Variation at the Corticotropin-releasing Hormone Gene (CRH) Locus and Individual Differences in Stress Physiology and Behavior in Captive Rhesus Macaques (Macaca Mulatta).
ProQuest, 2007 - 335 pages
This thesis was based on the premise that the manner in which an individual perceives and reacts to stress is persistent and heritable, affecting its interactions, and fitness, throughout its life. I hypothesized that variation in the corticotropin-releasing hormone gene (CRH) and its regulatory regions---a locus integral to an organism's stress responses---partially accounts for differences in temperament and behavior. The hypothesis was tested by: sequencing the CRH locus and roughly 3.5 kb of 5' flanking region in 20 rhesus monkeys (Macaca mulatta); identifying polymorphisms likely to be linked to differences in gene expression; and determining whether CRH genotype is associated with stress-related response or behavior in this species. Nucleotide variation was found at 40 sites, some of which also showed parallel variation in other primates---an indication that this polymorphism may have been maintained by balancing selection. One of two SNPs in the 5' regulatory region (CRH -530 C/G SNP) showed association between genotype ("normal," CC, or heterozygote, CG) and physiological response to the stress of experimental maternal separation. Furthermore, in young adult males, CRH concentration in CSF was higher in CG than in CC individuals. Among males, CG infants were more anxious and less gregarious and explorative than CC, but, unexpectedly, showed lower basal and stress-reactive levels of plasma cortisol. Their higher ACTH:cortisol ratios, however, suggested reduced adrenal sensitivity to pituitary ACTH, developed perhaps as an adaptation to chronic HPA overactivity. CG females, in contrast, did not differ from CC counterparts in these traits, but showed elevated acute cortisol response.
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SEQUENCE AND VARIATION IN THE M MULATTA
1 Cycle sequencing protocols
2 Percent sequence identity of rhesus CRH to human
5 Most common haplotypes for CRH 18site haplotype block
INTRA AND INTERSPECIES CRH VARIATION
1A Papio DNA samples used in study
1 CSF CRH difference between young adult 530 CC and CG rhesus
4A Sex x genotype x phase interactive effect on plasma cortisol
2 Eigenvalues and factor loadings on infant behavior
7A Genotype effects on factor scores
4 Summary of findings
1 CRH genotypephenotype associations and potential
3 Rhesus CRH gene regions polymorphic within other taxa
13B CRH promoter regulation in the hypothalamus with essential
ALLELEBASED ASSOCIATION WITH INDIVIDUAL
1 Operational definitions of infant behaviors used in factor analysis
ACTH ACTH:cortisol ratios adrenal desensitization aggressive allele frequencies amygdala analysis animals ANOVA association baboons baseline behavioral dimensions binding Capitanio CC and CG CC homozygotes CG heterozygotes CG individuals CG males Chinese ancestry common allele correlated corticotropin-releasing hormone cortisol cortisol levels CRH expression CRH genotype CRH promoter CRH transcription CSF CRH levels effect of genotype environment F1 scores flanking region functional G allele genetic genome glucocorticoids GRE half-site haplotype heterozygotes hippocampus homozygotes hormone HPA activity HPA axis human hypothalamus individual differences infant interaction intron less common levels of CRH minor allele Morgan Island mother Mutual Ventral NIHAC rhesus nucleotide Papio phenotypic physiological placental polymorphism potential primate protein receptor regulation relatively repeat reproductive response rhesus macaques rhesus monkeys rhesus populations sample scores selection sequence significant significantly social species stress reactivity suggests taxa temperament traits transcription factors variable variance variation Z-DNA