The Characteristics of Genetic Variants that Impact Gene Expression.
dc.contributor.author | Yuan, David Chih-Hsiang | en_US |
dc.date.accessioned | 2014-06-02T18:16:28Z | |
dc.date.available | NO_RESTRICTION | en_US |
dc.date.available | 2014-06-02T18:16:28Z | |
dc.date.issued | 2014 | en_US |
dc.date.submitted | en_US | |
dc.identifier.uri | https://hdl.handle.net/2027.42/107293 | |
dc.description.abstract | Mutation is the root of all genetic variation. A new mutation may exhibit little or no effect. A mutation in the coding region of a gene may affect the gene product’s structure and function. A mutation can also impact gene expression. Gene expression is the process through which information encoded in the DNA is converted to the molecular machinery carrying out specific biological functions, ultimately generating higher-order phenotypes. Mutations that modify gene expression can therefore contribute to phenotypic variation. In this dissertation, I characterize the effects of mutations and natural genetic variants that impact gene expression to better understand how mutations contribute to gene expression variation. To characterize an array of genetic variants, I used a fluorescent reporter controlled by the promoter of the Saccharomyces cerevisiae gene TDH3. I first investigate the effect of cis- and trans-regulatory mutations. Prior studies suggest that cis-acting expression quantitative trait loci may exhibit larger effect on average than trans-acting ones, yet little is known empirically regarding the difference in effect of cis- and trans-regulatory mutations. I directly compared cis-regulatory mutants to previously isolated trans-regulatory mutants and found that cis-regulatory mutations intrinsically have larger effects than trans-regulatory mutations. Next, I investigate the contribution of mutations to cis-regulatory variation in TDH3 expression. Determining the evolutionary contribution of mutation and selection among regulatory variation is challenging due to lack of functional annotation among regulatory sequences. Instead of choosing putatively non-functional sites as the neutral model, I used an empirical null distribution of functional effects of cis-regulatory mutations for comparison. The results suggest that mutation underlies TDH3 cis-regulatory variation in mean expression level while selection may have favored decreased expression noise via epistasis. Lastly, I investigate the effect of genotype-by-environment (GxE) interactions on mutations to gain further mechanistic insight into how the mutation process contributes to expression variation. I characterized cis-regulatory mutations in environments reflecting conditions in which TDH3 functions and found GxE interactions to be common. These results and their implications on the evolutionary impact of the mutation process are discussed. | en_US |
dc.language.iso | en_US | en_US |
dc.subject | Properties of Regulatory Mutations | en_US |
dc.subject | Gene Regulation | en_US |
dc.subject | Evolutionary Genetics | en_US |
dc.title | The Characteristics of Genetic Variants that Impact Gene Expression. | en_US |
dc.type | Thesis | en_US |
dc.description.thesisdegreename | PhD | en_US |
dc.description.thesisdegreediscipline | Molecular, Cellular, and Developmental Biology | en_US |
dc.description.thesisdegreegrantor | University of Michigan, Horace H. Rackham School of Graduate Studies | en_US |
dc.contributor.committeemember | Wittkopp, Trisha | en_US |
dc.contributor.committeemember | Zhang, Jianzhi | en_US |
dc.contributor.committeemember | Wierzbicki, Andrzej | en_US |
dc.contributor.committeemember | Kumar, Anuj | en_US |
dc.subject.hlbsecondlevel | Genetics | en_US |
dc.subject.hlbsecondlevel | Molecular, Cellular and Developmental Biology | en_US |
dc.subject.hlbtoplevel | Science | en_US |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/107293/1/daveyuan_1.pdf | |
dc.owningcollname | Dissertations and Theses (Ph.D. and Master's) |
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