Browsing by Subject "mutation"
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Item Fast neutron mutagenesis in soybean creates frameshift mutations(2021-12-01) Wyant, Skylar R; Rodriguez, Fernanda M; Carter, Corey K; Parrott, Wayne A; Jackson, Scott A; Stupar, Robert M; Morrell, Peter L; pmorrell@umn.edu; Morrell, Peter L; University of California Department of Ecology and Evolutionary Biology; University of Minnesota Department of Agronomy and Plant Genetics; University of Georgia Department of Crop and Soil SciencesThe mutagenic effects of ionizing radiation have been used for decades to create novel variants in experimental populations. Fast neutron (FN) bombardment as a mutagen has been especially widespread in plants, with extensive reports describing the induction of large structural variants, i.e., deletions, insertions, inversions, and translocations. However, the full spectrum of FN-induced mutations is poorly understood. We contrast small insertions and deletions (indels) observed in 27 soybean lines subject to FN irradiation with the standing indels identified in 107 diverse soybean lines. We use the same populations to contrast the nature and context (bases flanking a nucleotide change) of single nucleotide variants. The rate of accumulation of new single nucleotide changes in FN lines is marginally higher than expected based on spontaneous mutation. In both FN treated lines and in standing variation, C→T transitions and the corresponding reverse complement G→A transitions are the most abundant and occur most frequently in a CpG local context. These data indicate that most SNPs identified in FN lines are likely derived from spontaneous de novo processes that occurred in subsequent generations following mutagenesis, rather than from the FN irradiation mutagen. However, small indels in FN lines differ from standing variants. Short insertions, from 1 – 6 base pairs, are less abundant than in standing variation, and short deletions are more abundant and more prone to induce frameshift mutations that should disrupt the structure and function of encoded proteins. These findings indicate that FN irradiation generates numerous small indels in the genome, increasing the abundance of loss of function mutations that will impact single genes.Item Regulation of APOBEC3B catalyzed mutation in ovarian cancer(2015-08) Leonard, BrandonCancer is the second highest cause of death in the United States. A greater understanding of the underlying causes of this disease is critical to improve patient outcomes. For years, researchers have known that cancer is primarily a genetic disease, caused by mutations that can activate oncogenes and inactivate tumor suppressors. Several studies have also shown that UV radiation, smoking and certain defects in DNA repair cause some of the mutations that lead to cancer, but the sources of mutations found in many tumor types are yet to be explained. Here, we build upon our initial finding that APOBEC3B is a source of mutation in breast cancer by defining its role in ovarian cancer. Parallel analyses looking globally at mutation in cancer have shown that APOBEC3B also contributes to mutation in several other tumor types. Additional studies have elucidated a major signaling mechanism that regulates APOBEC3B expression in cancer. While many efforts have been made to directly inhibit APOBEC3B enzymatic activity, the advances described here have the potential to inform alternative therapeutic strategies aimed at transcriptionally downregulating APOBEC3B to slow tumor evolution and improve the durability of conventional anti-cancer drugs. Ultimately, a more comprehensive understanding of the basic biology of APOBEC3B catalyzed mutagenesis in cancer will translate to larger impacts in the clinical arena.