INTERCONNECTED GENOMIC LANDSCAPES OF SEQUENCE VARIATION, MEIOTIC RECOMBINATION, AND GERMLINE CHROMATIN IN C. ELEGANS
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Date
2024-08-07
Authors
Bush, Zachary
Journal Title
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Publisher
University of Oregon
Abstract
Meiosis is a specialized cell division used by sexually reproducing organisms to generate haploid gametes, such as sperm and eggs. During meiosis, cells must repair DNA damage and accurately segregate parental copies of each chromosome into daughter cells. Although there is potential for new DNA mutations and chromosome rearrangements in each meiotic division, meiotic cells preferentially use high-fidelity mechanisms of DNA repair such as crossovers to ensure faithful genome inheritance. Crossovers serve critical functions in repairing DNA damage and promote accurate chromosome segregation, but they also introduce genetic diversity in progeny. In the nematode Caenorhabditis elegans, like many species, there is sex-specific regulation of crossing over, but the mechanisms that lead to sexual dimorphisms in this process remain unclear. To investigate sex-specific regulation of crossing over, I leveraged the density of genetic variation in the Bristol and Hawaiian populations of C. elegans to generate high-resolution maps of crossovers in sperm and egg cells, respectively. In Chapter 2, I completed whole-genome assembly of the Bristol and Hawaiian strains of C. elegans and comprehensively detailed their genetic variation at multiple scales and complexities. I found while many genetic variants are small, such as single nucleotide polymorphisms (SNPs) and insertion/deletions (<50bp), most of the variation between these two populations is comprised of large (>50bp) sequence gains, losses, and rearrangements. Further, I demonstrate the role of specific chromosome structures in influencing where SNPs, indels, and rearrangements accumulate in the genome. In Chapter 3, I defined genomic variations between different laboratory lineages of the Bristol and Hawaiian strains to demonstrate the degree of genetic drift and genomic structural variations accumulating in laboratory model organisms. In chapter 4, I developed a method that leverages the SNPs identified in Chapter 2 to map crossovers with sub-kilobase precision C. elegans sperm and eggs, respectively. I found that the crossover distribution and rate is sexually dimorphic, as well as demonstrating that the chromosomal structures associated with different states of germline gene expression are differentially associated with crossing over in developing eggs versus sperm. By determining the genomic features associated with crossover sites in each sex, I have illuminated the potential mechanisms that lead to sexually dimorphic distributions of crossing over. Taken together, the work in this dissertation fills critical gaps in our knowledge of how specific chromosome structures influence mechanisms that promote genomic integrity for inheritance by the next generation. This dissertation includes previously unpublished co-authored material.
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Keywords
C. elegans, Chromatin, Genomics, Meiosis, Recombination, Variation