Master of Science
Hill, Kathleen A.
Comparing genetic variation between populations can provide insight into selective pressures in the environment. The Mouse Diversity Genotyping Array (MDGA) is a low-cost, high-throughput tool developed to capture and analyze variation at single nucleotide polymorphic (SNP) loci in inbred mouse strains. However, its ability to assess genetic variation in non-inbred mice and associate SNPs with the environment has not been extensively studied. First, SNPs between laboratory inbred and wild-caught mice were compared. No SNPs were associated with either macroenvironment. Instead, SNPs reflected genealogy and inbreeding strategies, consistent with the MDGA’s intended use. Second, mutations at SNP loci were compared between a mouse model of breast cancer metastasis with and without Receptor for Hyaluronan-Mediated Motility (RHAMM). Genetic homogeneity observed in the lung microenvironment without RHAMM is consistent with strong purifying selection. In conclusion, the MDGA is effective for associating SNPs with the environment only when selective pressures exceed genetic background effects.
Summary for Lay Audience
Genetic variation exists within and between populations and can be informative in identifying associations with genetic background, mutagenesis, population dynamics, selection, and their complex interactions. Single nucleotide polymorphisms (SNPs) are a source of genetic variation that is abundant in many organisms. The Mouse Diversity Genotyping Array (MDGA) is a powerful tool designed to detect SNPs at hundreds of thousands of loci to distinguish mice from different genetic backgrounds. This thesis uses the MDGA in a dual case-study approach to compare SNP variation between populations from different environments and associate SNPs with the environment, a step away from its intended use. In the first case study, I compare SNPs between mice bred and reared in the laboratory environment to natural populations in wild environments. Using the MDGA to assess genetic variation at 330,298 functional SNP loci, I find that SNPs are reflective of mouse genealogy and inbreeding strategies, as expected with the MDGA’s intended purpose. I did not identify any SNPs associated with the laboratory or wild environment. In the second case study, I compare mutations at 220,615 SNP loci in the context of cancer, before and after the direct manipulation of Receptor for Hyaluronan-Mediated Motility (RHAMM) whose presence or absence regulates the cellular environment. I observe genetic homogeneity when RHAMM is absent in the cellular environment, as opposed to genetic heterogeneity in the presence of RHAMM. I find no difference in the mutational mechanisms between environments with and without RHAMM. I speculate that the absence of RHAMM alters the selective pressures in the environment, giving rise to the genetic homogeneity observed. I conclude that genetic variation at SNP loci, assessed by the MDGA, can be used to associate genetic variation with the environment, but only when selective pressures in the environment exceeds the influence of genetic background.
Qi, Freda, "Mouse Genotyping Array-Based Analysis of Variation at Single Nucleotide Polymorphic Loci in the Context of Macro- and Micro-environments" (2023). Electronic Thesis and Dissertation Repository. 9252.