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SYSTEMATIC ANALYSIS OF SINGLE NUCLEOTIDE
POLYMORPHISMS IN THE HUMAN STEROID 5-ALPHA REDUCTASE
TYPE I GENE
by
Troy Phipps
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(BIOCHEMISTRY AND MOLECULAR BIOLOGY)
December 2006
Copyright 2006 Troy Phipps
Object Description
| Title | Systematic analysis of single nucleotide polymorphisms in the human steroid 5-alpha reductase type I gene |
| Author | Phipps, Troy |
| Author email | tphipps@usc.edu |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Biochemistry & Molecular Biology |
| School | Keck School of Medicine |
| Date defended/completed | 2006-10-18 |
| Date submitted | 2006 |
| Restricted until | Unrestricted |
| Date published | 2006-10-31 |
| Advisor (committee chair) | Frenkel, Baruch |
| Advisor (committee member) |
Coetzee, Gerry Stellwagen, Robert |
| Abstract | The human steroid 5-alpha reductase type I (SRD5A1) gene was sequenced in 101 men to identify genetic variants that may predispose/protect carriers to prostate cancer. We uncovered 30 single nucleotide polymorphisms (SNPs) along the gene length, with 7 polymorphic sites lying in the 3'-untranslated region (3'UTR). All SNPs were silent, but one 3'UTR SNP (named '1368T') was significantly over represented two fold in African-American men, possibly making this a useful admixture mapping marker. To further pursue the relevance of the SNPs in the 3'-UTR of this gene, we used cell culture assays to test for the potential effects at the RNA or protein level. Individual and different combinations of SRD5A1 3'-UTR SNPs (named "RNA haplotypes") had no effect on luciferase activity when cloned onto the 3' end of the luciferase cDNA. Moreover, steady state mRNA levels did not change when expressed either from luciferase or 'native' expression constructs containing the native SRD5A1 promoter, cDNA, 3'UTR, and a heterologous intron. Thus SRD5A1 3'UTR SNPs were truly neutral and non-functional in vitro, and are therefore unlikely to play a significant role in prostate cancer predisposition in vivo. If functional germline SRD5A1 3'UTR SNPs existed that altered reproductive fecundity, they were likely selected against by evolution, and may explain why only neutral SNPs were observed in three modern human populations. |
| Keyword | SRD5A1; haplotypes; prostate cancer; single nucleotide polymorphisms |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Type | texts |
| Legacy record ID | usctheses-m119 |
| Rights | Phipps, Troy |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | http://www.usc.edu/isd/libraries/services/ask_a_librarian/email/ |
| Filename | etd-Phipps-20061031 |
| Archival file | uscthesesreloadpub_Volume35/etd-Phipps-20061031.pdf |
Description
| Title | Page 1 |
| Full text | SYSTEMATIC ANALYSIS OF SINGLE NUCLEOTIDE POLYMORPHISMS IN THE HUMAN STEROID 5-ALPHA REDUCTASE TYPE I GENE by Troy Phipps A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (BIOCHEMISTRY AND MOLECULAR BIOLOGY) December 2006 Copyright 2006 Troy Phipps |
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