Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article


Master of Science




Hill, Kathleen A

2nd Supervisor

Turley, Eva



Characterization of genetic variation underlying complex phenotypes is incomplete yet critical to understanding mutational mechanisms and phenotypes. Heterozygote Instability (HI) is a new, poorly understood source of mutations needing models for mechanistic study. Two models ideal for characterizing HI-associated mutational mechanisms are outbred mice and mouse basal cell carcinoma (BCC). Both have discontinuous landscapes of heterozygosity essential to assess HI-induced mutations. Here, heterozygosity and copy number variants (CNVs) in two outbred mouse stocks are characterized with 1690, and 3935 autosomal CNVs detected. A positive correlation exists between chromosomal heterozygosity and CNV occurrence (R2 = 0.14 and 0.09), and 41 and 22% of CNVs co-localized with heterozygosity. Genetic variation in human BCC is documented to target characterization in mouse BCC toward filling an identified knowledge gap. An outbred BCC mouse model permits HI hypothesis testing in contexts of meiosis, mitosis, replication, and recombination in gametes, stem cells, and cancer cells.

Summary for Lay Audience

Mouse models are helpful to study complicated or elusive human genetic phenomena. DNA sequence differences are referred to as genetic variants and include differences in single bases and deletions or duplications of larger regions of sequences, called copy number variants (CNV). Genetic variants contribute to diseases and complex traits that have both genetic and environmental factors. Typically the chromosomes inherited from each parent are not identical, with the inheritance of single-base differences at the same location, referred to as heterozygosity. Recent research discovered that localized regions of heterozygosity increased mutations in plants. However, this phenomenon, known as Heterozygote Instability (HI), has yet to be investigated in mammals. This thesis explores HI in two mouse models of high heterozygosity by analyzing inherited variation in outbred mice and acquired variation in mouse models of skin cancer, basal cell carcinoma (BCC). Researchers have bred outbred mice to mimic the high genetic diversity found among humans. However, the genetic variants in their DNA are less characterized than the currently favoured laboratory inbred mouse, precluding exploration of mechanisms of mutation associated with heterozygosity. In the outbred mouse stocks, heterozygosity and CNVs must be characterized to study their co-localization and assess if regional variation in heterozygosity is associated with CNVs. This thesis characterized heterozygosity and CNVs in two stocks of outbred mice and detected CNVs associated with regional variation in heterozygosity. Additionally, the high heterozygosity in human skin and human BCC permits the study of mutagenesis in the context of HI. A systematic review of studies researching mutations in human tumors and BCC mouse models highlighted the striking lack of mutations characterized in mouse models of BCC. This disparity limits understanding of BCC mouse models, their traits and their applicability to study HI and complex traits. Experimental designs were presented to assess and detect the extent of genetic variants to determine whether mouse models are good mimics of human BCC. These mouse models of high genetic variation offer a means to elucidate the mechanisms of mutation that contribute to an elusive and complicated form of genomic instability, HI, relevant to complex human traits, including cancer formation.