Mismatches in resident and stranger serotonin transporter genotypes lead to escalated aggression, and the target for aggression is mediated by sex differences in male and female rhesus monkeys (Macaca mulatta).

A variety of studies show that the s-allele of the serotonin transporter genotype (5-HTT) is related to aggression. However, influences of sex and 5-HTT genotype of both subject and opponent have not received as much attention in aggression research. Using a nonhuman primate model, the present study explores differences in rates of aggression exhibited by 201 group-housed male and female rhesus monkeys (Macaca mulatta; 122 females; 79 males) exposed to an unfamiliar age- and sex-matched stranger while in the presence of other same-sex members of their social group. The study also assesses whether the rates of aggression increase when the home-cage resident, the unfamiliar stimulus animal, or both possess the short (s) allele of the 5-HTT. Results showed that, when compared to females, males exhibited higher rates of physical aggression toward the stranger, and when both the male resident and the male stranger possessed the s-allele, rates of physical aggression toward the stranger increased five-fold. Resident females also engaged in higher rates of physical aggression when they possessed the s-allele, although unlike the males, their physical aggression was directed toward familiar same-sex members of their social group. The findings of this study indicate that rates of physical aggression are modulated by 5-HTT resident and stranger suggest a role of sexual competition in the phenotype of the 5-HTT genotype. Importantly, when two males with impulse deficits, as a function of the s-allele, are placed together, rates of violence exhibited by the dyad escalate substantially.

Genetic variation and gene expression across multiple tissues and developmental stages in a nonhuman primate.

By analyzing multitissue gene expression and genome-wide genetic variation data in samples from a vervet monkey pedigree, we generated a transcriptome resource and produced the first catalog of expression quantitative trait loci (eQTLs) in a nonhuman primate model. This catalog contains more genome-wide significant eQTLs per sample than comparable human resources and identifies sex- and age-related expression patterns. Findings include a master regulatory locus that likely has a role in immune function and a locus regulating hippocampal long noncoding RNAs (lncRNAs), whose expression correlates with hippocampal volume. This resource will facilitate genetic investigation of quantitative traits, including brain and behavioral phenotypes relevant to neuropsychiatric disorders.

Significant genotype by diet (G × D) interaction effects on cardiometabolic responses to a pedigree-wide, dietary challenge in vervet monkeys (Chlorocebus aethiops sabaeus).

Nutrient composition of a diet (D) has been shown to interact with genetic predispositions (G) to affect various lipid phenotypes. Our aim in this study was to confirm G × D interaction and determine whether the interaction extends to other cardiometabolic risk factors such as glycemic measures and body weight. Subjects were vervet monkeys (Chlorocebus aethiops sabaeus; n = 309) from a multigenerational pedigreed colony initially fed with a plant-based diet, standard primate diet (18% calories from protein, 13% from fat, and 69% from carbohydrates), and subsequently challenged for 8 weeks with a diet modeled on the typical American diet (18% calories from protein, 35% from fat, and 47% from carbohydrates). Our results showed that although exposure to the challenge diet did not result in significant changes in weight, most lipid and glycemic biomarkers moved in an adverse direction (P < 0.01). Quantitative genetic analyses showed that cardiometabolic phenotypes were significantly heritable under both dietary conditions (P < 0.05), and there was significant evidence of G × D interaction for these phenotypes. We observed significant differences in the additive genetic variances for most lipid phenotypes (P < 10(-4) ), indicating that the magnitude of genetic effects varies by diet. Furthermore, genetic correlations between diets differed significantly from 1 with respect to insulin, body weight, and some lipid phenotypes (P < 0.01). This implied that distinct genetic effects are involved in the regulation of these phenotypes under the two dietary conditions. These G × D effects confirm and extend previous observations in baboons (Papio sp.) and suggest that mimicking the typical human nutritional environment can reveal genetic influences that might not be observed in animals consuming standard, plant-based diets.

Maternal and offspring dopamine D4 receptor genotypes interact to influence juvenile impulsivity in vervet monkeys.

The merging of psychological and genetic methodologies has led to an increasing appreciation of environmental moderators of the relationships between genotype and phenotype. Here we used a nonhuman-primate model to study the moderating effect of the mother's genotype on the association of a dopamine D4 receptor (DRD4) gene polymorphism with juvenile impulsivity, assessed in a standardized social-challenge test. The results showed that juvenile carriers of the rare 5-repeat variant of the exon III 48-base-pair repeat polymorphism scored significantly higher in social impulsivity than juveniles homozygous for the common 6-repeat allele. In addition, juvenile genotype interacted with maternal genotype to influence impulsivity, with the highest rates of impulsivity found in variant offspring with variant mothers. These results highlight the importance of considering the genotype of the parents in studies of early experience and vulnerability genes for impulsivity-related traits.

A non-human primate system for large-scale genetic studies of complex traits.

Non-human primates provide genetic model systems biologically intermediate between humans and other mammalian model organisms. Populations of Caribbean vervet monkeys (Chlorocebus aethiops sabaeus) are genetically homogeneous and large enough to permit well-powered genetic mapping studies of quantitative traits relevant to human health, including expression quantitative trait loci (eQTL). Previous transcriptome-wide investigation in an extended vervet pedigree identified 29 heritable transcripts for which levels of expression in peripheral blood correlate strongly with expression levels in the brain. Quantitative trait linkage analysis using 261 microsatellite markers identified significant (n = 8) and suggestive (n = 4) linkages for 12 of these transcripts, including both cis- and trans-eQTL. Seven transcripts, located on different chromosomes, showed maximum linkage to markers in a single region of vervet chromosome 9; this observation suggests the possibility of a master trans-regulator locus in this region. For one cis-eQTL (at B3GALTL, beta-1,3-glucosyltransferase), we conducted follow-up single nucleotide polymorphism genotyping and fine-scale association analysis in a sample of unrelated Caribbean vervets, localizing this eQTL to a region of <200 kb. These results suggest the value of pedigree and population samples of the Caribbean vervet for linkage and association mapping studies of quantitative traits. The imminent whole genome sequencing of many of these vervet samples will enhance the power of such investigations by providing a comprehensive catalog of genetic variation.

Developmental patterns of hair cortisol in male and female nonhuman primates: lower hair cortisol levels in vervet males emerge at puberty.

Studies have yielded inconsistent results with regard to effects of age and sex on short-term markers of hypothalamic pituitary adrenal (HPA) activity. Hair cortisol provides a retrospective proxy measure of the cumulative activity of the HPA axis over the preceding 3- to 4-month period. In order to describe potential developmental trends in this biomarker, we assessed hair cortisol levels between 1 and 12 years of age in a cross-sectional study of 350 vervets (222 females and 128 males). Monkeys were grouped according to age as 1 (young juvenile), 2 (juvenile), 3 (early adolescent), 4 (late adolescent-young adult), and 5-12 (adult) years of age such that fully mature animals were included in the 5-12 year old age group. We observed that hair cortisol level was higher among the younger monkeys and declined with age (p<.001). More importantly the effect of age significantly interacted with sex (p=.02), such that hair cortisol was consistently lower in males than females beginning at age 3 (p<.05 or better). The developmental decline began one year earlier in females than males suggesting an influence of the earlier maturational processes typical in both human and nonhuman primates. The advantage of lower cortisol levels in the males may be related to social group patterns of male emigration during adolescence in many nonhuman primate species.

Anatomic brain asymmetry in vervet monkeys.

Asymmetry is a prominent feature of human brains with important functional consequences. Many asymmetric traits show population bias, but little is known about the genetic and environmental sources contributing to inter-individual variance. Anatomic asymmetry has been observed in Old World monkeys, but the evidence for the direction and extent of asymmetry is equivocal and only one study has estimated the genetic contributions to inter-individual variance. In this study we characterize a range of qualitative and quantitative asymmetry measures in structural brain MRIs acquired from an extended pedigree of Old World vervet monkeys (n = 357), and implement variance component methods to estimate the proportion of trait variance attributable to genetic and environmental sources. Four of six asymmetry measures show pedigree-level bias and one of the traits has a significant heritability estimate of about 30%. We also found that environmental variables more significantly influence the width of the right compared to the left prefrontal lobe.

Heritability and genetic correlation of hair cortisol in vervet monkeys in low and higher stress environments.

Chronic activation of the hypothalamic-pituitary adrenal (HPA) system is a risk factor for a variety of physical and mental disorders, and yet the complexity of the system has made it difficult to define the role of genetic and environmental factors in producing long-term individual differences in HPA activity. Cortisol levels in hair have been suggested as a marker of total HPA activation over a period of several months. This study takes advantage of a pedigreed nonhuman primate colony to investigate genetic and environmental influences on hair cortisol levels before and after an environmental change. A sample of 226 adult female vervet monkeys (age 3-18) living in multigenerational, matrilineal social groups at the Vervet Research Colony were sampled in a stable low stress baseline environment and 6 months after the entire colony was moved to a new facility with more frequent handling and group disturbances (higher stress environment). Variance components analysis using the extended colony pedigree was applied to determine heritability of hair cortisol levels in the two environments. Bivariate genetic correlation assessed degree of overlap in genes influencing hair cortisol levels in the low and higher stress environments. The results showed that levels of cortisol in hair of female vervets increased significantly from the baseline to the post-move environment. Hair cortisol levels were heritable in both environments (h(2)=0.31), and there was a high genetic correlation across environments (rhoG=0.79), indicating substantial overlap in the genes affecting HPA activity in low and higher stress environments. This is the first study to demonstrate that the level of cortisol in hair is a heritable trait. It shows the utility of hair cortisol as a marker for HPA activation, and a useful tool for identifying genetic influences on long term individual differences in HPA activity. The results provide support for an additive model of the effects of genes and environment on this measure of long term HPA activity.

A novelty seeking phenotype is related to chronic hypothalamic-pituitary-adrenal activity reflected by hair cortisol.

Reduced hypothalamic pituitary adrenal (HPA) activity is associated with greater novelty seeking in humans. Hair cortisol represents an integrated proxy measure of total cortisol production/release over an extended period of time and may be a valuable tool for tracking the HPA system. Sampling approaches (collection of blood, saliva, urine, or feces) for socially housed nonhuman primates present a number of technical challenges for collection particularly when repeated sampling is necessary. Herein we describe a relationship between cortisol levels measured in hair collected from 230 socially housed female vervet (Chlorocebus aethiops sabaeus) monkeys and a free-choice novelty seeking phenotype. A predator-like object was placed at the periphery of the outdoor enclosures for 30 min and speed of approach (latency to approach within 1m) and persistence of interest (number of 1 min intervals within 1m) were scored. A composite Novelty Seeking score, combining these two measures, was calculated. The intra-class correlation coefficient (ICC=.68) for two different objects across years indicated that this score reflects a stable aspect of temperament. Hair samples were collected from each subject approximately 3-6 months following the second assessment; cortisol levels were determined from the hair. A significant inverse relationship of Novelty Seeking score with hair cortisol level (p<.01) was noted. The high hair cortisol groups had significantly lower Novelty Seeking scores than the low cortisol groups both years (p's<.05). These results suggest that low average cortisol levels promote novelty seeking, while high average levels inhibit novelty seeking behavior.

A web-based brain atlas of the vervet monkey, Chlorocebus aethiops.

Vervet monkeys are a frequently studied animal model in neuroscience research. Although equally distantly related to humans, the ancestors of vervets diverged from those of macaques and baboons more than 11 million years ago, antedating the divergence of the ancestors of humans, chimpanzees and gorillas. To facilitate anatomic localization in the vervet brain, two linked on-line electronic atlases are described, one based on registered MRI scans from hundreds of vervets (http://www.loni.ucla.edu/Research/Atlases/Data/vervet/vervetmratlas/vervetmratlas.html) and the other based on a high-resolution cryomacrotome study of a single vervet (http://www.loni.ucla.edu/Research/Atlases/Data/vervet/vervetatlas/vervetatlas.html). The averaged MRI atlas is also available as a volume in Neuroimaging Informatics Technology Initiative format. In the cryomacrotome atlas, various sulcal and subcortical structures have been anatomically labeled and surface rendered views are provided along the primary planes of section. Both atlases simultaneously provide views in all three primary planes of section, rapid navigation by clicking on the displayed images, and stereotaxic coordinates in the averaged MRI atlas space. Despite the extended time period since their divergence, the major sulcal and subcortical landmarks in vervets are highly conserved relative to those described in macaques.

High-fiber diet promotes weight loss and affects maternal behavior in vervet monkeys.

The dramatic increase in obesity in western societies has shifted the emphasis in nutrition research from the problems of undernutrition to the adverse consequences of being overweight. As with humans, Old World monkeys are at increased risk for type II diabetes and other chronic diseases when they gain excessive weight. To prevent overweight and obesity, promote animal health, and provide a more natural level of fiber in the diet, the standard commercial monkey chow diet at a vervet monkey breeding colony was changed to a higher fiber formulation in 2004. The new diet was also higher in protein and lower in carbohydrate and energy density than the standard diet. Because maternal behavior is known to be sensitive to differences in resource availability, data on weight and mother-infant interactions for 147 mothers with 279 infants born from 2000 through 2006 were assessed for effects of the diet change. The results showed that, even though food was provided ad libitum, the mean body weight of breeding females was 10% lower after the transition to the high-fiber diet. Behaviorally, mothers on the high-fiber diet were significantly more rejecting to their infants, and their infants had to play a greater role in maintaining ventral contact in the first few months of their lives. The effects of the diet change on maternal rejection were significantly related to the mother's body weight, with lower-weight mothers scoring higher in maternal rejection. These results demonstrate that maternal behavior is responsive to changes in maternal condition, and that beneficial changes in the diet may have unintended consequences on behavior.

Identification of brain transcriptional variation reproduced in peripheral blood: an approach for mapping brain expression traits.

Genome-wide gene expression studies may provide substantial insight into gene activities and biological pathways differing between tissues and individuals. We investigated such gene expression variation by analyzing expression profiles in brain tissues derived from eight different brain regions and from blood in 12 monkeys from a biomedically important non-human primate model, the vervet (Chlorocebus aethiops sabaeus). We characterized brain regional differences in gene expression, focusing on transcripts for which inter-individual variation of expression in brain correlates well with variation in blood from the same individuals. Using stringent criteria, we identified 29 transcripts whose expression is measurable, stable, replicable, variable between individuals, relevant to brain function and heritable. Polymorphisms identified in probe regions could, in a minority of transcripts, confound the interpretation of the observed inter-individual variation. The high heritability of levels of these transcripts in a large vervet pedigree validated our approach of focusing on transcripts that showed higher inter-individual compared with intra-individual variation. These selected transcripts are candidate expression Quantitative Trait Loci, differentially regulating transcript levels in the brain among individuals. Given the high degree of conservation of tissue expression profiles between vervets and humans, our findings may facilitate the understanding of regional and individual transcriptional variation and its genetic mechanisms in humans. The approach employed here-utilizing higher quality tissue and more precise dissection of brain regions than is usually possible in humans-may therefore provide a powerful means to investigate variation in gene expression relevant to complex brain related traits, including human neuropsychiatric diseases.

Identifying heritable brain phenotypes in an extended pedigree of vervet monkeys.

The area and volume of brain structural features, as assessed by high-resolution three-dimensional magnetic resonance imaging (MRI), are among the most heritable measures relating to the human CNS. We have conducted MRI scanning of all available monkeys >2 years of age (n = 357) from the extended multigenerational pedigree of the Vervet Research Colony (VRC). Using a combination of automated and manual segmentation we have quantified several correlated but distinct brain structural phenotypes. The estimated heritabilities (h(2)) for these measures in the VRC are higher than those reported previously for such features in humans or in other nonhuman primates: total brain volume (h(2) = 0.99, SE = 0.06), cerebral volume (h(2) = 0.98, SE = 0.06), cerebellar volume (h(2) = 0.86, SE = 0.09), hippocampal volume (h(2) = 0.95, SE = 0.07) and corpus callosum cross-sectional areas (h(2) = 0.87, SE = 0.07). These findings indicate that, in the controlled environment and with the inbreeding structure of the VRC, additive genetic factors account for almost all of the observed variance in brain structure, and suggest the potential of the VRC for genetic mapping of quantitative trait loci underlying such variance.

Long-term methamphetamine administration in the vervet monkey models aspects of a human exposure: brain neurotoxicity and behavioral profiles.

Methamphetamine (METH)-associated alterations in the human striatal dopamine (DA) system have been identified with positron emission tomography (PET) imaging and post-mortem studies but have not been well correlated with behavioral changes or cumulative METH intake. Animal studies that model some aspects of human long-term METH abuse can establish dose-dependency profiles of both behavioral changes and potential brain neurotoxicities for identifying consequences of particular cumulative exposures. Based on parameters from human and our monkey pharmacokinetic studies, we modeled a prevalent human METH exposure of daily multiple doses in socially housed vervet monkeys. METH doses were escalated over 33 weeks, with final dosages resulting in estimated peak plasma METH concentrations of 1-3 microM, a range measured in human abusers. With larger METH doses, progressive increases in abnormal behavior and decreases in social behavior were observed on 'injection' days. Anxiety increased on 'no injection' days while aggression decreased throughout the study. Thereafter, during 3 weeks abstinence, differences in baseline vs post-METH behaviors were not observed. Post-mortem analysis of METH brains showed 20% lower striatal DA content while autoradiography studies of precommissural striatum showed 35% lower [3H]WIN35428 binding to the DA transporter. No statistically significant changes were detected for [3H]dihydrotetrabenazine binding to the vesicular monoamine transporter (METH-lower by 10%) or for [3H]SCH 23390 and [3H]raclopride binding to DA D1 and D2 receptors, respectively. Collectively, this long-term, escalating dose METH exposure modeling a human abuse pattern, not associated with high-dose binges, resulted in dose-dependent behavioral effects and caused persistent changes in presynaptic striatal DA system integrity.

Dimensions of impulsivity are associated with poor spatial working memory performance in monkeys.

Impulsive behavior and novelty seeking are dimensions of temperament that are behavioral determinants of risk for attention deficit/hyperactivity disorder and its neurocognitive endophenotypes, and variation in the dopamine D4 receptor gene (DRD4) explains at least a portion of the variance in the traits. To further characterize the dimensional phenotype associated with impulsiveness, adolescent male monkeys were evaluated using ecologically valid tests of impulsive approach and aggression in response to social or nonsocial stimuli; subsequently, a delayed response task was implemented to assess spatial working memory performance. Subjects were selected into this study based on their response to the social challenge task or by DRD4 genotype, resulting in three groups: low-impulsivity/common DRD4 allele, high-impulsivity/common DRD4 allele, or rare DRD4 allele. All animals acquired the delayed response task and could perform at near ceiling levels when a approximately 0 s delay version was imposed, but as delays were lengthened, high-impulsive animals, regardless of DRD4 genotype, made fewer correct responses than did low-impulsive subjects; an inverse relationship existed for working memory and impulsivity. Notably, impulsive behavior evoked by social and nonsocial stimuli explained overlapping and independent portions of the variance in working memory performance. CSF levels of monoamine metabolites did not significantly differentiate the high- and low-impulsive animals, although monkeys carrying the DRD4 rare allele tended to exhibit higher monoamine turnover. These data indicate that dimensions of impulsivity may impact on working memory performance in qualitatively similar ways but through different mechanisms.

A quantitative trait locus for variation in dopamine metabolism mapped in a primate model using reference sequences from related species.

Non-human primates (NHP) provide crucial research models. Their strong similarities to humans make them particularly valuable for understanding complex behavioral traits and brain structure and function. We report here the genetic mapping of an NHP nervous system biologic trait, the cerebrospinal fluid (CSF) concentration of the dopamine metabolite homovanillic acid (HVA), in an extended inbred vervet monkey (Chlorocebus aethiops sabaeus) pedigree. CSF HVA is an index of CNS dopamine activity, which is hypothesized to contribute substantially to behavioral variations in NHP and humans. For quantitative trait locus (QTL) mapping, we carried out a two-stage procedure. We first scanned the genome using a first-generation genetic map of short tandem repeat markers. Subsequently, using >100 SNPs within the most promising region identified by the genome scan, we mapped a QTL for CSF HVA at a genome-wide level of significance (peak logarithm of odds score >4) to a narrow well delineated interval (<10 Mb). The SNP discovery exploited conserved segments between human and rhesus macaque reference genome sequences. Our findings demonstrate the potential of using existing primate reference genome sequences for designing high-resolution genetic analyses applicable across a wide range of NHP species, including the many for which full genome sequences are not yet available. Leveraging genomic information from sequenced to nonsequenced species should enable the utilization of the full range of NHP diversity in behavior and disease susceptibility to determine the genetic basis of specific biological and behavioral traits.

Characterization and heritability of obesity and associated risk factors in vervet monkeys.

OBJECTIVE: The objective was to determine the prevalence and heritability of obesity and risk factors associated with metabolic syndrome (MS) in a pedigreed colony of vervet monkeys. DESIGN: A cross-sectional study of plasma lipid and lipoprotein concentrations, glycemic indices, and morphometric measures with heritability calculated from pedigree analysis. A selected population of females was additionally assessed for insulin sensitivity and glucose tolerance. SUBJECTS: All mature male (n=98), pregnant (n=40) and non-pregnant female (n=157) vervet monkeys were included in the study. Seven non-pregnant females were selected on the basis of high or average glycated hemoglobin (GHb) for further characterization of carbohydrate metabolism. MEASUREMENTS: Morphometric measurements included body weight, length, waist circumference, and calculated BMI. Plasma lipids [total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C)] and glycemic measures (fasting blood glucose, insulin, and GHb) were measured. A homeostasis model assessment index was further reported. Glucose tolerance testing and hyperinsulinemic-euglycemic clamps were performed on 7 selected females. CONCLUSION: Vervet monkeys demonstrate obesity, insulin resistance, and associated changes in plasma lipids even while consuming a low-fat (chow) diet. Furthermore, these parameters are heritable. Females are at particular risk for central obesity and an unfavorable lipid profile (higher TG, TC, and no estrogen-related increase in HDL-C). Selection of females by elevated GHb indicated impaired glucose tolerance and was associated with central obesity. This colony provides a unique opportunity to study the development of obesity-related disorders, including both genetic and environmental influences, across all life stages.

A genetic linkage map of the vervet monkey (Chlorocebus aethiops sabaeus).

The spectacular progress in genomics increasingly highlights the importance of comparative biology in biomedical research. In particular, nonhuman primates, as model systems, provide a crucial intermediate between humans and mice. The close similarities between humans and other primates are stimulating primate studies in virtually every area of biomedical research, including development, anatomy, physiology, immunology, and behavior. The vervet monkey (Chlorocebus aethiops sabaeus) is an important model for studying human diseases and complex traits, especially behavior. We have developed a vervet genetic linkage map to enable mapping complex traits in this model organism and facilitate comparative genomic analysis between vervet and other primates. Here we report construction of an initial genetic map built with about 360 human orthologous short tandem repeats (STRs) that were genotyped in 434 members of an extended vervet pedigree. The map includes 226 markers mapped in a unique order with a resolution of 9.8 Kosambi centimorgans (cM) in the vervet monkey genome, and with a total length (including all 360 markers) of 2726 cM. At least one complex and 11 simple rearrangements in marker order distinguish vervet chromosomes from human homologs. While inversions and insertions can explain a similar number of changes in marker order between vervet and rhesus homologs, mostly inversions are observed when vervet chromosome organization is compared to that in human and chimpanzee. Our results support the notion that large inversions played a less prominent role in the evolution within the group of the Old World monkeys compared to the human and chimpanzee lineages.

Early-onset Alzheimer's disease is associated with greater pathologic burden.

Two subtypes of Alzheimer's disease (AD) have been commonly identified: early- and late-onset forms. Previous studies suggest that early-onset AD patients have more neuritic plaques (NPs) and neurofibrillary tangles (NFTs). In the current study, NP and NFT counts were performed for 8 brain regions in 25 subjects with definite AD. A repeated-measures analysis of variance of mean regional NP and NFT counts for early- and late-onset groups was performed. A significant between-subject effect indicating greater overall NP and NFT burden in the early-onset group was observed (NP: F = 6.8, df = 1, P = .015; NFT: F = 7.5, df = 1, P = .012). This analysis supports the hypothesis that early-onset AD is associated with greater pathologic burden than late-onset AD. This suggests that late-onset AD patients have less cognitive reserve than early-onset patients and require fewer pathologic changes to exhibit cognitive deterioration.

The association of DRD4 and novelty seeking is found in a nonhuman primate model.

OBJECTIVE: The association of novelty seeking with a repeat polymorphism in the coding region of the dopamine D4 receptor gene (DRD4) has been demonstrated in several human populations, but not in others. The objective of this study was to test the generality of the association in a captive nonhuman primate population of known history, using objective methods for assessing novelty seeking and a pedigree-based association design. METHODS: Four hundred and fifty two socially-living vervet monkeys (Cercopithecus aethiops) from a large multigenerational pedigree at the UCLA-VA Vervet Research Colony were studied. Two variants in the 48 base pair repeat in exon III of the DRD4 gene have been found in this population, a six-repeat (92%) and a less common five-repeat (8%). Novelty seeking was measured by the latency to approach a large and potentially threatening novel object placed in the home enclosure. Heritability of novelty seeking and the association of novelty seeking with the DRD4 polymorphism were assessed using variance component modeling as implemented in Sequential Oligogenic Linkage Analysis Routines. RESULTS: The variance component analysis indicated that the DRD4 variant explained a significant portion of the total variance in novelty seeking. The final model included a significant effect of the DRD4 polymorphism (P=0.03), which explained 13% of the phenotypic variance, and a significant remaining genetic effect (h=0. 467+/-0.095, P<0.0001). CONCLUSIONS: The association of DRD4 with novelty seeking has now been replicated in a nonhuman primate species, the vervet monkey.