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Thesis Format



Master of Science




Hill, Kathleen A.


The impact of heterozygosity as an intrinsic mutagen in mammals is unknown. In plant models, existent heterozygosity increases the local de novo meiotic mutation rate. Mice offer study of this phenomenon given well-established genomic technologies and strains with known, diverse genomic landscapes of heterozygosity. High resolution genotyping arrays assay heterozygous single-nucleotide polymorphic (SNP) loci and copy number variants (CNVs). Using a J statistic for spatial analysis, 60.9% of autosomes from 707 publicly available array samples have nonrandom spatial associations between heterozygous SNP loci and CNVs. By crossing C57BL/6J inbred mice to DBA/2J inbred mice, heterozygous SNP loci and de novo CNVs were analyzed. Of 43 de novo CNVs in F2 mice compared to both F1 and F2 heterozygous SNP landscapes, 33 and 7 were found to co-localize with heterozygous SNP loci, respectively. Heterozygosity may be an overlooked meiosis-linked contributor to CNV mutagenesis, affecting models of disease risk prediction and evolution.

Summary for Lay Audience

Understanding the factors that contribute to the rate, type, and distribution of DNA mutations across the genome is paramount to fully comprehending diversity in the form and function of an organism, development of genetic disorders, and the process of evolution. Heterozygosity – the condition of having two different nucleotide sequences at the same location between parental chromosomes – has been shown to exist nearby new and elevated levels of mutations arising during development of germ cells in plants. However, this relationship is yet to be demonstrated in mammals. Mice are ideal to study this due to the availability of strains with known diverse landscapes of heterozygosity. Single-nucleotide polymorphic (SNP) loci are sites within a genome that have variable nucleotide content between individuals in at least 1\% of the population and therefore may be sampled for heterozygosity. Copy number variants (CNVs) are a type of mutation characterized as large DNA duplications or deletions. Microarrays designed to target hundreds of thousands of sites across the genome are used to detect SNP heterozygosity and CNVs. I contributed to development of a spatial statistical analysis pipeline to determine whether heterozygous SNP loci and CNVs are nearby, far apart, or randomly distributed for 707 publicly available samples. I found that in 3,533 of 5,799 chromosomes with CNVs, heterozygous SNP loci and CNVs are nonrandomly distributed with respect to one another. I also generated six three-generation lineages of mice, crossing two different low heterozygosity inbred strains to produce F1 mice with an average of 20% SNP heterozygosity. Brother-sister mating of F1 mice produced F2 mice with an average of 10% SNP heterozygosity. Microarray analysis followed by application of the analytical pipeline showed that 1,024 of 1,338 chromosomes with CNVs had a nonrandom spatial relationship between heterozygous SNP loci and CNVs. I identified 43 CNVs in F2 mice that were not inherited from their parents. Interestingly, 33 of the non-inherited CNVs were nearby the heterozygous SNP loci found in their F1 parents. These findings indicate that heterozygosity may contribute to the formation of CNVs, therefore demanding reassessment of predictions of disease risk and evolutionary change.

Creative Commons License

Creative Commons Attribution-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-No Derivative Works 4.0 License.