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Statistical analysis of short template switch mutations in human genomes 10.17863/CAM.81659 Walker, Conor Goldman, Nick Scally, Aylwyn 0000000208071167 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. University of Cambridge 2021-10-01 Thesis Doctoral Doctor of Philosophy (PhD) eng European Molecular Biology Laboratory National Institute for Health Research https://www.repository.cam.ac.uk/handle/1810/334246 https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/10e30960-1a33-4916-b787-f4cf73c2888d/download b8a7ea87c9c4c1534694886310aa9e74 https://www.rioxx.net/licenses/all-rights-reserved/ human genetic variation hominid evolution statistical alignment pair hidden Markov models DNA replication template switching