Statistical analysis of short template switch mutations in human genomes

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.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2021

Author dc:creator

• Walker, Conor

Advisors dc:contributor.advisor

• Goldman, Nick
• Scally, Aylwyn

• human genetic variation
• hominid evolution
• statistical alignment
• pair hidden Markov models
• DNA replication
• template switching

Licence

• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

Author Identifier

0000-0002-0807-1167

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/334246