Genetic basis of behavior in Macaca mulatta

非人类灵长类动物行为模型为理解基因与环境相互作用在行为中的作用提供了一个独特的机会。临床和转化研究实验室的Christina Barr （M. Heilig）与现在在犹他大学的Dee Higley和Steven Suomi （NICHD）一起成为主要合作者。他们收集了大量由母亲抚养、交叉抚养和同伴抚养的动物的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收集了普尔斯维尔和摩根岛菌落的DNA。猕猴行为方面的遗传性，如攻击性、饮酒和神经化学等。测定脑脊液5HIAA水平。他们检测了饲养环境对酒精消耗的影响，并证明了与血清素转运体和MAOA基因型的相互作用。这些研究人员直接在LNG中研究候选基因与行为的关系。我们已经在猕猴和其他非人灵长类动物中检测到了HTR1A的种间和种内序列变异。HTR1A是5HT1A的无内含子编码位点（1266个碱基对- 422个氨基酸），5HT1A是一种G蛋白偶联的5 -羟色胺受体，作为5 -羟色胺神经末梢的自受体。本实验室之前的工作发现了两种变异（Biochem Biophys Res comm1995;210(2):530-6），描述了它们在人群中的频率和分布（human Mutation 1996; 7:35 5-43），并研究了它们的功能影响（Neuropsychopharmacology 1997; 17:18-26）。为了在神经科学研究中广泛使用的灵长类动物模型中评估该位点的多态性谱，我们克隆了4种猕猴（Macaca fascicularis, Macaca maura， Macaca mulatta和Macaca nemestrina）和长尾猴（Cercopithecus aethiops）的高度保守的5HT1A基因并对其进行了测序。种间变异支持已知的猕猴系统发育。这些序列变异与行为的关系正在研究中。T.纽曼开发了一个STR小组来确定猕猴的父系关系。除了HTR1A外，其他几种神经遗传候选基因，如COMT， DAT， OPRM1和CRH，正在各种灵长类动物中进行平行测序和研究。值得注意的是，在猕猴中发现了与人类MAOA和HTTLPR位点相似的功能多态性。研究人员正在追踪这些与行为的联系，包括gx E相互作用。研究表明，猕猴HTTLPR变异仅在早期生活压力（同伴抚养）的背景下才容易增加酒精摄入量和增强应激诱导的皮质醇反应（Spinelli et al, 2007）。OPRM1预测酒精消费（Barr et al, 2007）和压力诱发的行为，包括与母亲分离相关的发声（Barr et al， PNAS, 2008）。同样在应激反应领域，CRH单倍型预测CSF CRH、HPA活性、气质和酒精消耗（Barr et al, 2008）。

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).