Genetic basis of behavior in Macaca mulatta

非人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。克里斯蒂娜巴尔在临床和转化研究实验室（M。Heilig）与Dee Higley（现就职于犹他州大学）和Steven Suomi（NICHD）一起担任主要合作者。他们收集了大量的动物神经化学和行为数据，这些动物是由它们的母亲抚养的，交叉抚养的和同伴抚养的。我们已经建立了200多个成纤维细胞系，并协助从普尔斯维尔和摩根岛殖民地收集DNA。猕猴行为方面的遗传性，如攻击性、饮酒和神经化学。建立CSF 5 HIAA水平。他们检测了养育环境对饮酒的影响，并证明了与5-羟色胺转运体和MAOA基因型的相互作用。这些研究人员直接在LNG工作，研究候选基因与行为的关系。我们在猕猴和其他非人灵长类动物中检测到HTR 1A的种间和种内序列变异。HTR 1A是5 HT 1A的无内含子编码位点（1266个碱基对-422个氨基酸），5 HT 1A是G蛋白偶联的5-羟色胺受体，其用作5-羟色胺神经末梢上的自身受体。该实验室先前的工作发现了两种变体（Biochem Biophys Res Commun 1995;210（2）：530-6），表征了它们在人群中的频率和分布（Human Mutation 1996;7：135-43），并研究了它们的功能效应（Neuropsychopharmacology 1997; 17：18-26）。为了评估该基因座在神经科学研究中大量使用的灵长类动物模型中的多态性谱，我们从四种猕猴（食蟹猴，毛猴，猕猴和猕猴）和黑尾猴（Cercopithecus aethiops）中克隆并测序了高度保守的5 HT 1A基因。种间变异支持了猕猴的已知遗传学。这些序列变异与行为的关系正在研究中。STR基因座是由T.纽曼确定猕猴的亲子关系。除了HTR 1A，其他几个神经遗传学候选基因，如COMT，DAT，OPRM 1和CRH正在测序，并在各种灵长类动物物种中进行平行研究。值得注意的是，在猕猴中发现了与人类MAOA和HTTLPR基因座相似的功能多态性。这些都被用于与行为的联系，包括G x E相互作用。猕猴HTTLPR变体仅在早期生活压力（同伴养育）的背景下显示出易于增加酒精消耗和增强压力诱导的皮质醇反应（Spinelli et al，2007）。OPRM 1预测酒精消耗（巴尔等人，2007）和压力诱导的行为，包括与母亲分离相关的发声（巴尔等人，PNAS，2008）。同样在应激反应领域，CRH单倍型可预测CSF CRH、HPA活性、气质和饮酒（巴尔等人，2008）。 在全基因组的整合方法中，我们使用下一代测序发现了167，000个新的猕猴单核苷酸多态性，并确定了早期母体剥夺导致的脑组蛋白甲基化和转录组变化的差异（巴尔等人，在制备中）。

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).