Genetics of primary cerebral gyrification: Heritability of length, depth and area of primary sulci in an extended pedigree of Papio baboons.

Genetic control over morphological variability of primary sulci and gyri is of great interest in the evolutionary, developmental and clinical neurosciences. Primary structures emerge early in development and their morphology is thought to be related to neuronal differentiation, development of functional connections and cortical lateralization. We measured the proportional contributions of genetics and environment to regional variability, testing two theories regarding regional modulation of genetic influences by ontogenic and phenotypic factors. Our measures were surface area, and average length and depth of eleven primary cortical sulci from high-resolution MR images in 180 pedigreed baboons. Average heritability values for sulcal area, depth and length (h(2)(Area)=.38+/-.22; h(2)(Depth)=.42+/-.23; h(2)(Length)=.34+/-.22) indicated that regional cortical anatomy is under genetic control. The regional pattern of genetic contributions was complex and, contrary to previously proposed theories, did not depend upon sulcal depth, or upon the sequence in which structures appear during development. Our results imply that heritability of sulcal phenotypes may be regionally modulated by arcuate U-fiber systems. However, further research is necessary to unravel the complexity of genetic contributions to cortical morphology.

Genetic influences on behavioral inhibition and anxiety in juvenile rhesus macaques.

In humans and other animals, behavioral responses to threatening stimuli are an important component of temperament. Among children, extreme behavioral inhibition elicited by novel situations or strangers predicts the subsequent development of anxiety disorders and depression. Genetic differences among children are known to affect risk of developing behavioral inhibition and anxiety, but a more detailed understanding of genetic influences on susceptibility is needed. Nonhuman primates provide valuable models for studying the mechanisms underlying human behavior. Individual differences in threat-induced behavioral inhibition (freezing behavior) in young rhesus monkeys are stable over time and reflect individual levels of anxiety. This study used the well-established human intruder paradigm to elicit threat-induced freezing behavior and other behavioral responses in 285 young pedigreed rhesus monkeys. We examined the overall influence of quantitative genetic variation and tested the specific effect of the serotonin transporter promoter repeat polymorphism. Quantitative genetic analyses indicated that the residual heritability of freezing duration (behavioral inhibition) is h(2) = 0.384 (P = 0.012) and of 'orienting to the intruder' (vigilance) is h(2) = 0.908 (P = 0.00001). Duration of locomotion and hostility and frequency of cooing were not significantly heritable. The serotonin transporter polymorphism showed no significant effect on either freezing or orienting to the intruder. Our results suggest that this species could be used for detailed studies of genetic mechanisms influencing extreme behavioral inhibition, including the identification of specific genes that are involved in predisposing individuals to such behavior.

Characterization of a composite gradient gel for the electrophoretic separation of lipoproteins.

We describe a protocol for making a new type of gradient gel, the Composite gradient gel, that was designed to resolve plasma lipoproteins using nondenaturing gradient gel electrophoresis. The new gel format allows analysis both of high density lipoproteins (HDLs) and low density lipoproteins (LDLs) on the same gel. The gel gave highly repeatable (r2 = 0.999) size estimates. We compared lipoprotein phenotypes determined from the new gradient gel with those obtained using specialized HDL and LDL gradient gels. The comparisons indicated that the Composite gel gave lipoprotein particle size estimates for HDLs and LDLs that were virtually identical to those obtained, respectively, from the specialized HDL and LDL gradient gels. We measured median diameters, which reflect the distributions of absorbance, for LDLs and for HDLs and found that the Composite gel gave lipoprotein size distributions that were virtually identical to those measured using the specialized LDL and HDL gels. Finally, comparison of fractional absorbance for six lipoprotein size intervals obtained from the Composite and specialized gels revealed a close correlation (r2 = 0.828). Thus, it appears that both LDL and HDL size phenotypes may be evaluated simultaneously using a single gradient gel format.

Dietary and genetic effects on LDL size measures in baboons.

Genetic and dietary effects on LDL phenotypes, including predominant LDL particle diameter, LDL size distribution, and non-HDL cholesterol and apoB concentrations, were investigated in 150 pedigreed baboons that are members of 19 sire groups. Baboons were fed a sequence of three defined diets differing in levels of fat and cholesterol. Increasing dietary fat had relatively little effect on two measures of LDL particle size. However, increasing the level of cholesterol in the diet resulted in larger increases of the predominant LDL particle diameters and in the proportion of stain on LDLs > 28 nm. As expected, apoB and non-HDL cholesterol concentrations significantly increased when levels of dietary fat and cholesterol were increased. Correlations among the LDL phenotypes suggested that several different aspects of the LDL phenotype were captured by the four LDL measures across the three diets. Genetic effects indicated by sire group membership were significant both for expression of the LDL phenotypes and for response to changes in diet.

Genetic control of apolipoprotein A-I distribution among HDL subclasses.

We conducted genetic analyses to determine the components of variation for size distributions of apolipoprotein (apo) A-I among human plasma lipoproteins resolved on the basis of size. Analyses used data for 717 individuals in 26 pedigrees. Apo A-I distributions among lipoprotein size classes were measured by nondenaturing gradient gel electrophoresis (GGE) and immunoblotting procedures. Curves were fitted to apo A-I absorbance profiles to estimate fractional absorbance in each of five high-density lipoprotein (HDL) subclasses. Multivariate regression analyses revealed several covariates (sex, age, diabetes, and apo A-I concentrations) that were significantly associated with variation in one or more HDL subclasses. Female gender and elevated apo A-I concentrations were associated with increases in proportion of apo A-I in larger HDLs, while increasing age and diabetes were associated with decreases. The analyses showed significant heritabilities. h2, for each variable representing the different HDL subclasses. Both genetic and nongenetic effects on apo A-I size distributions were generally exerted across the range of lipoprotein sizes, as suggested by high genetic and environmental correlations between HDL subclass variables. Decomposition of total overall variance showed that unidentified environmental factors accounted for 48% of variation in apo A-I size distribution, while genetic factors explained about 36% and the identified covariates explained the remaining 16%. When considered separately, apo A-I concentration explained only 5% of the total variation in apo A-I size distribution, indicating that apo A-I concentration is a poor predictor of apo A-I size distribution. In summary, the data suggest that there are significant genetic and environmental effects on apo A-I size distribution in humans, and that they are general metabolic effects rather than effects on specific HDL subclasses.

Effect of diabetes on lipoprotein size.

The effects of diabetes on lipoprotein particle sizes were assessed using samples from 94 subjects with non-insulin-dependent diabetes mellitus. From a larger population of nondiabetic subjects who showed normal glucose tolerance, we selected an exact match in terms of age, sex, and menopausal status. We designed a protocol to make nondenaturing gradient gels for the resolution of LDL subfractions and generated two measures of LDL size: diameter of the predominant LDL species and proportion of LDL cholesterol (LDL-C) in particles larger than 25.5 nm (large LDL-C). Similarly, we made two measures of HDL size, large HDL cholesterol (HDL-C) and large HDL-apoAI, which represents the proportion of HDL-C and apoAI, respectively, occurring on particles larger than HDL-3. In pairwise comparisons, diabetes was associated with significantly (P < .004) smaller lipoprotein particles for all measures except large HDL-C. Each of the size measures was significantly and positively correlated with each of the others, suggesting that common metabolic mechanisms influence lipoprotein particle sizes across classes of lipoproteins. In addition, each of the size measures was correlated with a variety of measures of HDL and beta-lipoprotein concentrations, which included HDL-C, LDL-C, triglycerides, and apoAI, apoB, and apoE. We used stepwise regression analyses to select from the measures of lipoprotein concentrations those independently correlated with each of the lipoprotein size measures. After adjusting for these metabolic correlates of lipoprotein size measures, we found the effect of diabetes on lipoprotein size measures was no longer significant except for a modest effect (P = .027) on large HDL-apoAI.