Date on Master's Thesis/Doctoral Dissertation

8-2014

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Biochemistry and Molecular Biology

Committee Chair

Samuelson, David J.

Committee Co-Chair (if applicable)

Shull, James

Committee Member

Shull, James

Committee Member

Klinge, Carolyn

Committee Member

Gregg, Ronald

Committee Member

Kalbfleisch, Ted

Subject

Breast--Cancer--Genetic aspects

Abstract

Breast cancer is a complex disease, which is influenced by genetic, epigenetic and environmental components. Genetic susceptibility to breast cancer is made up of high, moderate and low penetrance alleles. High and moderate penetrance alleles are rare and constitute only a small percentage of the genetic susceptibility. Most variation in genetic susceptibility is controlled by low- penetrance, common polymorphisms. Comparative genetics uses model organisms to study human disease. Rat strains exhibit different susceptibility phenotypes to chemical induced carcinogenesis. The Wistar-Furth (WF) rat strain is susceptible to chemically induced mammary carcinogenesis, while the Wistar-Kyoto (WKy) and Copenhagen (COP) rat strains are resistant. Selective breeding and linkage analyses of these rat strains after treatment with 7,12-dimethylbenz[a]anthracene (DMBA) have been used to identify eight rat mammary cancer quantitative trait loci (QTLs) in the rat. This dissertation focuses on two of these QTLs, mammary carcinoma susceptibility loci 1b and 6 (Mcs1b and Mcs6). Mcs6 has been identified and physically confirmed using WF.WKy congenic animals and maps to a 33Mb region. This locus will have to be mapped to a narrower interval in order for functional studies to be practical. I was able to map the Mcs6 locus to a region of 8.5Mb on rat chromosome 7. The Mcs1b locus maps to a region of 1.8Mb on rat chromosome 2. Mcs1b contains the rat orthologous region to a breast cancer risk associated region marked by SNP rs889312. This makes the Mcs1b congenic rat an ideal model for studying the mechanism of rs889312. The goal of my project is to identify all Mcs1b sequence variants between the two rat strains and test for gene regulatory functions. I was able to identify 70 SNPs and 2 INDELs using next- generation sequencing. Three rat SNPs have gene regulatory function differences between the two rat alleles. Out of the seven human SNPs that tag SNP rs889312, four exhibit gene regulatory differences between the major and minor alleles, and therefore, may be functional orthologs to the rat Mcs1b candidate SNPs. Overall, I was able to fine map the Mcs6 region and identify several candidate rat and human Mcs1b/ MCS1B SNPs.

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