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Vanderbilt University
1.
Broeckelmann, Eva Marie.
Dynamics of long-range gene regulation at the BMP2 locus.
Degree: MS, Interdisciplinary Studies: Human Genetics, 2013, Vanderbilt University
URL: http://hdl.handle.net/1803/12090 
► A member of the TGF-â superfamily of cytokines, BMP2 not only plays a critical role in pattern formation and morphogenesis during early embryonic development, but…
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▼ A member of the TGF-â superfamily of cytokines, BMP2 not only plays a critical role in pattern formation and morphogenesis during early embryonic development, but also promotes osteoblast differentiation and bone formation, making it a vital factor for the maintenance of bone health. Expanding on earlier studies of the regulatory landscape surrounding Bmp2 by BAC transgenesis in mice that had lead to the identification of the osteoblast enhancer ECR1, the work presented here further scrutinizes the particular role of ECR1 during osteogenesis and provides striking evidence for the hypothesis that – despite its indispensable role for Bmp2 expression in osteoblasts -, it is in fact not entirely autonomous, but requires additional enhancer activity to control the full scope of osteoblast-specific expression. Subsequent analysis of the chromosomal conformation during transcriptional activation does not only support this hypothesis and substantiate the dynamic nature of looping interactions at the locus, but combined with additional epigenetic characteristics also serves to highlight several distant loci within the gene desert as excellent candidates for putative enhancer function.
Advisors/Committee Members: Xiangli Yang (committee member), Michelle Southard-Smith (committee member), Douglas P. Mortlock (Committee Chair).
Subjects/Keywords: gene regulation; Bmp2
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APA (6th Edition):
Broeckelmann, E. M. (2013). Dynamics of long-range gene regulation at the BMP2 locus. (Thesis). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/12090
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Broeckelmann, Eva Marie. “Dynamics of long-range gene regulation at the BMP2 locus.” 2013. Thesis, Vanderbilt University. Accessed March 07, 2021.
http://hdl.handle.net/1803/12090.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Broeckelmann, Eva Marie. “Dynamics of long-range gene regulation at the BMP2 locus.” 2013. Web. 07 Mar 2021.
Vancouver:
Broeckelmann EM. Dynamics of long-range gene regulation at the BMP2 locus. [Internet] [Thesis]. Vanderbilt University; 2013. [cited 2021 Mar 07].
Available from: http://hdl.handle.net/1803/12090.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Broeckelmann EM. Dynamics of long-range gene regulation at the BMP2 locus. [Thesis]. Vanderbilt University; 2013. Available from: http://hdl.handle.net/1803/12090
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Vanderbilt University
2.
Kodaman, Nuri.
The Genetics of Cardiovascular Risk Factor Correlations.
Degree: PhD, Human Genetics, 2015, Vanderbilt University
URL: http://hdl.handle.net/1803/15219
► Cardiovascular disease (CVD) is the leading cause of death worldwide. The vast possibilities of interaction between genetic and environmental factors that contribute to CVD can…
(more)
▼ Cardiovascular disease (CVD) is the leading cause of death worldwide. The vast possibilities of interaction between genetic and environmental factors that contribute to CVD can be simplified by identifying conditions that favor the emergence of specific risk factor networks. If the relationships among CVD risk factors that give rise to these networks are under genetic control, then such relationships can be considered heritable phenotypes in themselves, amenable to genetic analysis. We characterized correlational networks of cardiovascular risk factors in a large cohort of urban and rural men and women in Ghana, and investigated how they may be perturbed by factors such as sex and urban lifestyle. We also assessed the comparative relevance of individual risk factors to thrombosis within and across networks, using as a proxy their association with an intermediate phenotype of CVD, plasminogen activator inhibitor type-1 (PAI-1). We found that the relationships between risk factors and PAI-1 were far more sensitive to differences in sex and environment than were the relationships among the risk factors themselves. To lay the theoretical groundwork for our subsequent genetic analyses, we modeled multiple types of biological SNP-by-covariate interactions and derived the statistical parameters to which they should give rise. In doing so, we demonstrated that even the strongest gene-by-covariate interactions at the biological level could display weak statistical interactions using general linear models. Moreover, we quantified the expected strength of the interaction relative to the marginal effect, depending on the nature of biological interaction. We then developed the ordinal joint interaction model (OJIM), which can not only identify biological SNP-by-covariate interactions where they exist, but also pick up marginal effects and leverage the change in residual correlation induced by marginal effects. In our analyses of the Ghanaian study population, the OJIM had more power than univariate or bivariate analysis to detect lipid SNPs of known biological significance, indicating that context-dependent genetic effects are probably quite common, and that the OJIM can identify them where they exist. We also used the OJIM to interrogate exome-wide data of our Ghanaian study population, and identified genetic variants that may increase thrombotic risk by influencing the covariance between these risk factors and PAI-1.
Advisors/Committee Members: Nancy J. Brown (committee member), David E. McCauley (committee member), Melinda C. Aldrich (committee member), Douglas P. Mortlock (Committee Chair).
Subjects/Keywords: genetic epidemiology; epidemiology; GXE interaction; t-PA; West Africa; fibrinolysis; cardiovascular disease risk factors; method development; ordinal regression
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APA (6th Edition):
Kodaman, N. (2015). The Genetics of Cardiovascular Risk Factor Correlations. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/15219
Chicago Manual of Style (16th Edition):
Kodaman, Nuri. “The Genetics of Cardiovascular Risk Factor Correlations.” 2015. Doctoral Dissertation, Vanderbilt University. Accessed March 07, 2021.
http://hdl.handle.net/1803/15219.
MLA Handbook (7th Edition):
Kodaman, Nuri. “The Genetics of Cardiovascular Risk Factor Correlations.” 2015. Web. 07 Mar 2021.
Vancouver:
Kodaman N. The Genetics of Cardiovascular Risk Factor Correlations. [Internet] [Doctoral dissertation]. Vanderbilt University; 2015. [cited 2021 Mar 07].
Available from: http://hdl.handle.net/1803/15219.
Council of Science Editors:
Kodaman N. The Genetics of Cardiovascular Risk Factor Correlations. [Doctoral Dissertation]. Vanderbilt University; 2015. Available from: http://hdl.handle.net/1803/15219
Vanderbilt University
3.
Clendenning, Dawn Elizabeth.
Determining the role of Growth Differentiation Factor-6 (Gdf6) in the development of the coronal suture.
Degree: PhD, Human Genetics, 2012, Vanderbilt University
URL: http://hdl.handle.net/1803/12174
► HUMAN GENETICS DETERMINING THE ROLE OF GROWTH DIFFERENTIATION FACTOR-6 (GDF6) IN THE DEVELOPMENT OF THE CORONAL SUTURE DAWN ELIZABETH CLENDENNING Dissertation under the direction of…
(more)
▼ HUMAN GENETICS
DETERMINING THE ROLE OF GROWTH DIFFERENTIATION FACTOR-6 (GDF6) IN THE DEVELOPMENT OF THE CORONAL SUTURE
DAWN ELIZABETH CLENDENNING
Dissertation under the direction of Professor
Douglas P.
Mortlock
Growth differentiation factor-6 (Gdf6) is a member of the Bone Morphogenetic Protein (BMP) family of secreted signaling proteins. The Gdf6 mutant mouse presents with fusions in the bones of the wrist and ankle, hypoplasia of the thyroid cartilage, abnormalities of the bones of the middle ear, and craniosynostosis of the coronal suture. Craniosynostosis is the premature fusion of one or more of the cranial sutures, the joints that separate the flat bones of the skull.
The primary objective of this work was to determine the developmental timing of the coronal suture defect, when and where Gdf6 is expressed during cranial development, what mechanism leads to fusion of the coronal suture, and how Gdf6 interacts with other members of the BMP family in coronal suture development. We found that Gdf6 is expressed in the rudiment of the frontal bone early in suture development. Loss of Gdf6 leads to the osteogenic differentiation of the coronal suture mesenchyme, which must remain undifferentiated to remain a site for cranial growth. Furthermore, Gdf6 interacts with fellow BMP family member Bmp4 not only in the development of the coronal suture, but in multiple skeletal elements. Additionally, we found that the BMP antagonist Noggin does not play an important role in embryonic suture development. The findings of this project not only further the the study of craniosynostosis but also broadens the knowledge of the roles of BMPs.
Advisors/Committee Members: Douglas P. Mortlock (committee member), Patricia Labosky (committee member), Xiangli Yang (committee member), Michelle Southard-Smith (committee member), Ela W. Knapik (Committee Chair).
Subjects/Keywords: Bone Morphogenetic Proteins; skeletal development; craniosynostosis; cranial sutures; Gdf6
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APA (6th Edition):
Clendenning, D. E. (2012). Determining the role of Growth Differentiation Factor-6 (Gdf6) in the development of the coronal suture. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/12174
Chicago Manual of Style (16th Edition):
Clendenning, Dawn Elizabeth. “Determining the role of Growth Differentiation Factor-6 (Gdf6) in the development of the coronal suture.” 2012. Doctoral Dissertation, Vanderbilt University. Accessed March 07, 2021.
http://hdl.handle.net/1803/12174.
MLA Handbook (7th Edition):
Clendenning, Dawn Elizabeth. “Determining the role of Growth Differentiation Factor-6 (Gdf6) in the development of the coronal suture.” 2012. Web. 07 Mar 2021.
Vancouver:
Clendenning DE. Determining the role of Growth Differentiation Factor-6 (Gdf6) in the development of the coronal suture. [Internet] [Doctoral dissertation]. Vanderbilt University; 2012. [cited 2021 Mar 07].
Available from: http://hdl.handle.net/1803/12174.
Council of Science Editors:
Clendenning DE. Determining the role of Growth Differentiation Factor-6 (Gdf6) in the development of the coronal suture. [Doctoral Dissertation]. Vanderbilt University; 2012. Available from: http://hdl.handle.net/1803/12174
Vanderbilt University
4.
Wang, Weiguang.
Function of Atf4 in Endochondral Bone Formation.
Degree: PhD, Pharmacology, 2011, Vanderbilt University
URL: http://hdl.handle.net/1803/12726
► Activating transcription factor 4 (Atf4) is a leucine zip transcription factor. Atf4 mutant (Atf4-/-) mice show severe low bone mass and short stature phenotype. Atf4…
(more)
▼ Activating transcription factor 4 (Atf4) is a leucine zip transcription factor. Atf4 mutant (Atf4-/-) mice show severe low bone mass and short stature phenotype. Atf4 is expressed in growth plate chondrocytes. Atf4-/- growth plate shows disturbed and shortened proliferative chondrocyte zone, expanded hypertrophic zone and decreased expression of Indian hedgehog (Ihh). Atf4 directly binds to the Ihh promoter and activates its transcription. Reactivation of Hh signaling pharmacologically in mouse limb explants corrects the Atf4-/- chondrocyte proliferation and short limb phenotypes. Chondrocyte-specific overexpression of Atf4 in Atf4-/- mice restores Ihh expression and Hh signaling, and completely rescues the cartilage defects presented in Atf4-/- embryos. These data demonstrate a chondrocyte-autonomous function of Atf4 in chondrogenesis. Unexpectedly, Atf4 overexpression in chondrocytes of Atf4-/-;Col2α1-Atf4 mice also rescues the Osteocalcin expression and bone formation normalize in Atf4-/- mice. The differentiation of Atf4-/- osteoblasts induced by the conditioned medium of Atf4-/-;Col2a1-Atf4 cartilage can be blocked by a neutralizing Ihh antibody, indicating that Atf4 in chondrocytes indirectly regulates osteoblast differentiation via Ihh. My study thus identifies a novel autonomous function of Atf4 in chondrocytes for regulating both chondrogenesis and osteogenesis in endochondral ossification.
Advisors/Committee Members: Xiangli Yang (committee member), Chin Chiang (committee member), Charles C Hong (committee member), Douglas P Mortlock (committee member), Florent Elefteriou (committee member).
Subjects/Keywords: chondrocyte; Ihh; Endochondral ossification; Atf4; osteoblast
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APA (6th Edition):
Wang, W. (2011). Function of Atf4 in Endochondral Bone Formation. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/12726
Chicago Manual of Style (16th Edition):
Wang, Weiguang. “Function of Atf4 in Endochondral Bone Formation.” 2011. Doctoral Dissertation, Vanderbilt University. Accessed March 07, 2021.
http://hdl.handle.net/1803/12726.
MLA Handbook (7th Edition):
Wang, Weiguang. “Function of Atf4 in Endochondral Bone Formation.” 2011. Web. 07 Mar 2021.
Vancouver:
Wang W. Function of Atf4 in Endochondral Bone Formation. [Internet] [Doctoral dissertation]. Vanderbilt University; 2011. [cited 2021 Mar 07].
Available from: http://hdl.handle.net/1803/12726.
Council of Science Editors:
Wang W. Function of Atf4 in Endochondral Bone Formation. [Doctoral Dissertation]. Vanderbilt University; 2011. Available from: http://hdl.handle.net/1803/12726
Vanderbilt University
5.
Fish, Alexandra Elizabeth.
Leveraging gene expression and local ancestry to investigate
regulatory epistasis in humans.
Degree: PhD, Human Genetics, 2017, Vanderbilt University
URL: http://hdl.handle.net/1803/11250
► Epistasis is a phenomenon wherein the effect of a genetic variant on a phenotype is dependent on the genomic context. Better understanding epistastic relationships between…
(more)
▼ Epistasis is a phenomenon wherein the effect of a genetic variant on a phenotype is dependent on the genomic context. Better understanding epistastic relationships between variants, often termed interactions, can shed light on novel genomic loci associated with complex disease, which may improve our understanding of the underlying biological mechanisms. Additionally, capturing epistastic effects in models of disease risk may help improve predictions of at-risk populations, or the prediction of a variant’s deleteriousness in precision medicine initiatives. However, the study of epistasis faces unique methodological challenges, and consequently, evidence for regulatory epistasis remains elusive in humans. In this work, I address two major challenges within the field of regulatory epistasis: the development of statistical best practices, and the investigation of epistasis within haplotypes. In Chapter 2, I illustrate that traditional quality control procedures are insufficient to correct for confounding in studies of epistasis, and develop a set of additional guidelines for future studies. Once these were applied, I found little evidence for epistasis between common, unlinked variants influencing gene expression levels. In Chapter 3, I leverage unique properties of admixed populations to investigate epistasis within ancestral haplotypes disrupted by ancestry-specific recombination events. I find several examples of epistasis with plausible biological support, which serve as a proof of principle for the utility of this approach. Overall, these findings indicate that regulatory epistasis likely has small effects, occurs within haplotypes, or occurs between distant genomic regions; we recommend future studies of epistasis focus on these possibilities.
Advisors/Committee Members: William Scott Bush (committee member), John Anthony Capra (committee member), Melinda Aldrich (committee member), Joseph Lee Rodgers (committee member), Douglas P. Mortlock (Committee Chair).
Subjects/Keywords: epistasis; gene expression; admixed populations; eQTL; PheWAS
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APA ·
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APA (6th Edition):
Fish, A. E. (2017). Leveraging gene expression and local ancestry to investigate
regulatory epistasis in humans. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/11250
Chicago Manual of Style (16th Edition):
Fish, Alexandra Elizabeth. “Leveraging gene expression and local ancestry to investigate
regulatory epistasis in humans.” 2017. Doctoral Dissertation, Vanderbilt University. Accessed March 07, 2021.
http://hdl.handle.net/1803/11250.
MLA Handbook (7th Edition):
Fish, Alexandra Elizabeth. “Leveraging gene expression and local ancestry to investigate
regulatory epistasis in humans.” 2017. Web. 07 Mar 2021.
Vancouver:
Fish AE. Leveraging gene expression and local ancestry to investigate
regulatory epistasis in humans. [Internet] [Doctoral dissertation]. Vanderbilt University; 2017. [cited 2021 Mar 07].
Available from: http://hdl.handle.net/1803/11250.
Council of Science Editors:
Fish AE. Leveraging gene expression and local ancestry to investigate
regulatory epistasis in humans. [Doctoral Dissertation]. Vanderbilt University; 2017. Available from: http://hdl.handle.net/1803/11250
Vanderbilt University
6.
Veatch, Olivia Jean.
Identifying biological pathways implicated in defined subgroups of phenotypic expression for Autism Spectrum Disorders and evaluating small molecule effects on expression of ASMT.
Degree: PhD, Human Genetics, 2013, Vanderbilt University
URL: http://hdl.handle.net/1803/15041
► Autism Spectrum Disorder is a neurodevelopmental condition with evidence for genetic susceptibility. However, effect sizes for implicated loci are small, and current evidence does not…
(more)
▼ Autism Spectrum Disorder is a neurodevelopmental condition with evidence for genetic susceptibility. However, effect sizes for implicated loci are small, and current evidence does not explain the heritability. Phenotypic heterogeneity could be complicating genetic factor identification. We used multiple sources of behavioral and physiological data to identify ASD subgroups. Principal Components Analysis refined these data from an ASD dataset into 15 components best explaining phenotypic variance. Clustering identified two distinct groups, primarily based on phenotype severity. Using an independent dataset, we identified 15 data components and confirmed the severity-based dichotomy. There is significant familial clustering within groups, suggesting the clusters recapitulate genetic etiology. We performed separate family-based analyses of genetic data based on subgroup. Pathway analysis was performed. Five biological pathways uniquely associate with the ‘less severe’ subgroup. Ten genes potentially drive these associations. Five different pathways uniquely associate with the ‘more severe’ subgroup. 24 genes potentially drive associations with this subgroup. There is minimal overlap when comparing genes associated with different subgroups. We validated results in an independent dataset and see unique biological mechanisms associate with the ‘more severe’ and ‘less severe’ subgroups. Our results suggest meaningful subgroup definitions can help clarify the genetics of ASD. Uncovering pathways associated with subgroups further elucidated potential genes involved in trait expression. To progress toward understanding how these findings could be useful for treatment, functional characterization was necessary. Ample evidence indicates many drugs have altered efficacy and side effects in relation to genetic background. For many compounds used to treat ASD comorbid symptoms, individuals exhibit sleep problems. We evaluated the enzyme catalyzing the final reaction in melatonin synthesis, Acetylserotonin O-methyltransferase. We screened cell lines generated from patient DNA for differential expression effects against compounds presently used to treat symptoms. We replicated previous findings indicating homozygous presence of ASD risk alleles at promoter SNPs results in decreased gene expression. We also observe previously unreported expression effects attributable to heterozygosity at promoter SNPs, and a SNP in the 5'-UTR. Results show no significant changes in gene expression upon exposure to small molecule compounds for the non-risk haplotype.
Advisors/Committee Members: Douglas P. Mortlock (committee member), Colleen M. Niswender (committee member), Jeremy M. Veenstra-VanderWeele (committee member), Jonathan L. Haines (committee member), Tricia A. Thornton-Wells (Committee Chair).
Subjects/Keywords: Autism Spectrum Disorder; Human Genetics; Multivariate Statistics; Pharmacogenetics; Phenotyping; Ne
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APA (6th Edition):
Veatch, O. J. (2013). Identifying biological pathways implicated in defined subgroups of phenotypic expression for Autism Spectrum Disorders and evaluating small molecule effects on expression of ASMT. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/15041
Chicago Manual of Style (16th Edition):
Veatch, Olivia Jean. “Identifying biological pathways implicated in defined subgroups of phenotypic expression for Autism Spectrum Disorders and evaluating small molecule effects on expression of ASMT.” 2013. Doctoral Dissertation, Vanderbilt University. Accessed March 07, 2021.
http://hdl.handle.net/1803/15041.
MLA Handbook (7th Edition):
Veatch, Olivia Jean. “Identifying biological pathways implicated in defined subgroups of phenotypic expression for Autism Spectrum Disorders and evaluating small molecule effects on expression of ASMT.” 2013. Web. 07 Mar 2021.
Vancouver:
Veatch OJ. Identifying biological pathways implicated in defined subgroups of phenotypic expression for Autism Spectrum Disorders and evaluating small molecule effects on expression of ASMT. [Internet] [Doctoral dissertation]. Vanderbilt University; 2013. [cited 2021 Mar 07].
Available from: http://hdl.handle.net/1803/15041.
Council of Science Editors:
Veatch OJ. Identifying biological pathways implicated in defined subgroups of phenotypic expression for Autism Spectrum Disorders and evaluating small molecule effects on expression of ASMT. [Doctoral Dissertation]. Vanderbilt University; 2013. Available from: http://hdl.handle.net/1803/15041
Vanderbilt University
7.
Jorge, Benjamin S.
Genetic Variation in the Voltage-gated Potassium Channel Genes KCNV2 and KCNB1 Contributes to Epilepsy Susceptibility.
Degree: PhD, Neuroscience, 2014, Vanderbilt University
URL: http://hdl.handle.net/1803/14387
► Epilepsy is a common neurological disease characterized by an enduring predisposition to generate seizures. Although multiple factors contribute to epilepsy, the majority of cases are…
(more)
▼ Epilepsy is a common neurological disease characterized by an enduring predisposition to generate seizures. Although multiple factors contribute to epilepsy, the majority of cases are genetic in origin. Variable expressivity is commonly observed in families with inherited mutations in epilepsy-associated genes, suggesting that variation in genetic modifiers may contribute to epilepsy phenotypes. We previously identified the modulatory voltage-gated potassium channel subunit, Kcnv2, as a candidate modifier gene in a transgenic mouse model of epilepsy. This dissertation outlines: the validation of Kcnv2 as a quantitative modifier of epilepsy in mice; the identification of KCNV2 variants in pediatric epilepsy patients; the determination of Kcnv2 regulatory regions; and the identification of mutations in a delayed-rectifier potassium channel gene, KCNB1, in individuals with epileptic encephalopathy. These studies highlight the importance of delayed-rectifier potassium current in governing neuronal excitability and demonstrate the utility of identifying and characterizing genetic modifiers to elucidate mechanisms of pathogenesis.
Advisors/Committee Members: Kevin C. Ess, M.D., Ph.D. (committee member), Jennifer A. Kearney, Ph.D. (committee member), Douglas P. Mortlock, Ph.D. (committee member), Alfred L. George, Jr., M.D. (Committee Chair).
Subjects/Keywords: potassium channel; epileptic encephalopathy; mouse model; genetics; whole-exome sequencing; epilepsy
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APA (6th Edition):
Jorge, B. S. (2014). Genetic Variation in the Voltage-gated Potassium Channel Genes KCNV2 and KCNB1 Contributes to Epilepsy Susceptibility. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/14387
Chicago Manual of Style (16th Edition):
Jorge, Benjamin S. “Genetic Variation in the Voltage-gated Potassium Channel Genes KCNV2 and KCNB1 Contributes to Epilepsy Susceptibility.” 2014. Doctoral Dissertation, Vanderbilt University. Accessed March 07, 2021.
http://hdl.handle.net/1803/14387.
MLA Handbook (7th Edition):
Jorge, Benjamin S. “Genetic Variation in the Voltage-gated Potassium Channel Genes KCNV2 and KCNB1 Contributes to Epilepsy Susceptibility.” 2014. Web. 07 Mar 2021.
Vancouver:
Jorge BS. Genetic Variation in the Voltage-gated Potassium Channel Genes KCNV2 and KCNB1 Contributes to Epilepsy Susceptibility. [Internet] [Doctoral dissertation]. Vanderbilt University; 2014. [cited 2021 Mar 07].
Available from: http://hdl.handle.net/1803/14387.
Council of Science Editors:
Jorge BS. Genetic Variation in the Voltage-gated Potassium Channel Genes KCNV2 and KCNB1 Contributes to Epilepsy Susceptibility. [Doctoral Dissertation]. Vanderbilt University; 2014. Available from: http://hdl.handle.net/1803/14387
Vanderbilt University
8.
Levinson, Rebecca Terrall.
The Phenotypic Consequences of Distinct Genetic Variation in an Electronic Medical Record.
Degree: PhD, Human Genetics, 2016, Vanderbilt University
URL: http://hdl.handle.net/1803/14698
► While genetic association studies have been able to elucidate the importance of genetics in human disease outcomes, these studies are limited by the necessity of…
(more)
▼ While genetic association studies have been able to elucidate the importance of genetics in human disease outcomes, these studies are limited by the necessity of collecting specifically tailored cohorts and that they frequently only test a single outcome. This focus on a single disease at a time ignores the interconnected nature of both biological pathways and disease phenotypes. My dissertation uses phenome-wide association scans (PheWAS), a method of testing one predictor for association with many disease outcomes, to expand our knowledge of multiple genetic variants and types of genetic variation. We used BioVU, a biobank linked to de-identified electronic medical records (EMRs), to explored a variety of applications for PheWAS. Each chapter presents a project where PheWAS was implemented as a starting point due to a specific hypothesis, before follow-up analyses based on the PheWAS outcome and out existing knowledge of the gene, protein, or variant were performed. The projects presented here begin with the most straight-forward scenario, directly genotyped single SNPs, and progress to imputed deletions before exploring ways to use PheWAS in multi-dimensional studies. In conclusion, I used PheWAS to uncover novel genotype-phenotype associations, and further explored these associations using other data types in the EMR. While PheWAS can be a useful tool for discovering unexpected disease consequences of genetic predictors, using it successfully requires sufficient knowledge of the genetic variation tested to evaluate the biological relevance of association signals
Advisors/Committee Members: Joshua C Denny (committee member), Bingshan Li (committee member), Douglas P Mortlock (committee member), David C Samuels (committee member), Melinda C Aldrich (Committee Chair).
Subjects/Keywords: PheWAS
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APA (6th Edition):
Levinson, R. T. (2016). The Phenotypic Consequences of Distinct Genetic Variation in an Electronic Medical Record. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/14698
Chicago Manual of Style (16th Edition):
Levinson, Rebecca Terrall. “The Phenotypic Consequences of Distinct Genetic Variation in an Electronic Medical Record.” 2016. Doctoral Dissertation, Vanderbilt University. Accessed March 07, 2021.
http://hdl.handle.net/1803/14698.
MLA Handbook (7th Edition):
Levinson, Rebecca Terrall. “The Phenotypic Consequences of Distinct Genetic Variation in an Electronic Medical Record.” 2016. Web. 07 Mar 2021.
Vancouver:
Levinson RT. The Phenotypic Consequences of Distinct Genetic Variation in an Electronic Medical Record. [Internet] [Doctoral dissertation]. Vanderbilt University; 2016. [cited 2021 Mar 07].
Available from: http://hdl.handle.net/1803/14698.
Council of Science Editors:
Levinson RT. The Phenotypic Consequences of Distinct Genetic Variation in an Electronic Medical Record. [Doctoral Dissertation]. Vanderbilt University; 2016. Available from: http://hdl.handle.net/1803/14698
Vanderbilt University
9.
Bush, William Scott.
A Knowledge-Driven Multi-Locus Analysis of Multiple Sclerosis Susceptiblity.
Degree: PhD, Human Genetics, 2009, Vanderbilt University
URL: http://hdl.handle.net/1803/10678
► Evaluating epistasis in whole-genome association studies is an important challenge in human genetics, as many common diseases are thought to have complex underlying genetic architectures…
(more)
▼ Evaluating epistasis in whole-genome association studies is an important challenge in human genetics, as many common diseases are thought to have complex underlying genetic architectures that include small independent effects and interactions between many genes. In this project, I applied a simple bioinformatics approach for generating and ranking biologically supported multi-locus models of multiple sclerosis (MS) susceptibility, using data sources implying interaction of molecules, sources implying gene relationship to disease, and literature-based information. Putative gene-gene interaction models were constructed based on these relationships. These models were evaluated in whole-genome association dataset consisting of 931 MS case/pseudo-control pairs, 2,950 population-based controls, and a replication sample of 808 MS cases and 1,720 controls. Using this approach, I highlight the potential utility of this knowledge-driven analysis technique, and propose a potential role for inositol-based signaling molecules in multiple sclerosis susceptibility.
Advisors/Committee Members: Jay R. Snoddy (committee member), James E. Crowe (committee member), Jonathan L. Haines (committee member), Marylyn D. Ritchie (committee member), Douglas P. Mortlock (Committee Chair).
Subjects/Keywords: Genomics – Methodology; Inositol – Pathophysiology; Epistasis (Genetics); Multiple sclerosis – Genetic aspects; disease gene discovery; knowledge-based analysis; Disease susceptibility – Genetic aspects – Data processing
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APA (6th Edition):
Bush, W. S. (2009). A Knowledge-Driven Multi-Locus Analysis of Multiple Sclerosis Susceptiblity. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/10678
Chicago Manual of Style (16th Edition):
Bush, William Scott. “A Knowledge-Driven Multi-Locus Analysis of Multiple Sclerosis Susceptiblity.” 2009. Doctoral Dissertation, Vanderbilt University. Accessed March 07, 2021.
http://hdl.handle.net/1803/10678.
MLA Handbook (7th Edition):
Bush, William Scott. “A Knowledge-Driven Multi-Locus Analysis of Multiple Sclerosis Susceptiblity.” 2009. Web. 07 Mar 2021.
Vancouver:
Bush WS. A Knowledge-Driven Multi-Locus Analysis of Multiple Sclerosis Susceptiblity. [Internet] [Doctoral dissertation]. Vanderbilt University; 2009. [cited 2021 Mar 07].
Available from: http://hdl.handle.net/1803/10678.
Council of Science Editors:
Bush WS. A Knowledge-Driven Multi-Locus Analysis of Multiple Sclerosis Susceptiblity. [Doctoral Dissertation]. Vanderbilt University; 2009. Available from: http://hdl.handle.net/1803/10678
Vanderbilt University
10.
Liang, Xueying.
Investigation of genetic susceptibility to late-onset Alzheimer disease through genomic convergence.
Degree: PhD, Human Genetics, 2007, Vanderbilt University
URL: http://hdl.handle.net/1803/11992
► With the exception of ApoE gene, no universally accepted genetic association has been identified with the complex Late-onset Alzheimer Disease (LOAD). A broad region of…
(more)
▼ With the exception of ApoE gene, no universally accepted genetic association has been identified with the complex Late-onset Alzheimer Disease (LOAD). A broad region of chromosome 10 has engendered continued interest generated from both preliminary genetic linkage and candidate gene studies.
To better examine this region, we applied the genomic convergence approach by combining unbiased genetic linkage with candidate gene association studies. We genotyped 36 SNPs across 80.2 Mb in 567 multiplex families to narrow the peak region of linkage using both covariate and subset analyses. Simultaneously, we examined seven functional candidate genes that also fell within the broad area of linkage. Although a two point LOD score of 2.69 was obtained in the linkage analysis, the associated candidate genes were not under the linkage peak, suggesting a more extensive heterogeneity on chromosome10 than previously expected.
We then converged linkage analysis and gene expression data to identify genes that were under linkage peaks and also differentially expressed in AD cases and controls based on the rationale that genes showing positive results in multiple studies are more likelihood to be involved in AD. We identified and examined 28 genes on chromosome 10 for the association with AD. Both single marker and haplotypic associations were tested in overall and eight subsets that were stratified by age, gender, ApoE status and clinical diagnosis. Gene-gene interaction was tested to detect important genes in this complex disease. PTPLA gene showed allelic, genotypic and haplotypic association in the overall dataset. The SORCS1 gene showed very significant association in the female dataset (allelic association
p=0.00002, a 3-locus haplotype has
p=0.00098). Two SNPs in CACNB2 gene showed gene-gene interaction in overall dataset using Multifactor Dimensionality Reduction (MDR).
The work presented in this dissertation applied a multifactorial, multistep approach, genomic convergence, which combined linkage analysis, gene expression data, and candidate gene association analysis to identify and prioritize candidate susceptibility genes for AD. This study suggests that genetic variations in PTPLA, SORCS1 and CACNB2 genes might alter the risk for Alzheimer disease by affecting multiple pathways.
Advisors/Committee Members: Scott M. Williams (committee member), Jonathan L. Haines (committee member), Douglas P. Mortlock (committee member), Harry E. Gwirtsman (committee member), Marylyn D. Ritchie (Committee Chair).
Subjects/Keywords: Alzheimer Disease; gene-gene interaction; genomic convergence; association; candidate gene; chromosome 10; linkage; SNP; genetics; Alzheimer's disease – Susceptibility
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APA (6th Edition):
Liang, X. (2007). Investigation of genetic susceptibility to late-onset Alzheimer disease through genomic convergence. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/11992
Chicago Manual of Style (16th Edition):
Liang, Xueying. “Investigation of genetic susceptibility to late-onset Alzheimer disease through genomic convergence.” 2007. Doctoral Dissertation, Vanderbilt University. Accessed March 07, 2021.
http://hdl.handle.net/1803/11992.
MLA Handbook (7th Edition):
Liang, Xueying. “Investigation of genetic susceptibility to late-onset Alzheimer disease through genomic convergence.” 2007. Web. 07 Mar 2021.
Vancouver:
Liang X. Investigation of genetic susceptibility to late-onset Alzheimer disease through genomic convergence. [Internet] [Doctoral dissertation]. Vanderbilt University; 2007. [cited 2021 Mar 07].
Available from: http://hdl.handle.net/1803/11992.
Council of Science Editors:
Liang X. Investigation of genetic susceptibility to late-onset Alzheimer disease through genomic convergence. [Doctoral Dissertation]. Vanderbilt University; 2007. Available from: http://hdl.handle.net/1803/11992
Vanderbilt University
11.
Spencer, Kylee L.
Variants in complement factor pathway genes and a novel locus on chromosome 16p12 influence age-related macular degeneration susceptibility.
Degree: PhD, Human Genetics, 2007, Vanderbilt University
URL: http://hdl.handle.net/1803/14024
► Age-related macular degeneration (AMD) is a complex, late-onset disease that is the leading cause of blindness in the elderly. Age, smoking, and variants in complement…
(more)
▼ Age-related macular degeneration (AMD) is a complex, late-onset disease that is the leading cause of blindness in the elderly. Age, smoking, and variants in complement factor H (CFH), LOC387715, complement factor B (CFB), and complement component 2 (CC2) are the strongest susceptibility factors for AMD.
CFH inhibits activation of the alternative complement cascade, avoiding injury to self tissues by preventing excessive immune responses. Five “CFH-like” genes reside nearby on chromosome 1, and likely have similar roles in immune regulation. Deletion of CFHL1 and CFHL3 confers protection from AMD (Hughes et al. 2006). We have confirmed this protective effect (frequency=0.8%, frequency controls=2.6%,
p=0.025). However, we also observed a protective haplotype without the deletion (haplotype frequency in cases=12%, controls=21%,
p<0.001), suggesting that other protective variants have yet to be identified.
As variants in CFH modify AMD susceptibility, exploration of other genes within the complement cascade is warranted. Variation in adjacent genes CFB and CC2 has been associated with decreased risk(Gold et al. 2006), though subsequent studies were unable to determine whether the effect of CC2 E318D was independent of polymorphisms in CFB or caused by LD between them(Maller et al. 2006). We dissected this region, and confirmed that both loci contribute to decreased risk of AMD, though the effect of CC2 is much smaller than CFB(CC2 E318D
p=0.02, CFB R32Q
p<0.0001).
The search for novel AMD loci continues. A previous linkage screen identified chromosome 16p12 as a likely location for a novel AMD locus. After increasing SNP density across chr16p12, we combined linkage and association results, gene expression data, and the known biology of genes in the interval to select 4 candidates: CACNG3, HS3ST4, IL4R, and Q7Z6F8. CACNG3 is the strongest candidate (2pt LOD=3.3, haplotypes in family-based and case-control datasets
p<0.01, ATA haplotype frequency cases=6.1%, frequency controls=10.3%,
p=0.004). A common duplication covers the upstream sequence and first exon of CACNG3, and we hypothesize that this variation may have functional effects that influence susceptibility.
Advisors/Committee Members: Jeffrey A. Canter (committee member), Paul Sternberg (committee member), David E. McCauley (committee member), Jonathan L. Haines (committee member), Douglas P. Mortlock (Committee Chair).
Subjects/Keywords: complex genetic disease
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APA (6th Edition):
Spencer, K. L. (2007). Variants in complement factor pathway genes and a novel locus on chromosome 16p12 influence age-related macular degeneration susceptibility. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/14024
Chicago Manual of Style (16th Edition):
Spencer, Kylee L. “Variants in complement factor pathway genes and a novel locus on chromosome 16p12 influence age-related macular degeneration susceptibility.” 2007. Doctoral Dissertation, Vanderbilt University. Accessed March 07, 2021.
http://hdl.handle.net/1803/14024.
MLA Handbook (7th Edition):
Spencer, Kylee L. “Variants in complement factor pathway genes and a novel locus on chromosome 16p12 influence age-related macular degeneration susceptibility.” 2007. Web. 07 Mar 2021.
Vancouver:
Spencer KL. Variants in complement factor pathway genes and a novel locus on chromosome 16p12 influence age-related macular degeneration susceptibility. [Internet] [Doctoral dissertation]. Vanderbilt University; 2007. [cited 2021 Mar 07].
Available from: http://hdl.handle.net/1803/14024.
Council of Science Editors:
Spencer KL. Variants in complement factor pathway genes and a novel locus on chromosome 16p12 influence age-related macular degeneration susceptibility. [Doctoral Dissertation]. Vanderbilt University; 2007. Available from: http://hdl.handle.net/1803/14024
Vanderbilt University
12.
Speirs, Christina Koo Yang.
Prostaglandin Gbetagamma signaling stimulates gastrulation movements by limiting cell adhesion through Snail stabilization.
Degree: PhD, Biological Sciences, 2009, Vanderbilt University
URL: http://hdl.handle.net/1803/14101
► Prostaglandin E2 (PGE2) influences many processes in vertebrates, including development, homeostasis, and disease through its GPCRs EP receptors 1-4. PGE2 regulates gastrulation movements during zebrafish…
(more)
▼ Prostaglandin E2 (PGE2) influences many processes in vertebrates, including development, homeostasis, and disease through its GPCRs EP receptors 1-4. PGE2 regulates gastrulation movements during zebrafish embryogenesis, but how it does so was previously unclear, as PGE2 can affect cell adhesion, motility, proliferation, and survival. Our studies reveal that the loss of PGE2 synthesis impairs all gastrulation movements, epiboly, internalization, convergence, and extension, in part due to increased cell adhesion in the embryo. The increase of tight junctions (ZO1) and adherens junctions (E-cadherin) occurs in a germ layer-dependent fashion. In the mesendoderm, PGE2 modulates E-cadherin by stabilizing Snail through the inhibition of Gsk3β by a novel interaction with the Gβγ subunits (in collaboration with K. Jernigan and E. Lee). Moreover, the reduction of PGE2 synthesis results in an endoderm deficiency without significant effect on the mesoderm, possibly due to decreased Nodal signaling. Finally, we present preliminary characterization of a fish harboring a reverse genetics TILLING-generated ep4a nonsense mutation that strongly depletes function of the gene, but manifests no apparent phenotype. In conclusion, our findings suggest that PGE2 signaling can coordinate cell fate specification and movement, in part through its negative regulation of cell adhesion in zebrafish gastrulae.
Advisors/Committee Members: Joshua T. Gamse (committee member), Douglas P. Mortlock (committee member), Bruce Appel (committee member), Lilianna Solnica-Krezel (committee member), James G. Patton (Committee Chair).
Subjects/Keywords: development; cell motility; protrusion formation; E-cadherin
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APA (6th Edition):
Speirs, C. K. Y. (2009). Prostaglandin Gbetagamma signaling stimulates gastrulation movements by limiting cell adhesion through Snail stabilization. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/14101
Chicago Manual of Style (16th Edition):
Speirs, Christina Koo Yang. “Prostaglandin Gbetagamma signaling stimulates gastrulation movements by limiting cell adhesion through Snail stabilization.” 2009. Doctoral Dissertation, Vanderbilt University. Accessed March 07, 2021.
http://hdl.handle.net/1803/14101.
MLA Handbook (7th Edition):
Speirs, Christina Koo Yang. “Prostaglandin Gbetagamma signaling stimulates gastrulation movements by limiting cell adhesion through Snail stabilization.” 2009. Web. 07 Mar 2021.
Vancouver:
Speirs CKY. Prostaglandin Gbetagamma signaling stimulates gastrulation movements by limiting cell adhesion through Snail stabilization. [Internet] [Doctoral dissertation]. Vanderbilt University; 2009. [cited 2021 Mar 07].
Available from: http://hdl.handle.net/1803/14101.
Council of Science Editors:
Speirs CKY. Prostaglandin Gbetagamma signaling stimulates gastrulation movements by limiting cell adhesion through Snail stabilization. [Doctoral Dissertation]. Vanderbilt University; 2009. Available from: http://hdl.handle.net/1803/14101
Vanderbilt University
13.
Kenealy, Shannon.
Investigating the genetic susceptibility to multiple sclerosis: a genomic convergence approach.
Degree: PhD, Molecular Physiology and Biophysics, 2006, Vanderbilt University
URL: http://hdl.handle.net/1803/11989
► Multiple sclerosis (MS) is a debilitating neuroimmunological and neuro-degenerative disease. Despite substantial evidence for polygenic inheritance, the MHC is the only region that clearly and…
(more)
▼ Multiple sclerosis (MS) is a debilitating neuroimmunological and neuro-degenerative disease. Despite substantial evidence for polygenic inheritance, the MHC is the only region that clearly and consistently demonstrates linkage and association in MS studies. The goal of the work presented in this dissertation was to identify additional chromosomal regions harboring MS susceptibility genes. Our studies entailed a new genomic convergence approach incorporating information gained from positional (linkage and association) and functional (comparative sequence) studies. In conjunction with high-throughput genotyping and powerful new statistical analyses methods, this approach identified several regions suggesting the presence of MS loci.
We began our investigation with a genomic linkage screen that identified seven chromosomal regions of interest in a data set of multiplex MS families. To narrow these regions, we developed an approach for more detailed linkage studies that capitalized on new methods for rapid and accurate genotyping of SNPs. In addition to increasing marker coverage in each region, we genotyped an expanded data set and devised covariate analyses schemes to account for genetic effect in the MHC. This method
continued to provide evidence of linkage to several chromosomal regions and was successful in substantially narrowing two regions to only a few Mb.
We then developed a systematic approach to expedite follow-up association studies in the positional candidate regions. In an attempt to increase the likelihood of detecting variants associated with MS, we employed a novel method to select SNPs located in multi-species conserved sequences. Use of this method on chromosome 1q44 resulted in the identification of four subregions demonstrating significant association with MS susceptibility.
The work presented in this dissertation confirmed several regions warranting further investigation for genes conferring susceptibility to MS, including chromosomes 1q44, 2q35, 9q34, and 18p11. It is our hope that these studies will result in the discovery of several genes associated with MS and that our genomic convergence approach will provide researchers with a method for unraveling the genetic heterogeneity of MS and other complex genetic diseases.
Advisors/Committee Members: Professor Jonathan L. Haines (committee member), Professor Douglas P. Mortlock (committee member), Professor John A. Phillips (committee member), Professor Subramaniam Sriram (committee member), Professor Scott M. Williams (committee member), Professor Marshall L. Summar (Committee Chair).
Subjects/Keywords: chromosome 1q; genetic linkage; allelic association; SNPs; Multiple sclerosis – Genetic aspects
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APA (6th Edition):
Kenealy, S. (2006). Investigating the genetic susceptibility to multiple sclerosis: a genomic convergence approach. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/11989
Chicago Manual of Style (16th Edition):
Kenealy, Shannon. “Investigating the genetic susceptibility to multiple sclerosis: a genomic convergence approach.” 2006. Doctoral Dissertation, Vanderbilt University. Accessed March 07, 2021.
http://hdl.handle.net/1803/11989.
MLA Handbook (7th Edition):
Kenealy, Shannon. “Investigating the genetic susceptibility to multiple sclerosis: a genomic convergence approach.” 2006. Web. 07 Mar 2021.
Vancouver:
Kenealy S. Investigating the genetic susceptibility to multiple sclerosis: a genomic convergence approach. [Internet] [Doctoral dissertation]. Vanderbilt University; 2006. [cited 2021 Mar 07].
Available from: http://hdl.handle.net/1803/11989.
Council of Science Editors:
Kenealy S. Investigating the genetic susceptibility to multiple sclerosis: a genomic convergence approach. [Doctoral Dissertation]. Vanderbilt University; 2006. Available from: http://hdl.handle.net/1803/11989
Vanderbilt University
14.
Mitchell, Sabrina L.
Investigation into the molecular and physiologic relationship between peptide tyrosine tyrosine and N-acetylglutamate synthase.
Degree: PhD, Human Genetics, 2010, Vanderbilt University
URL: http://hdl.handle.net/1803/15010
► Neither genome size nor gene number is indicative of organism complexity. Complex regulation of genes within a genome likely contributes to organism complexity. Coordinate regulation…
(more)
▼ Neither genome size nor gene number is indicative of organism complexity. Complex regulation of genes within a genome likely contributes to organism complexity. Coordinate regulation of genes through shared cis regulatory elements is one such mechanism. Peptide tyrosine tyrosine (PYY) and N-acetylglutamate synthase (NAGS) are divergently transcribed and thus share a 5’ flanking region, raising the possibility these genes are coordinately regulated through common cis regulatory elements. These genes are separated by less than 1000 base pairs and may be regulated by a bidirectional promoter. The purpose of this project is to investigate the molecular and physiologic relationship between PYY and NAGS. To locate the promoter region, the transcriptional start sites (TSSs) for these genes were identified in multiple tissues. Results of these experiments demonstrate the major TSSs for PYY and NAGS are separated by greater than 1000 base pairs indicating they are not under control of a bidirectional promoter by the strict definition. However, they may share cis regulatory elements in the intergenic region. Expression of PYY and NAGS was determined in a panel of human tissues, revealing distinct expression patterns for these genes. Importantly, PYY and NAGS are similarly expressed in the ileum, indicating that if the genes are coordinately regulated it is in a tissue-specific manner. To better understand the physiologic connection between these two genes, plasma PYY levels were measured in patients with diminished capacity for nitrogen processing. Plasma PYY levels were increased in these patients and therefore may contribute to some of the clinical symptoms in this group. Finally, results from in vivo studies in mouse point toward possible coordinate expression of PYY and NAGS in response to different feeding conditions. Taken together the data are consistent with the coordinate regulation of PYY and NAGS, and lead to a model in which these genes are coordinately regulated as a means to prevent overconsumption of dietary protein. This mechanism may explain, in part, why protein is more satiating than other macronutrients and may also help elucidate the mechanisms of nitrogen balance.
Advisors/Committee Members: Dana C. Crawford (committee member), Alyssa H. Hasty (committee member), P. Anthony Weil (committee member), Deborah G. Murdock (committee member), Marshall L. Summar (committee member), Douglas P. Mortlock (Committee Chair).
Subjects/Keywords: urea cycle disorders; nitrogen; urea cycle; protein
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CSE |
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APA (6th Edition):
Mitchell, S. L. (2010). Investigation into the molecular and physiologic relationship between peptide tyrosine tyrosine and N-acetylglutamate synthase. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/15010
Chicago Manual of Style (16th Edition):
Mitchell, Sabrina L. “Investigation into the molecular and physiologic relationship between peptide tyrosine tyrosine and N-acetylglutamate synthase.” 2010. Doctoral Dissertation, Vanderbilt University. Accessed March 07, 2021.
http://hdl.handle.net/1803/15010.
MLA Handbook (7th Edition):
Mitchell, Sabrina L. “Investigation into the molecular and physiologic relationship between peptide tyrosine tyrosine and N-acetylglutamate synthase.” 2010. Web. 07 Mar 2021.
Vancouver:
Mitchell SL. Investigation into the molecular and physiologic relationship between peptide tyrosine tyrosine and N-acetylglutamate synthase. [Internet] [Doctoral dissertation]. Vanderbilt University; 2010. [cited 2021 Mar 07].
Available from: http://hdl.handle.net/1803/15010.
Council of Science Editors:
Mitchell SL. Investigation into the molecular and physiologic relationship between peptide tyrosine tyrosine and N-acetylglutamate synthase. [Doctoral Dissertation]. Vanderbilt University; 2010. Available from: http://hdl.handle.net/1803/15010
. 
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