Genetic basis of behavior in Macaca mulatta

National Institute On Alcohol Abuse And Alcoholism

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Abstract

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. 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,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). [unreadable] 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.