Mitochondrial DNA mutations in single-cell ageing and health
File(s)
Author(s)
Green, Alistair
Type
Thesis
Abstract
Ageing is associated with a range of chronic diseases and has diverse hallmarks. Dysfunctional mitochondria due to pathological mitochondrial DNA (mtDNA) mutations can have catastrophic impacts on cell and tissue health, and have been implicated in ageing. These mtDNA mutations can occur at all points in an organism's life due to the constant turnover of mitochondria. We begin by observing a striking coincidence between preliminary estimates of the expected time to fixation for a post-developmental mtDNA mutation and human lifespan, which leads us to ask, is this coincidence backed up by data?
To answer this question we develop a computational pipeline for identifying mtDNA mutations from multiple single-cell sequencing data types. We use this variant calling pipeline on cells taken from early mouse embryos, and find that competition between these cells is triggered by the presence of mtDNA mutations. We then derive the analytic form of the heteroplasmy distribution of somatic mtDNA mutations using coalescent theory, and show that while the mutation rate modulates the absolute number of mutations, it is the copy number and turnover rate of mtDNA that determines how quickly mtDNA mutations can spread to the entire cell.
Finally we find somatic mtDNA mutations across single-cell datasets from multiple species and tissues, and find that our indicative coincidence between the estimated expected time to fixation and human lifespan is in fact a true coincidence backed up by data. Further, we discover that: somatic mtDNA mutations constitute the vast majority of the mutational burden of aged tissues, that these mutations avoid selection, and that their presence covaries with many of the hallmarks of ageing.
To answer this question we develop a computational pipeline for identifying mtDNA mutations from multiple single-cell sequencing data types. We use this variant calling pipeline on cells taken from early mouse embryos, and find that competition between these cells is triggered by the presence of mtDNA mutations. We then derive the analytic form of the heteroplasmy distribution of somatic mtDNA mutations using coalescent theory, and show that while the mutation rate modulates the absolute number of mutations, it is the copy number and turnover rate of mtDNA that determines how quickly mtDNA mutations can spread to the entire cell.
Finally we find somatic mtDNA mutations across single-cell datasets from multiple species and tissues, and find that our indicative coincidence between the estimated expected time to fixation and human lifespan is in fact a true coincidence backed up by data. Further, we discover that: somatic mtDNA mutations constitute the vast majority of the mutational burden of aged tissues, that these mutations avoid selection, and that their presence covaries with many of the hallmarks of ageing.
Version
Open Access
Date Issued
2022-09
Date Awarded
2023-09
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Jones, Nicholas
Publisher Department
Mathematics
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)