Neurogenetics of Stress Response and Reward Sensitivity in Primates Dopamine neurotransmission underlies many reward-dependent and reinforcing processes. Tandem repeats in the third exon of the dopamine receptor D4 gene (DRD4) exist across a variety of animal species (humans, vervets, dogs, dolphins, bears, raccoons, horses, and chimpanzees). Some species, including macaque species, exhibit variation in the number of repeats present, with various alleles differing in frequencies across species. In humans, the DRD4 7-repeat allele (7R) reduces efficacy of the receptor and is linked with traits such as sensation seeking. This has been replicated in vervet monkeys, in which a DRD4 length variant was also observed. Of interest, in the dog, which has been subject to intense artificial selection, a repeat polymorphism predicts social impulsivity and activity-impulsivity endophenotypes. We have identified 4R, 5R, 6R, and 7R alleles using archived samples from the NIH animal center colony of rhesus macaques. Compared to the ancestral allele (4R), the loss-of-function 7R allele predicted increased incidence of physical aggression toward an unknown age- and sex-matched conspecific. Through collaboration with investigators at the University of Chicago (Maestripieri and colleagues), we performed a study to examine whether juvenile and adolescent animals behaviors were predicted by DRD4 genotype. Using DNA collected from the free-ranging population on the island of Cayo Santiago, we found that DRD4 genotype predicted time spent with mom and restlessness, suggesting that this polymorphism results in significant behavioral differences in at least behavioral measures of impulsivity and risk-taking. Behavioral restlessness is a common symptom in many psychiatric disorders, especially ADHD, but may also be linked to risk for reward- and reward-seeking behavior, and, therefore, the addictions. One system of potential relevance to the addictions via its effects on anxiety and reward is the oxytocin system. We screened the rhesus OXTR gene and identified 17 SNPs, including 4 non-synonymous SNPs in the first exon for the rhesus Oxytocin receptor gene (OXYR). This is a location at which there is high interspecific conservation yet high frequencies of non-synonymous SNPs in humans as well. Cladistic clustering of haplotypes demonstrated there to be ancient haplotypes, suggesting selection for variation at this gene. We also found there to be ancient polymorphisms maintained in humans and the existence of alternative haplotypes within this region indicating that human variation is being maintained by balancing selection. Oxytocin is a neuropeptide that produces affiliative, amnesic and anxiolytic affects. Given its roles in some of these processes, it has been proposed as a potential therapeutic agent for the treatment of anxiety and stress-related disorders, including the addictions. Functional variation that influences oxytocin system function may, therefore, be a particularly good candidate for performing gene x stress interaction studies. We are currently examining whether OXTR genotype moderates the effects of intranasal oxytocin administration on anxiety and sociality. Since this is a feed-forward system, we are currently also screening the Oxytocin gene, and have found potentially functional SNPs, which may be good candidates for looking at effects on behavior and also G x G (gene by gene) interactions with OXTR polymorphisms. Parallel studies are to be performed in datasets from domestic animals and humans. Whole Genome and Exome Sequencing in Domestic Animals to Identify Genes Contributing to Aggressive Behavior The systems that likely permitted early domestication range from those involving fear and impulse control to those involving reward and sociality. In this sense, the effects of artificial selection of genes predicting behavioral differences between domesticates and their ancestors may be relevant to personality traits and risk for the psychiatric disorders and addictions. In general, domestic animals have lower levels of aggression than do their non-domesticated ancestors. Aggression is a behavioral trait that appears to be under selection, as it facilitates access to resources and mating opportunities across mammals, including in domestic species. However, in humans, exaggerated aggression is known to be a hallmark of a number of psychiatric and personality disorders, including those prevalent in alcohol dependent subjects. One approach that could be used to determine the genetic factors that contribute to variation in aggression is the study of the genetics of domestication. At its most basic, domestication is a suite of heritable traits affecting behavior. Among most domestic animal species, there is diminution in aggression and an ability to coexist with humans. The domesticated fox (Vulpes vulpes) and the house cat (Felis silvestris catus) may be good candidates for modeling how genetic variation contributes to aggressive behavior in humans. The house cat manifests a suite of heritable behaviors characteristic of domesticates relative to wildcats, and the commercially abundant silver fox is being increasingly recognized as a superior model of domestication. However, few studies have attempted to identify intra- or inter-specific variation among these species. Here, we explore a draft whole genome sequence of a domestic cat, a wild Asian leopard cat (Prionailurus bengalensis) and interspecies hybrid offspring differing in their levels of tameness (ALC X DC). We also explored genetic variation in two selected fox lines that are distinguished by marked differences in reactivity and temperament (tame vs. aggressive). We whole genome sequenced, at approximately 15X coverage, archived samples from one domestic cat (DC), one Asian leopard cat (ALC) and interspecies hybrid offspring (ALC X DC). Tame-selected aggressive selected and unselected farm foxes from the Institute of Cytology and Genetics, Novosibersk, Russia and twelve wild caught foxes from Maryland were characterized for genome-wide protein-coding variation. Exploiting the phylogenetically close relationship between the domestic dog (Canis familiaris) and fox, we used a canine (dog) -based exon assay (Agilent) on the Ion Proton platform. In general, domestic animals have lower levels of aggression than do their non-domesticated ancestors. Systems permissive of domestication and underlying a tame phenotype range from those involving fear and impulse control to those driving reward and sociality. Between tame and aggressive animals, we identified damaging cSNPs in gene systems influencing anxiety-like behavior, transcription control, DNA repair, epigenetic processes, synaptic plasticity/transmission, reward, and circadian rhythms. As these systems can contribute to vulnerability to or resilience to human psychiatric disorders, identification of genetic variation among domesticated animals with exaggerated differences in their degrees of tameness may inform us of the human condition and aid in identifying appropriate models for examining treatment response to compounds being developed for the treatment of various psychiatric disorders.

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Alcohol Abuse and Alcoholism
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