The relationship between somatic structural alteration of the genome and healthy ageing
Lead Research Organisation:
Queen Mary University of London
Department Name: Barts Cancer Institute
Abstract
It is increasingly clear that somatic mutations accrue steadily in ageing tissues. However, precisely how this relates to healthy ageing is unknown, and the molecular and cellular mechanisms that cause somatic mutation in otherwise healthy tissue remain poorly defined. Here, we propose to investigate the accrual of structural alterations (SAs) in ageing human colon. We will determine the spectrum of SA that is consistent with healthy ageing (e.g. the SAs that can accrue without leading to a pathology), and profile the size, type and rate of SA accrual to reveal the underlying molecular and cellular mechanisms that underpin 'healthy' human somatic mutagenesis.
Publications
Baker AM
(2019)
Crypt fusion as a homeostatic mechanism in the human colon.
in Gut
Gabbutt C
(2021)
Evolution's cartographer: Mapping the fitness landscape in cancer.
in Cancer cell
Gabbutt C
(2022)
Fluctuating methylation clocks for cell lineage tracing at high temporal resolution in human tissues.
in Nature biotechnology
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| BB/M009513/1 | 01/10/2015 | 31/03/2024 | |||
| 1902605 | Studentship | BB/M009513/1 | 01/10/2017 | 30/12/2021 | Calum Gabbutt |
| Description | A number of findings associated with the dynamic behaviour of human epithelium have been made in the course of this award. These include publishing a paper describing the existence of a new homeostatic mechanism within the human gut, termed crypt fusion (in which two neighbouring crypts fuse together into a single daughter crypt), and exploring the effect that the existence of this process has upon previous estimates of the crypt fission rate. Furthermore, we have published a method to probe the stem cell dynamics (that is, how many stem cells lie at the base of the gland and how often, on average, these stem cells replace each other) of colonic crypts and other glandular tissue using naturally occurring methylation errors. This method utilises relatively inexpensive methylation arrays and is broadly applicable to glandular tissue, allowing for measurement of the otherwise elusive contemporary dynamics of normal tissue. Applying this tool to colon and small intestinal tissue has revealed that small intestinal glands have slightly more stem cells per crypt which replace each other less frequently than colonic crypts, however these differences are small and therefore unlikely to explain the discrepancy in cancer incidence rates between the two tissues. |
| Exploitation Route | The existence of crypt fusion within the human colon refines our understanding of homeostasis of the gut, and potentially provides an additional axis upon which selection of mutant phenotypes can occur. Future studies are required to investigate whether fusion is a random process or whether regulatory mechanisms are present. Further, we have published an open-source method to infer clonal dynamics from methylation array data, which may be employed by the wider community. |
| Sectors | Healthcare,Pharmaceuticals and Medical Biotechnology |
| Title | Methylation clocks - individual colon, small intestine and endometrial crypts |
| Description | Illumina EPIC methylation arrays from individual glands, including 31 normal colon crypts, 28 small intestine crypts, 12 (A)FAP colon crypts and 32 endometrial glands. |
| Type Of Material | Database/Collection of data |
| Year Produced | 2022 |
| Provided To Others? | Yes |
| Impact | Publication of our 2022 Nature Biotechnology paper https://doi.org/10.1038/s41587-021-01109-w |
| URL | https://ega-archive.org/studies/EGAS00001005514 |
| Description | Quantitative measurement of clonal evolution in human colon |
| Organisation | University of Southern California |
| Country | United States |
| Sector | Academic/University |
| PI Contribution | We developed a mathematical model to describe the impact of the stem cell dynamics of normal colon epithelial stem cells to the distribution of methylation patterns within a crypt. Further, we developed a Bayesian inference tool to infer the parameters controlling the stem cell replacement process. |
| Collaborator Contribution | Our collaborator at USC provided us with data derived from Illumina EPIC methylation arrays of individual colon and small intestinal crypts from 15 patients. Along with this, our collaborator provided expert pathological insight into the likely stem cell dynamics of glandular tissue and the use of methylation as lineage tracing marker. |
| Impact | The preliminary results of this work have been presented to academic conferences, and a paper is currently being written with a view to publish before the end of the year. |
| Start Year | 2019 |
| Description | St Mark's hospital collaboration |
| Organisation | St Mark's Academic Institute |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | I I have had a long standing collaboration with a number of clinical academics at St Mark's hospital, working on predicting cancer development risk in inflammatory bowel disease (with Prof. Ailsa Hart), predicting sporadic colorectal cancer risk (with Dr. Adam Humphries) and understanding adenoma formation in the small intestine in patients with familial predisposition to cancer (with Dr Andrew Latchford). Our laboratory leads the molecular and epidemiological work associated with these three research projects. |
| Collaborator Contribution | St Mark's have provided clinical material, trainee clinical fellows and funding via charitable donations to the St Mark's Institute, to support the projects described above. St Mark's made me an honorary senior scientist in 2016. |
| Impact | The collaboration with St Mark's was particularly instrumental to securing the Barts Charity award "Derivation of biomarkers for cancer risk prediction in Ulcerative Colitis". The multiple publications arising from this collaboration are reported elsewhere. The collaboration is multidisciplinary, involved epidemiological work, molecular biology, histopathology, and translational biomarker research. |
| Start Year | 2013 |
| Title | flipflop |
| Description | The software allowed for inference of the clonal dynamics of individual clonal units (e.g. colon crypts or endometrial glands) from Illumina EPIC methylation arrays. The package also includes the selection of appropriate CpG loci to perform inference upon. |
| Type Of Technology | New/Improved Technique/Technology |
| Year Produced | 2021 |
| Open Source License? | Yes |
| Impact | We employed the developed software to infer that small intestinal crypts contain marginally more stem cells that replace each other less frequently than colon crypts. Furthermore, endometrial glands have a greater intra-individual heterogeneity in the number of stem cells than colon/small intestine. These results are detailed in https://doi.org/10.1038/s41587-021-01109-w |
| URL | https://github.com/CalumGabbutt/flipflop |