Date of Award

8-9-2014

Document Type

Open Access Dissertation

Department

Biological Sciences

First Advisor

Michael Felder

Abstract

With recent strides in epigenetics, mainstream media informs the public that we can “beat our genes” by, for instance, changing our diet. Genetics, however, still plays a role in phenotype. Folate and other methyl-donor pathway components are widely supplemented due to their ability to prevent neural tube defects during prenatal development. In addition to vitamins, these compounds are also added to commercial flour, energy drinks, and other supplements. Several lines of evidence suggest that these supplements act through epigenetic mechanisms, including altering DNA methylation. Increasing evidence suggests potential deleterious effects of excessive folate. Given the benefits of these compounds, risk statements must be made with caution.

We hypothesized that excess dietary methyl donors during development might contribute to the apparent rise in neurobehavioral disorders such as attention-deficit disorder (ADD), obsessive compulsive disorder (OCD) and autism spectrum disorders (ASD). To test these hypotheses, we used wildderived Peromyscus (deer mice) stocks. Peromyscus are common native North American mammals and exhibit great natural variation. We used two species that are known to differ in physiology, epigenetic control, and behavior. Specifically, P. maniculatus (BW stock) are susceptible to repetitive behaviors and are more aggressive in a neutral space. P. polionotus (PO stock) exhibit greater sociality and less repetitive behavior and are better able to buffer stress.

In addition the two species can form fertile hybrids in BW female x PO male crosses thus enabling genetic basis of such phenotypes to be determined.

Here we have determined genetic mechanisms by which behaviors differ between BW and PO. Additionally, we discovered behavioral differences in a naturally occurring wide band agouti (ANb) deer mouse (on a BW background) when compared to BW. Using the same methyl-donor diet used in the classic mouse agouti viable yellow allele (Avy), we demonstrated that the effects of the diet are different across three genotypes (while two genotypes, BW and ANb, are very similar). These effects included various adult defects, mortality, and behavioral changes. Here we also present data from additional behavioral parameters in both PO and BW animals developmentally exposed to the methyldonor diet. We also present data showing paternal genotype affects DNA methylation status at the imprinting control region of the Peg10/Sgce locus.

This work was funded by NIH P40 OD 010961 and by a SPARC Grant from the Office of the VP for Research at the University of South Carolina.

Rights

© 2014, Kimberly R. Shorter

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