Brain Magnetic Resonance Imaging (MRI) is a powerful tool for in vivo investigations of the relationship between brain structure and behavior. Using MRI, many aspects of normal and abnormal human brain morphology have been demonstrated to be genetically mediated, and in some instances, the responsible genes have been identified. While studies of crosses between inbred mouse strains have demonstrated that Quantitative Trait Loci (QTLs) responsible for normal variations in brain morphology can be identified, the vast structural and behavioral differences between mice and humans render these murine QTLs less likely to be relevant to the human.
The vervet monkey is an Old World primate that is ideal to serve as an intermediate animal model for the investigation of the genetic underpinnings of brain morphology as well as for more general investigations of genetic/morphologic/biochemical/behavioral relationships. We propose here to perform MRI of all 433 adolescent and adult members of the UCLA Vervet Research Colony (VRC), which consists of the descendants of fifty-seven founder animals maintained in a behaviorally naturalistic setting. Most of the colony members have already undergone extensive genetic analysis as part of ongoing efforts to create a map of the vervet genome, making this extended pedigree ideal for estimating heritability, identifying QTLs and mapping genes associated with morphologic variability. Rich behavioral and biochemical phenotypes of members of the colony have already been collected and are currently being supplemented by microarray maps of gene expression.
The MRI scans will be used to define brain phenotypes including brain volume, cerebellar volume, corpus callosal area and hippocampal volume. The heritability of these phenotypes will be estimated, and QTLs associated with the heritable phenotypes will be identified using more than 350 polymorphic markers already identified in the vervet genome. Enhanced with the MRI phenotypes from this project, the VRC will be an extraordinary resource for the study of relationships between genes, brain and behavior in the living primate. Moreover, the QTLs that are identified will serve to identify candidate genes that may account for brain variability in human populations. Controlling for such genes will increase the power of human MRI studies to discover genes that are associated with abnormal brain morphology in a number of human neurological and psychiatric diseases.
- Aim 1: To phenotype all of the adult and juvenile vervets in the VRC with regard to brain volume, cerebellar volume, hippocampal volume, corpus callosal area, ventricular volume, right-left asymmetry and overall normality of their MRI scans.
Hypothesis 1: Phenotypes derived from the MRI studies will be correlated with other phenotypes characterized in the colony and will contribute to a better understanding of brain/behavior relationships.
- Aim 2: To map the chromosomal location of Quantitative Trait Loci (QTL) associated with normal variability of brain structures in the vervet monkey.
Hypothesis 2: Brain structures, including total brain volume, cerebellar volume, hippocampal volume, corpus callosum cross-sectional area, ventricular volume and right-left asymmetry, all of which have been shown to be heritable traits in humans, are also heritable traits in the vervet monkey.
Hypothesis 3: Identifiable QTL are associated with normal variability in brain structures in the vervet.
Hypothesis 4: Synteny between the vervet and human genomes will eventually allow human genetic regions homologous to vervet genetic regions responsible for brain morphology to be identified.