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Vanderbilt University
1.
Gandhi, Vishal V.
Investigating mitochondrial deoxyribonucleotide metabolism and its role in a family of genetic diseases.
Degree: PhD, Human Genetics, 2011, Vanderbilt University
URL: http://hdl.handle.net/1803/14867 
► Abnormal regulation of mitochondrial deoxyribonucleoside triphosphate pools can lead to mitochondrial DNA depletion syndromes, a set of genetic diseases associated with depletion of mitochondrial DNA.…
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▼ Abnormal regulation of mitochondrial deoxyribonucleoside triphosphate pools can lead to mitochondrial DNA depletion syndromes, a set of genetic diseases associated with depletion of mitochondrial DNA. Besides mitochondrial DNA depletion syndromes, improper maintenance of mitochondrial deoxyribonucleoside triphosphate pools and mitochondrial DNA have also been implicated in a host of other human pathologies. The unifying objective of this dissertation was to enhance our knowledge of the regulation of mitochondrial deoxyribonucleoside triphosphate pools. The first step was to investigate the characteristics of mitochondrial and cytoplasmic deoxyribonucleoside triphosphate levels. I calculated mitochondrial and cytoplasmic deoxyribonucleoside triphosphate concentrations from previously published data. Cytoplasmic and mitochondrial deoxyribonucleoside triphosphates are strongly correlated in normal cells but not in transformed cells. Following up this discovery with analysis of gene expression, I discovered that, consistent with the trends in deoxyribonucleoside triphosphate concentrations in cells, genes coding for enzymes that maintain cytoplasmic and mitochondrial deoxyribonucleoside triphosphates have correlated expression across normal tissues but not across transformed tissues. To further understand the influence of cytoplasmic deoxyribonucleoside triphosphates on mitochondrial deoxyribonucleoside triphosphates, I simulated the metabolism of mitochondrial deoxyribonucleosides with a computational model. Cytoplasmic deoxyribonucleotides have a substantial and indispensable contribution to mitochondrial deoxyribonucleoside triphosphates in most circumstances. My results further show that import from the cytoplasm would need to occur at either deoxyribonucleoside diphosphate or triphosphate levels.
Advisors/Committee Members: Emmanuele DiBenedetto (committee member), David Samuels (committee member), Scott Williams (committee member), Todd Hulgan (committee member), Tricia Thornton-Wells (Committee Chair).
Subjects/Keywords: depletion; dNTP; mitochondria; nucleotide; mtDNA
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APA (6th Edition):
Gandhi, V. V. (2011). Investigating mitochondrial deoxyribonucleotide metabolism and its role in a family of genetic diseases. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/14867
Chicago Manual of Style (16th Edition):
Gandhi, Vishal V. “Investigating mitochondrial deoxyribonucleotide metabolism and its role in a family of genetic diseases.” 2011. Doctoral Dissertation, Vanderbilt University. Accessed April 12, 2021.
http://hdl.handle.net/1803/14867.
MLA Handbook (7th Edition):
Gandhi, Vishal V. “Investigating mitochondrial deoxyribonucleotide metabolism and its role in a family of genetic diseases.” 2011. Web. 12 Apr 2021.
Vancouver:
Gandhi VV. Investigating mitochondrial deoxyribonucleotide metabolism and its role in a family of genetic diseases. [Internet] [Doctoral dissertation]. Vanderbilt University; 2011. [cited 2021 Apr 12].
Available from: http://hdl.handle.net/1803/14867.
Council of Science Editors:
Gandhi VV. Investigating mitochondrial deoxyribonucleotide metabolism and its role in a family of genetic diseases. [Doctoral Dissertation]. Vanderbilt University; 2011. Available from: http://hdl.handle.net/1803/14867
Vanderbilt University
2.
Simonti, Corinne Nicole.
Leveraging Biobanks and PheWAS to Uncover the Health Consequences of Recent Human Evolution.
Degree: PhD, Human Genetics, 2017, Vanderbilt University
URL: http://hdl.handle.net/1803/11256
► The genomics era has seen a staggering increase in the number of whole genome sequences. This has bolstered studies of human populations, and revealed regions…
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▼ The genomics era has seen a staggering increase in the number of whole genome sequences. This has bolstered studies of human populations, and revealed regions of the genome bearing signatures of selection and other demographic events. However, tying these regions to phenotypic effects in humans is difficult. I addressed this challenge by leveraging densely phenotyped biobank populations from the eMERGE network, a collection of 10 clinical biobanks across the US that connect electronic health records (EHRs) to genotyping data. The eMERGE data enabled me to interrogate the function of human genetic variation on a broad array of phenotypes using the phenome-wide association study (PheWAS) framework. Each chapter describes a project in which I tested hypotheses about the impact of evolutionarily important variants on human health. In the first, I examine the clinical impact of interbreeding between humans and Neanderthals; in the next, I evaluate variants whose allele frequencies have increased drastically since human divergence from chimpanzee; and finally I consider variants affected by GC-biased gene conversion, a recombination-associated mutational process that favors the fixation of G and C alleles. In conclusion, I used large clinical biobanks to uncover novel genotype-phenotype associations that reveal the effects of recent demographic events and evolutionary processes that have shaped the human genome.
Advisors/Committee Members: John A. Capra (committee member), Will Bush (committee member), David Samuels (committee member), Josh Denny (committee member), Doug Mortlock (Committee Chair).
Subjects/Keywords: PheWAS; Biobank; Neanderthal; Evolution
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APA (6th Edition):
Simonti, C. N. (2017). Leveraging Biobanks and PheWAS to Uncover the Health Consequences of Recent Human Evolution. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/11256
Chicago Manual of Style (16th Edition):
Simonti, Corinne Nicole. “Leveraging Biobanks and PheWAS to Uncover the Health Consequences of Recent Human Evolution.” 2017. Doctoral Dissertation, Vanderbilt University. Accessed April 12, 2021.
http://hdl.handle.net/1803/11256.
MLA Handbook (7th Edition):
Simonti, Corinne Nicole. “Leveraging Biobanks and PheWAS to Uncover the Health Consequences of Recent Human Evolution.” 2017. Web. 12 Apr 2021.
Vancouver:
Simonti CN. Leveraging Biobanks and PheWAS to Uncover the Health Consequences of Recent Human Evolution. [Internet] [Doctoral dissertation]. Vanderbilt University; 2017. [cited 2021 Apr 12].
Available from: http://hdl.handle.net/1803/11256.
Council of Science Editors:
Simonti CN. Leveraging Biobanks and PheWAS to Uncover the Health Consequences of Recent Human Evolution. [Doctoral Dissertation]. Vanderbilt University; 2017. Available from: http://hdl.handle.net/1803/11256
Vanderbilt University
3.
Wiley, Laura Katherine.
Addressing Barriers to Clinical Implementation of Pharmacogenomics.
Degree: PhD, Human Genetics, 2016, Vanderbilt University
URL: http://hdl.handle.net/1803/11632
► Pharmacogenomics offers one of the best use cases for widespread clinical implementation of genomic medicine, as variants tend to have moderate allele frequencies, many of…
(more)
▼ Pharmacogenomics offers one of the best use cases for widespread clinical implementation of genomic medicine, as variants tend to have moderate allele frequencies, many of the affected medications are relatively common, and the magnitude of effect tends to be clinically meaningful. Using pharmacogenomic-guided warfarin dosing as an example, this dissertation addresses potential barriers and solutions to the clinical implementation of pharmacogenomics. Warfarin is a blood thinner that has a narrow therapeutic index and wide dosing variation, with many known pharmacogenomic markers associated with stable warfarin dose. A number of different methods to reduce disparities in pharmacogenomic-guided warfarin dosing among African Americans were tested. Additionally data from Vanderbilt’s clinical implementation of pharmacogenomic-guided warfarin dosing were analyzed to assess process outcomes (e.g. how did the actual warfarin dose ordered compare to the recommended dose) and patient outcomes (e.g., what kinds of clinical events did the patient experience immediately following warfarin initiation). A summary of policy and technological challenges for clinical implementation of precision medicine, along with potential solutions, are presented.
Advisors/Committee Members: David Samuels (committee member), Dan Roden (committee member), Josh Peterson (committee member), Joshua C. Denny (Committee Chair), Melinda Aldrich (Committee Chair).
Subjects/Keywords: warfarin; precision medicine; translational bioinformatics; policy
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APA (6th Edition):
Wiley, L. K. (2016). Addressing Barriers to Clinical Implementation of Pharmacogenomics. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/11632
Chicago Manual of Style (16th Edition):
Wiley, Laura Katherine. “Addressing Barriers to Clinical Implementation of Pharmacogenomics.” 2016. Doctoral Dissertation, Vanderbilt University. Accessed April 12, 2021.
http://hdl.handle.net/1803/11632.
MLA Handbook (7th Edition):
Wiley, Laura Katherine. “Addressing Barriers to Clinical Implementation of Pharmacogenomics.” 2016. Web. 12 Apr 2021.
Vancouver:
Wiley LK. Addressing Barriers to Clinical Implementation of Pharmacogenomics. [Internet] [Doctoral dissertation]. Vanderbilt University; 2016. [cited 2021 Apr 12].
Available from: http://hdl.handle.net/1803/11632.
Council of Science Editors:
Wiley LK. Addressing Barriers to Clinical Implementation of Pharmacogenomics. [Doctoral Dissertation]. Vanderbilt University; 2016. Available from: http://hdl.handle.net/1803/11632
Vanderbilt University
4.
Brooks, Andrew Wallace.
The Role of Host-Associated Factors on Metazoan Microbiome Assembly.
Degree: PhD, Human Genetics, 2019, Vanderbilt University
URL: http://hdl.handle.net/1803/12320
► Gut microbiomes, the genetic repertoire for millions to trillions of microbes residing throughout each metazoan’s digestive tract, are shaped by their host and environment. Composed…
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▼ Gut microbiomes, the genetic repertoire for millions to trillions of microbes residing throughout each metazoan’s digestive tract, are shaped by their host and environment. Composed of up to 500 times the genetic diversity of the human genome and distributed across more than 1,000 microbial species, microbiomes result from ecological assembly of microbial communities known as microbiota. The advent of high throughput genetic sequencing hastened the characterization of microbiota and microbiomes, revealing an under-appreciated diversity of microbial taxa, ecological compositions, and functional capabilities. It is within these gastrointestinal communities that this body of work aims to assess variation associating intrinsically with host physiology, genetics, metabolism, immunity, and evolutionary relatedness, as well as extrinsically with lifestyle, diet, environment, and sociality. Research presented here addresses a diverse set of hypotheses about how animal and human hosts shape their associated microbiomes. This breadth of topics reflects the newly appreciated importance of host-associated microbiomes, and exemplifies the many important questions that still need to be addressed in such a fledgling field. While disparate questions were addressed in each project, the results presented here reveal novel insights about how animals and humans shape their complex communities of associated microorganisms.
Advisors/Committee Members: David Samuels (committee member), Antonis Rokas (committee member), Patrick Abbot (committee member), Seth R. Bordenstein (Committee Chair), John A. Capra (Committee Chair).
Subjects/Keywords: Microbiome; Metagenome; Metagenomics; Human Gut; Microbiology; Genetics; Phylosymbiosis
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APA ·
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MLA ·
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to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Brooks, A. W. (2019). The Role of Host-Associated Factors on Metazoan Microbiome Assembly. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/12320
Chicago Manual of Style (16th Edition):
Brooks, Andrew Wallace. “The Role of Host-Associated Factors on Metazoan Microbiome Assembly.” 2019. Doctoral Dissertation, Vanderbilt University. Accessed April 12, 2021.
http://hdl.handle.net/1803/12320.
MLA Handbook (7th Edition):
Brooks, Andrew Wallace. “The Role of Host-Associated Factors on Metazoan Microbiome Assembly.” 2019. Web. 12 Apr 2021.
Vancouver:
Brooks AW. The Role of Host-Associated Factors on Metazoan Microbiome Assembly. [Internet] [Doctoral dissertation]. Vanderbilt University; 2019. [cited 2021 Apr 12].
Available from: http://hdl.handle.net/1803/12320.
Council of Science Editors:
Brooks AW. The Role of Host-Associated Factors on Metazoan Microbiome Assembly. [Doctoral Dissertation]. Vanderbilt University; 2019. Available from: http://hdl.handle.net/1803/12320
Vanderbilt University
5.
O'Brien, Timothy Daniel.
Investigating the Genetic Influences of the Germline and Somatic Genomes in Three Subtypes of Lung Cancer.
Degree: PhD, Human Genetics, 2017, Vanderbilt University
URL: http://hdl.handle.net/1803/12384
► Lung cancer is classified into two main types: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC has several subtypes, but the…
(more)
▼ Lung cancer is classified into two main types: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC has several subtypes, but the two most commonly occurring subtypes are lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). These classifications are mostly based upon histological and pathological characteristics, but there is increasing evidence of genetic and molecular differences as well. Although previous work has identified differences between subtypes of NSCLC at the somatic level, little work has been done to look at differences in all three subtypes across both the germline and somatic genomes. I hypothesized that a comprehensive detailed comparison of these lung cancer subtypes at both genomes would reveal shared and distinct mechanisms of disease. In this work, I used single nucleotide polymorphisms (SNPs) identified as significant (p < 1 x 10-3) in a genome wide association study (GWAS) to identify regulatory variants associated with each lung cancer subtype. I used these regulatory SNPs to identify sets of regulated genes in the genome for each subtype. I also expanded this germline work across other lung diseases and cancer types to extend the utility of the pipeline. At the somatic level, I identified genes that were differentially expressed in lung tumor versus normal tissue. Additionally, I identified mutational signatures and sets of potential driver genes in the somatic genomes for each subtype. I also identified biological pathways enriched with the germline and somatic gene sets. Finally, I performed a detailed comparison of calling somatic single nucleotide variants (SNVs) from whole exome sequencing (WES) versus transcriptome sequencing (RNA-Seq) in NSCLC. Overall, across all comparisons and genomes, I observed very little overlap between the three lung cancer subtypes. However, I found one gene, CHRNA5, disrupted by regulatory variants in the germline genomes and differentially expressed in the somatic genomes. This gene encodes a nicotinic acetylcholine receptor and may play a role in lung cancer due to its finding across both genomes and all three subtypes.
Advisors/Committee Members: John A. Capra (committee member), Melinda Aldrich (committee member), Jirong Long (committee member), Nancy Cox (committee member), Zhongming Zhao (committee member), David Samuels (Committee Chair).
Subjects/Keywords: RNA-Seq; WES; somatic mutations; differential expression; enhancer; eQTL; lung cancer subtypes; GWAS
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APA ·
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MLA ·
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CSE |
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to Zotero / EndNote / Reference
Manager
APA (6th Edition):
O'Brien, T. D. (2017). Investigating the Genetic Influences of the Germline and Somatic Genomes in Three Subtypes of Lung Cancer. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/12384
Chicago Manual of Style (16th Edition):
O'Brien, Timothy Daniel. “Investigating the Genetic Influences of the Germline and Somatic Genomes in Three Subtypes of Lung Cancer.” 2017. Doctoral Dissertation, Vanderbilt University. Accessed April 12, 2021.
http://hdl.handle.net/1803/12384.
MLA Handbook (7th Edition):
O'Brien, Timothy Daniel. “Investigating the Genetic Influences of the Germline and Somatic Genomes in Three Subtypes of Lung Cancer.” 2017. Web. 12 Apr 2021.
Vancouver:
O'Brien TD. Investigating the Genetic Influences of the Germline and Somatic Genomes in Three Subtypes of Lung Cancer. [Internet] [Doctoral dissertation]. Vanderbilt University; 2017. [cited 2021 Apr 12].
Available from: http://hdl.handle.net/1803/12384.
Council of Science Editors:
O'Brien TD. Investigating the Genetic Influences of the Germline and Somatic Genomes in Three Subtypes of Lung Cancer. [Doctoral Dissertation]. Vanderbilt University; 2017. Available from: http://hdl.handle.net/1803/12384
. 
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