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.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-03242017-124753 |
| Date | 04 April 2017 |
| Creators | Simonti, Corinne Nicole |
| Contributors | John A. Capra, Doug Mortlock, Will Bush, David Samuels, Josh Denny |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-03242017-124753/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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