。 OPRM1预测酒精消耗（Barr等，2007）和压力诱导的行为，包括与母体分离相关的发声Barr等，PNAS，2008）。同样在压力反应的领域，CRH单倍型预测了CSF CRH，HPA活性，气质和饮酒（Barr等，2008）。 在整个基因组的整合方法中，我们使用了下一代测序，发现167,000个新型猕猴单核苷酸多态性，并确定脑组蛋白甲基化和转录组变化的差异（Barr等人，制备中）。