Statistical analysis of short template switch mutations in human genomes
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Authors
Walker, Conor
Date
2021-10-01Awarding Institution
University of Cambridge
Qualification
Doctor of Philosophy (PhD)
Type
Thesis
Metadata
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Walker, C. (2021). Statistical analysis of short template switch mutations in human genomes (Doctoral thesis). https://doi.org/10.17863/CAM.81659
Abstract
Many complex rearrangements arise in human genomes through template switch mutations, which occur during DNA replication when there is a transient polymerase switch to an alternate template nearby in three-dimensional space. These variants are routinely captured at kilobase-to-megabase scales in studies of genetic variation by using methods for structural variant calling. However, the genomic and evolutionary consequences of replication-based rearrangements remain poorly characterised at smaller scales, where they are usually interpreted as complex clusters of independent substitutions, insertions and deletions. In this thesis, I describe statistical methods for the detection and interpretation of short template switch mutations within DNA sequence data. I then use my methods to explore small-scale template switch mutagenesis within human genome evolution, population variation, and cancer. I show that small-scale, replication- based rearrangements are a ubiquitous feature of the germline and somatic mutational landscape of human genomes.
Keywords
human genetic variation, hominid evolution, statistical alignment, pair hidden Markov models, DNA replication, template switching
Sponsorship
European Molecular Biology Laboratory
National Institute for Health Research
Identifiers
This record's DOI: https://doi.org/10.17863/CAM.81659
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