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Youjie Zhang Dissertation_2018.pdf (3.21 MB)

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Genomic and Microbiomic Architectural Contributions to Aerobic Exercise Capacity

Zhang, Youjie
http://rave.ohiolink.edu/etdc/view?acc_num=mco1525427606919417

Abstract Details

2018, Doctor of Philosophy (PhD), University of Toledo, Biomedical Sciences (Molecular Medicine).
The beneficial effect of physical exercise has been well established. Genetic predisposition to low exercise capacity is a strong predictor of morbidity and mortality related to multiple diseases such as hypertension, diabetes, and obesity. Genetic predisposition is being increasingly recognized as predisposition caused by the inherited host and microbiotal genome, ie., the microbiome of the commensal microbes living within the host. The microbiome is shaped by both environment and host genetics, and functions to modulate metabolic phenotypes, behavior, and brain function. While the independent contributions of the genome and the microbiome are investigated, studies to delineate the interplay between the nuclear and the mitochondrial genomes of the host and the microbiome to promote health or disease are limited due to paucity of appropriate models. To address this void, this dissertation describes the construction and characterization of four new inbred rat models. First, to study the genetics of exercise, we developed models of health and disease by inbreeding rats divergent in aerobic exercise capacity. These novel inbred strains were developed over 20 generations of inbreeding the selectively bred low and high capacity runner rats and named as LCR/Bj and HCR/Bj respectively. Next, to facilitate studies of the nuclear-mitochondrial genomic interactions, we also developed conplastic animals by “switching” mitochondrial genomes between low and high capacity runner rats, and named them LCR.HCRmt/Bj (LCR rat with mitochondrial genome of the HCR rat) and HCR.LCRmt/Bj (HCR rat with mitochondrial genome of the LCR rat). We screened the whole genomes of the LCR/Bj and HCR/Bj rats by NextGen sequencing and identified over 4.4 million of high quality single nucleotide variants between each of these two inbred strains and the Brown Norway reference genome. Thousands of variants between LCR/Bj and HCR/Bj nuclear DNA (nDNA) are predicted to influence gene structure and protein translation. We also sequenced and compared mitochondrial DNA (mtDNA) with publicly available mtDNA from common inbred strains, and found that LCR/Bj mitochondrial mtDNA was identical to the mtDNA reported from Wistar Kyoto inbred strain, while HCR/Bj mtDNA was identical to the mtDNA reported from Fischer 344 × Brown Norway F1-hybrid strain. This genomic information on the LCR/Bj, HCR/Bj, LCR.HCRmt/Bj, HCR.LCRmt/Bj rat models provides a framework for genetic mapping studies of identify inherited factors for exercise capacity and disease susceptibility, facilitates development of engineered models on homogenous genomic backgrounds for gene structure-function studies, and serve as platforms for function validation of human genome-wide association studies in the research field of exercise. To explore the nuclear-mitochondrial genomic interaction in health and disease, we systemically characterized the phenotypes in our inbred and conplastic strains. We show that genetic predisposition to low exercise capacity led to multiple pathophysiological features including increased body weight, metabolic abnormalities, increased accumulation of adipose tissue, high blood pressure, altered cardiac function, depression-like behavior, and deteriorated cognition. We also revealed tissue specific interaction between nDNA and mtDNA in determining metabolism, blood pressure, cardiac function, and long-term memory. Our novel inbred and conplastic strains with detailed genomic characterization provide invaluable resources to comprehensively study the effect of host genome on exercise capacity and complex diseases. To establish the link between host genome and microbiome in determining health and diseases, we did 16S rRNA sequencing and analyzed gut microbiota in fecal samples from our inbred and conplastic animals. Surprisingly, fecal microbial communities of LCR/Bj and HCR/Bj were significant different, which we interpret as being the result of selection of differential host genomes. Of the enriched bacteria we identified, majority are documented as high heritable through human gut microbiotal studies. Correlation analysis further demonstrated that certain gut microbiota closely associated with multiple traits including exercise capacity, body metabolism, heart function, and depression. These findings second the notion that targeting the microbiome could be a novel therapeutic approach to treat common diseases. Moreover, our models with genetic susceptibility to certain disease-associated gut microbiota can fulfill the urgent demand for animal models of translational microbiome research.
Bina Joe (Committee Chair)
Lauren Koch (Committee Member)
Jennifer Hill (Committee Member)
Mark Wooten (Committee Member)
Kathryn Eisenmann (Committee Member)
Joshua Park (Committee Member)
135 p.
Biomedical Research

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Citations

  • Zhang, Y. (2018). Genomic and Microbiomic Architectural Contributions to Aerobic Exercise Capacity [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=mco1525427606919417

    APA Style (7th edition)

  • Zhang, Youjie. Genomic and Microbiomic Architectural Contributions to Aerobic Exercise Capacity. 2018. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=mco1525427606919417.

    MLA Style (8th edition)

  • Zhang, Youjie. "Genomic and Microbiomic Architectural Contributions to Aerobic Exercise Capacity." Doctoral dissertation, University of Toledo, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=mco1525427606919417

    Chicago Manual of Style (17th edition)

mco1525427606919417
219
© 2018, all rights reserved.
This open access ETD is published by University of Toledo Health Science Campus and OhioLINK.