Amygdalar and hippocampal substrates of anxious temperament differ in their heritability.

Anxious temperament (AT) in human and non-human primates is a trait-like phenotype evident early in life that is characterized by increased behavioural and physiological reactivity to mildly threatening stimuli. Studies in children demonstrate that AT is an important risk factor for the later development of anxiety disorders, depression and comorbid substance abuse. Despite its importance as an early predictor of psychopathology, little is known about the factors that predispose vulnerable children to develop AT and the brain systems that underlie its expression. To characterize the neural circuitry associated with AT and the extent to which the function of this circuit is heritable, we studied a large sample of rhesus monkeys phenotyped for AT. Using 238 young monkeys from a multigenerational single-family pedigree, we simultaneously assessed brain metabolic activity and AT while monkeys were exposed to the relevant ethological condition that elicits the phenotype. High-resolution (18)F-labelled deoxyglucose positron-emission tomography (FDG-PET) was selected as the imaging modality because it provides semi-quantitative indices of absolute glucose metabolic rate, allows for simultaneous measurement of behaviour and brain activity, and has a time course suited for assessing temperament-associated sustained brain responses. Here we demonstrate that the central nucleus region of the amygdala and the anterior hippocampus are key components of the neural circuit predictive of AT. We also show significant heritability of the AT phenotype by using quantitative genetic analysis. Additionally, using voxelwise analyses, we reveal significant heritability of metabolic activity in AT-associated hippocampal regions. However, activity in the amygdala region predictive of AT is not significantly heritable. Furthermore, the heritabilities of the hippocampal and amygdala regions significantly differ from each other. Even though these structures are closely linked, the results suggest differential influences of genes and environment on how these brain regions mediate AT and the ongoing risk of developing anxiety and depression.

Genetic influences on response to novel objects and dimensions of personality in Papio baboons.

Behavioral variation within and between populations and species of the genus Papio has been studied extensively, but little is known about the genetic causes of individual- or population-level differences. This study investigates the influence of genetic variation on personality (sometimes referred to as temperament) in baboons and identifies a candidate gene partially responsible for the variation in that phenotype. To accomplish these goals, we examined individual variation in response to both novel objects and an apparent novel social partner (using a mirror test) among pedigreed baboons (n = 578) from the Southwest National Primate Research Center. We investigated the frequency and duration of individual behaviors in response to novel objects and used multivariate factor analysis to identify trait-like dimensions of personality. Exploratory factor analysis identified two distinct dimensions of personality within this population. Factor 1 accounts for 46.8 % of the variance within the behavioral matrix, and consists primarily of behaviors related to the "boldness" of the subject. Factor 2 accounts for 18.8 % of the variation, and contains several "anxiety" like behaviors. Several specific behaviors, and the two personality factors, were significantly heritable, with the factors showing higher heritability than most individual behaviors. Subsequent analyses show that the behavioral reactions observed in the test protocol are associated with animals' social behavior observed later in their home social groups. Finally we used linkage analysis to map quantitative trait loci for the measured phenotypes. Single nucleotide polymorphisms in a positional candidate gene (SNAP25) are associated with variation in one of the personality factors, and CSF levels of homovanillic acid and 3-methoxy-4-hydroxyphenylglycol. This study documents heritable variation in personality among baboons and suggests that sequence variation in SNAP25 may influence differences in behavior and neurochemistry in these nonhuman primates.

On the genetic architecture of cortical folding and brain volume in primates.

Understanding the evolutionary forces that produced the human brain is a central problem in neuroscience and human biology. Comparisons across primate species show that both brain volume and gyrification (the degree of folding in the cerebral cortex) have progressively increased during primate evolution and there is a strong positive correlation between these two traits across primate species. The human brain is exceptional among primates in both total volume and gyrification, and therefore understanding the genetic mechanisms influencing variation in these traits will improve our understanding of a landmark feature of our species. Here we show that individual variation in gyrification is significantly heritable in both humans and an Old World monkey (baboons, Papio hamadryas). Furthermore, contrary to expectations based on the positive phenotypic correlation across species, the genetic correlation between cerebral volume and gyrification within both humans and baboons is estimated as negative. These results suggest that the positive relationship between cerebral volume and cortical folding across species cannot be explained by one set of selective pressures or genetic changes. Our data suggest that one set of selective pressures favored the progressive increase in brain volume documented in the primate fossil record, and that a second independent selective process, possibly related to parturition and neonatal brain size, may have favored brains with progressively greater cortical folding. Without a second separate selective pressure, natural selection favoring increased brain volume would be expected to produce less folded, more lissencephalic brains. These results provide initial evidence for the heritability of gyrification, and possibly a new perspective on the evolutionary mechanisms underlying long-term changes in the nonhuman primate and human brain.

Genetic determination of HDL variation and response to diet in baboons.

We fed 634 baboons three diets to assess the separate effects of increasing dietary fat and cholesterol intakes on three independent measures of HDL phenotype: concentrations of HDL cholesterol and apoAI, and size distributions of HDL cholesterol. Increasing dietary fat significantly increased concentrations of HDL cholesterol and apoAI (both, P<0.0001), but did not affect HDL particle sizes, whereas increasing dietary cholesterol increased HDL cholesterol (P<0.0001) concentrations and HDL particle sizes (P=0.08), but did not affect apoAI concentrations. A substantial proportion of variation in each of the HDL traits was influenced by genes (heritabilities ranged from 25 to 61%) and a common set of genes influenced HDL variation on each of the diets (genetic correlations ranged from 0.64 to 1.0). However, genes exerted a smaller effect on HDL response to changes of dietary fat and of dietary cholesterol. Therefore, dietary fat and cholesterol alter HDL levels and characteristics, but the dietary responses are not strongly mediated by additive genetic effects.

Heritability of brain volume, surface area and shape: an MRI study in an extended pedigree of baboons.

To evaluate baboons (Papio hamadryas) as a primate model for the study of the genetic control of brain size and internal structure, we performed high resolution (<500 microm) magnetic resonance imaging on 109 pedigreed baboons. Quantitative genetic analysis of these MR images using a variance components approach indicates that native (untransformed) brain volume exhibits significant heritability among these baboons (h(2) = 0.52, P = 0.0049), with age and sex also accounting for substantial variation. Using global spatial normalization, we transformed all images to a standard population-specific reference, and recalculated the heritability of brain volume. The transformed images generated heritability estimates of h(2) = 0.82 (P = 0.00022) for total brain volume, h(2) = 0.86 (P = 0.0006) for cerebral volume, h(2) = 0.73 (P = 0.0069) for exposed surface area of the cerebrum and h(2) = 0.67 (P = 0.01) for gray matter volume. Regional differences in the genetic effects on brain structure were calculated using a voxel-based morphometry (VBM) approach. This analysis of regional variation shows that some areas of motor cortex and the superior temporal gyrus show relatively high heritability while other regions (e.g. superior parietal cortex) exhibit lower heritability. The general pattern of regional differences is similar to that observed in previous studies of humans. The present study demonstrates that there is substantial genetic variation underlying individual variation in brain size and structure among Papio baboons, and that broad patterns of genetic influence on variation in brain structure may be similar in baboons and humans.

Designing new microsatellite markers for linkage and population genetic analyses in rhesus macaques and other nonhuman primates.

Identification of polymorphic microsatellite loci in nonhuman primates is useful for various biomedical and evolutionary studies of these species. Prior methods for identifying microsatellites in nonhuman primates are inefficient. We describe a new strategy for marker development that uses the available whole genome sequence for rhesus macaques. Fifty-four novel rhesus-derived microsatellites were genotyped in large pedigrees of rhesus monkeys. Linkage analysis was used to place 51 of these loci into the existing rhesus linkage map. In addition, we find that microsatellites identified this way are polymorphic in other Old World monkeys such as baboons. This approach to marker development is more efficient than previous methods and produces polymorphisms with known locations in the rhesus genome assembly. Finally, we propose a nomenclature system that can be used for rhesus-derived microsatellites genotyped in any species or for novel loci derived from the genome sequence of any nonhuman primate.

An initial genetic linkage map of the rhesus macaque (Macaca mulatta) genome using human microsatellite loci.

Rhesus macaques (Macaca mulatta) are the most widely used nonhuman primate species in biomedical research. To create new opportunities for genetic and genomic studies using rhesus monkeys, we constructed a genetic linkage map of the rhesus genome. This map consists of 241 microsatellite loci, all previously mapped in the human genome. These polymorphisms were genotyped in five pedigrees of rhesus monkeys totaling 865 animals. The resulting linkage map covers 2048 cM including all 20 rhesus autosomes, with average spacing between markers of 9.3 cM. Average heterozygosity among those markers is 0.73. This linkage map provides new comparative information concerning locus order and interlocus distances in humans and rhesus monkeys. The map will facilitate whole-genome linkage screens to locate quantitative trait loci (QTLs) that influence individual variation in phenotypic traits related to basic primate anatomy, physiology, and behavior, as well as QTLs relevant to risk factors for human disease.

A panel of 20 highly variable microsatellite polymorphisms in rhesus macaques (Macaca mulatta) selected for pedigree or population genetic analysis.

This paper reports 20 new microsatellite loci that are highly polymorphic in rhesus macaques (Macaca mulatta). We screened known human microsatellite loci to identify markers that are polymorphic in rhesus macaques, and then selected specific loci that show substantial levels of heterozygosity and robust, reliable amplification. The 20 loci reported here were chosen to include one highly informative microsatellite from each rhesus monkey autosomal chromosome. Fourteen of the 20 polymorphisms are tetranucleotide repeats, and all can be analyzed using standard PCR and electrophoresis procedures. These new rhesus markers have an average of 15.5 alleles per locus and average heterozygosity of 0.83. This panel of DNA polymorphisms will be useful for a variety of different genetic analyses, including pedigree testing, paternity analysis, and population genetic studies. Many of these loci are also likely to be informative in other closely related Old World monkey species.