A comprehensive survey of somatic mutation landscapes in normal human cells

Somatic mutations play an important role in cancer development and may contribute to the ageing process. These genetic alterations can be driven by endogenous factors such as errors during DNA replication, defects in DNA repair mechanisms, and oxidative damage, or by exogenous mutagens such as ultraviolet radiation, tobacco smoke, and alcohol. The accumulation of somatic mutations over a lifetime involves multiple mutational processes, each with distinct mutation patterns, known as mutational signatures. Recent studies have shown that the somatic mutation burden varies between cell types, tissues, organs and individuals. However, due to technical limitations, the number of cell types or tissue structures studied has previously been limited; thus, the cause of the variation remains to be uncovered. This thesis investigates the mutational catalogues of 733 sequences from 48 tissue structures of 129 donors aged 9-91 years. Using the highly accurate RE-NanoSeq method, which is based on duplex sequencing of single DNA molecules with < 5x10e-9 errors per base pair, I can detect somatic mutations in any tissue, regardless of their clonality. Mutation rates vary within and across tissue types, with the lowest in the seminiferous tubules and the highest in liver hepatocytes. Interestingly, post-mitotic cells such as the heart, cerebellum, skeletal muscle, and adipose tissue accumulate somatic mutations at a rate similar to that of their actively dividing counterparts. Additionally, epithelial cells exhibit different mutation accumulation rates depending on their tissue location, including colonic crypts, the oesophagus, and the kidney. I also observe a complex landscape of mutational signatures and their attribution across a broad range of tissue structures. Clock-like signatures encompassing SBS1 and SBS5 or ID1 and ID2 are present to varying degrees across all tissue structures. While some mutational signatures, such as SBS4, SBS7, or SBS88, are associated with unique aetiologies, many signatures have unknown causes. Furthermore, two previously undiscovered mutational signatures, SBSLiver and SBS4-like, are identified and described in this study.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2025

Author dc:creator

• Pham, My

Advisors dc:contributor.advisor

• Rahbari, Raheleh
• Stratton, Michael

• Mutation burden
• Mutation rate
• Mutational signatures
• Normal cells
• Somatic mutation

Licence

• https://www.repository.cam.ac.uk/bitstreams/a0c61484-ae09-4acb-b62d-99364f532f19/download
• https://creativecommons.org/licenses/by-nc-nd/4.0/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.124977

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/395494