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Somatic evolution in healthy and chronically inflamed colon and skin


Type

Thesis

Change log

Authors

Ólafsson, Sigurgeir 

Abstract

The human body is made up of trillions of cells which cooperate to reproduce their genetic material. While all the cells are a part of a whole, each is also an individual and will selfishly give rise to a clonal expansion of cells within a tissue given the chance, even to the detriment of the organism. This thesis discusses the evolutionary forces acting on cells within the body, specifically on epithelial cells in the colon and skin. After a general introduction of the evolutionary forces acting on normal cells and the methods used to study them, Chapter 2 focuses specifically on genetic drift within the colon, where clones expand through the process of crypt fission. I apply a statistical framework called Approximate Bayesian Computation to estimate the crypt fission rate in the normal colon and in individuals with Familial adenomatous polyposis (FAP). I estimate the rate of crypt fission to be one every 27 years in the normal colon and one every 13 years in (FAP). In Chapter 3, I describe somatic evolution in the colon under conditions of chronic inflam- mation. I used whole-genome sequencing of individual colonic crypts from patients with inflammatory bowel disease (IBD) to show that the IBD-colon is characterized by a higher mutation burden and larger clonal expansions than the healthy colon. I also show that muta- tions in immune-related genes, including PIGR, ZC3H12A and genes in the interleuking 17 and toll-like receptor pathways, are under positive selection in the colons of IBD patients and may contribute to the disease pathogenesis. In Chapter 4, I focus on the skin. I performed whole-exome sequencing of microbiopsies of epidermis from patients with psoriasis, a second chronic inflammatory disease. In contrast to IBD, I did not find increased mutation burden and clonal spread in psoriasis, except when the skin had been treated with psoralens + UVA (PUVA) phototreatment. The selection landscape of psoriatic skin resembles that of normal skin, and mutations in NOTCH1, FAT1, TP53, PPM1D and NOTCH2 are positively selected. ZFP36L2 was the only gene found to be enriched in mutations that has not been previously reported in normal skin, but it is as yet uncertain if selection of ZFP36L2 mutant cells is a feature specific to psoriatic skin or not. Finally, Chapter 5 discusses my findings in the broader context of cancer and complex-trait genomics. I discuss how a causal relationship between somatic evolution and non-neoplastic diseases may be established and the different ways somatic evolution may affect disease progression for good or ill. I further discuss how to design a study to search for germline determinants of somatic evolution and the need for developing methods to enable such studies to be conducted at scale.

Description

Date

2021-09-19

Advisors

Anderson, Carl
Campbell, Peter

Keywords

Inflammatory bowel disease, Psoriasis, Somatic mutations

Qualification

Doctor of Philosophy (PhD)

Awarding Institution

University of Cambridge
Sponsorship
Wellcome Trust