The Interplay Between DNA Replication Timing and Mutations

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Abstract

Human DNA replication begins with interspaced origins firing at different times in S-phase to ensure a timely, accurate duplication of the genome. DNA replication timing describes this spatiotemporal pattern, which is cell type-specific and highly conserved. Two aspects of replication timing are apparent; the first is that replication timing is influenced by genetically encoded factors as mutations in certain genes can alter the global and local pattern. The second aspect is that replication timing influences the mutational landscape as mutations are broadly biased toward late replication. This dissertation investigates the dual observation that the genetic landscape can both modulate and be modulated by replication timing. I first perform a genetic screen across 60 genetic diseases or gene knockouts to identify trans-acting modulators of replication timing. This reveals MCM10 as a novel candidate modulator as mutations in this gene significantly alter the replicative pattern in different ways from the established modulator RIF1. I next investigate how the mutational landscapes in five cell types are varied in their relationships to replication timing. Many mutational pathways operate with a bias toward late replicating regions, but the directionality and degree of this bias can differ for the same mutational pathways. Through mutational signature analysis, I find that the same mutational pathways vary in replication timing bias and replicative strand asymmetry between cell types and individuals. I then identify factors that partly explain this variability, the most important of which is mutation load. Mutations in samples with a greater somatic mutation load are disproportionately more abundant in late replicating regions. I then propose the effect of mutation load on late bias could be explained by mutations in the gene BCL6. In the final chapter of this dissertation, I discover and characterize mutQTLs, a novel class of cis-acting quantitative trait loci for mutation rate which I hypothesize may partially be explained by known cis-acting quantitative trait loci for replication timing. Straightforwardly, I find mutations modulate the accumulation of other mutations. Together, this dissertation illustrates the complex relationship between DNA replication timing and the genomic landscape as both influence and are influenced by the other.

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258 pages
Supplemental file(s) description: Supplemental Table 3.1, Supplemental Table 2.1.
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2022-12
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Keywords
DNA replication timing; MCM10; Mutation signatures; Mutations; RIF1; X-chromosome
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Committee Chair
Koren, Amnon
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Aquadro, Charles
Clark, Andrew
Degree Discipline
Genetics, Genomics and Development
Degree Name
Ph. D., Genetics, Genomics and Development
Degree Level
Doctor of Philosophy
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Government Document
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Attribution-NonCommercial-ShareAlike 4.0 International
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dissertation or thesis
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