Genetic basis of behavior in Macaca mulatta

非人灵长类动物行为模型为理解基因x环境交互作用在行为中的作用提供了独特的机会。临床和翻译研究实验室的Christina Barr(M.Heilig)与现供职于犹他大学的Dee Higley和Steven Suomi(NICHD)一起是主要合作者。他们收集了密集的神经化学和行为数据，这些数据是由他们的母亲、交叉养育和同伴饲养的动物饲养的。我们已经建立了200多个成纤维细胞系，并协助收集了Poolesville和Morgan Island殖民地的DNA。建立了猕猴行为方面的遗传力，如攻击性、饮酒和神经化学，如脑脊液5HIAA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基因的交互作用。这些研究人员直接在液化天然气公司工作，研究候选基因与行为的关系。我们已经在猕猴和其他非人类灵长类动物中检测到了HTR1A的种间和种内序列变异。HTR1a是5HT1a的无内含子编码区(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，是5-羟色胺神经末梢的自身受体。该实验室以前的工作发现了两个变种(Biochem BiPhys res Commun 1995；210(2)：530-6)，描述了它们在人类群体中的频率和分布(人类突变1996；7：135-43)，并研究了它们的功能效应(Neuromental opPharmacology 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基因的多态图谱，我们从四个猕猴物种(猕猴、恒河猴和恒河猴)中克隆和测序了高度保守的5HT1A基因。这种种间变异支持猕猴已知的系统发育。这些序列变体与行为的关系正在研究中。T.Newman开发了一个STR小组来确定猕猴的父子关系。除了HTR1A外，其他几个神经遗传学候选基因，如COMT、DAT、OPRM1和CRH正在进行测序，并在不同的灵长类物种中以并行方式进行研究。值得注意的是，在猕猴中发现了类似于人类MAOA和HTTLPR基因座的功能多态。这些都是为了与行为联系起来，包括G×E互动。猕猴HTTLPR变异体被证明只在早期生活压力(同伴养育)的背景下容易增加酒精摄入量和增强压力诱导的皮质醇反应(Spinelli等人，2007年)。OPRM1预测酒精消费(Barr等人，2007年)和压力诱导的行为，包括与母体分离相关的发声Barr等人，PNAS，2008年)。在应激反应领域，CRH单倍型预测了脑脊液CRH、HPA活性、气质和饮酒(Barr等人，2008年)。 在一种全基因组的综合方法中，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，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(Barr等人，正在准备中)。

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).