Somatic phylogenies: a window into human biology in health and disease

All somatic cells in the human body originate from the fertilised egg, or ‘zygote’. Co-ordinated processes of cell division and differentiation result in the incredible complexity observed following development. Thereafter, each tissue must maintain its function for the decades of life that follow, while minimising risks such as cancer. Crucial to understanding the strategies employed to meet these demands is knowing what cell gives rise to what i.e. the structure of the somatic lineage tree. For this purpose, it is fortuitous that most cell divisions result in the acquisition of somatic mutations that are passed on to all of its future progeny. Therefore theoretically, if all somatic mutations in each cell of an organism were known, the organism’s full somatic lineage tree could be determined. While this is not yet possible at the scale of an entire organism, advances in clonal expansion and whole-genome sequencing technologies have facilitated such experiments on the scale of hundreds of cells in a single individual. This thesis contains three results chapters, each utilising somatic phylogenies in different ways. The first looks at early human development. Due to the small number of cells in early development, a near complete phylogeny can be determined. Assessing contributions of early lineages to different tissues is used to determine the developmental relationships and origins of tissues. The second looks at the clinically important context of gene therapy for sickle cell disease. Comparisons of somatic phylogenies from before and after the gene therapy procedure gives insights into the biology of sickle cell disease and the safety of gene therapy in this context. Finally, the third chapter looks at somatic phylogenies from a different perspective: as a way of testing our assumptions regarding mechanisms of mutation acquisition. The observation that some mutations do not fit these assumptions leads to the surprising conclusion that some mutation-causing DNA lesions persist unrepaired for months to years. Overall, this thesis demonstrates the power of interrogating somatic phylogenies to answer important questions in diverse biological disciplines. As technological advances allow such experiments on ever larger scales, the power of this approach will only increase.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2022

Author dc:creator

• Spencer Chapman, Michael

Advisors dc:contributor.advisor

• Campbell, Peter
• Green, Anthony

• Somatic mutation
• Mutagenesis
• Lineage tracing
• Human development
• Gene therapy
• Sickle cell disease
• Somatic phylogeny
• DNA lesions

Licence

• https://creativecommons.org/licenses/by-nd/4.0/

Language dc:language

eng

Author Identifier

0000-0002-5320-8193

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/345992