Novel techniques for measuring the effect of neighbouring bases on mutation and their applications
type: CreativeWork
description: Understanding factors influencing mutations can improve detection of novel mutations, the diagnostic signatures of disease-causing mutagens, and facilitate the development of more accurate models of genetic divergence. Hypermutability of CpG demonstrates the existence of mutation motifs, sequences of flanking bases that influence point mutation processes. These motifs can also be indicative of specific underlying mutation mechanisms. I developed novel log-linear models for identifying mutation motifs that allow further comparisons of these mutation motifs, and of the complete mutation spectra between samples. Mutation motifs are visualised using a sequence logo type method. In this thesis, I applied the methods to examine each of the possible 12 point mutations in about 13.6 million human germline mutations (inferred from single-nucleotide polymorphisms recorded in the Ensembl database) and about 181,000 melanoma mutations from the COSMIC database. My method recovered the well-known CpG effect, which a conventional motif detection method failed to do. I established that all point mutations have significant and distinct mutation motifs. While the major effects of flanking bases lie within 2 bp of the mutated position, I refute previous reports that the effect magnitude decays monotonically with distance. Comparison between autosomes and X-chromosomes supported a reduced contribution from methylation-induced C to T mutation on the X-chromosome, consistent with a previous prediction. In addition, analyses of malignant melanoma confirmed reported characteristic features of this cancer, such as strand asymmetry of mutation processes. Further, I found that neighbouring influences in malignant melanoma differ significantly from those affecting germline mutations. Interestingly, for C to T mutation, the CpG effect was no longer evident, and was largely substituted by different neighbouring mechanisms. Moreover, the observed neighbouring influence is able to reflect the chem…
abstract: Understanding factors influencing mutations can improve detection of novel mutations, the diagnostic signatures of disease-causing mutagens, and facilitate the development of more accurate models of genetic divergence. Hypermutability of CpG demonstrates the existence of mutation motifs, sequences of flanking bases that influence point mutation processes. These motifs can also be indicative of specific underlying mutation mechanisms. I developed novel log-linear models for identifying mutation motifs that allow further comparisons of these mutation motifs, and of the complete mutation spectra between samples. Mutation motifs are visualised using a sequence logo type method. In this thesis, I applied the methods to examine each of the possible 12 point mutations in about 13.6 million human germline mutations (inferred from single-nucleotide polymorphisms recorded in the Ensembl database) and about 181,000 melanoma mutations from the COSMIC database. My method recovered the well-known CpG effect, which a conventional motif detection method failed to do. I established that all point mutations have significant and distinct mutation motifs. While the major effects of flanking bases lie within 2 bp of the mutated position, I refute previous reports that the effect magnitude decays monotonically with distance. Comparison between autosomes and X-chromosomes supported a reduced contribution from methylation-induced C to T mutation on the X-chromosome, consistent with a previous prediction. In addition, analyses of malignant melanoma confirmed reported characteristic features of this cancer, such as strand asymmetry of mutation processes. Further, I found that neighbouring influences in malignant melanoma differ significantly from those affecting germline mutations. Interestingly, for C to T mutation, the CpG effect was no longer evident, and was largely substituted by different neighbouring mechanisms. Moreover, the observed neighbouring influence is able to reflect the chem…
author: Zhu, Yicheng
language: en_AU
date published: 2020
date modified: 2026-07-24T00:54:33Z
provider: Australian National University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Australian National University

PropertyValue
property ID: Handle
value: http://hdl.handle.net/1885/201728