Date of Award
Program or Major
Doctor of Philosophy
W Kelley Thomas
Mutations are the initial force responsible for all aspects of genetic variation, and are a central part to evolution in all organisms. Yet despite its importance, the previously high cost that is associated with surveying mutations at a genome-wide scale has limited the understanding of the mutation process in eukaryotes. However, recent high-throughput sequencing technology has greatly reduced the cost of surveying mutations. By applying high-throughput sequencing to mutation accumulation experiments, we have begun to characterize the genome-wide mutation spectrum of eukaryotes.
Across all eukaryotes, we observe a biased rate of G/C-> A/T mutations that exceeds the number of A/T->G/C mutations. This finding is consistent with spontaneous deamination of cytosine or methylated cytosine. Alternate forces such as selection or G/C biased gene conversion must be driving eukaryotic genomes toward a higher G/C composition than expected from mutation bias.
In Paramecium tetraurelia, we observe a nuclear mutation rate ∼75 fold lower than previously expected. When the base substitution rate per generation is extrapolated to the rate per expressed sexual cycle, it is equivalent to that observed in multicellular species with comparable genome sizes. This suggests that natural selection operates at germline expression, and favors a minimum rate that opposes random genetic drift.
Using a natural population of Daphnia pulex we catalogue simple sequence repeats (SSR) and determine average heterozygosity of each SSR type. We find that SSR heterozygosity is motif specific, and positively correlated with repeat number as well as motif length. We identify a motif-dependent end-nucleotide polymorphism bias. Our observations also confirm the high frequency of multiple unit variation at large microsatellite loci.
We observe that structural variants in C. elegans and S. cerevisiae, which are ∼1000 fold larger than base substitution rates on a per nucleotide basis, occur on the same order of magnitude as base substitutions. The rate and direction of structural gains and losses differ between yeast and C. elegans, and we hypothesize that the rate of structural variants corresponds with the coding portion of the genome. We also confirm a high rate of gene inversion and gene loss in the life history of C. elegans.
Sung, Way, "Study of the rate and spectrum of spontaneous mutations" (2011). Doctoral Dissertations. 629.