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- W4382022295 abstract "Abstract Progressive dysfunction of mitochondria, organelles responsible for energy provision to cells, is a major hallmark of ageing. How the dysfunction steadily accrues over a lifetime remains unclear, given the transient nature of free radical damage and the high turnover of mitochondria. Here, we leveraged whole-genome sequencing data from single-cell derived foetal and adult haematopoietic stem/progenitor cell colonies to study the clonal dynamics of turnover and selection in mitochondrial genomes throughout life. We found that genetic drift and independent convergence of mitochondrial mutations complicate their use as lineage marks in single-cell sequencing experiments. Point mutations accrued linearly with age at an average rate of 0.007 mutations/genome/year. Using the distribution of mtDNA allele frequencies with age, we infer that a cell’s complement of mitochondrial genomes is replicated every 4-19 weeks in adults, with faster turnover rates during foetal development. Clock-like accumulation of mutations coupled with rapid turnover induces complex evolutionary dynamics in mitochondria as individuals age. Nonsense mutations are disadvantageous regardless of their heteroplasmy level. Missense variants, however, are positively selected at low heteroplasmy but negatively selected at high heteroplasmy, suggesting that some mutations improve fitness of individual mitochondria, even though fitness of the whole cell deteriorates if their expansion proceeds too far. Thus, age-related decline in mitochondrial function can arise from preferential cellular accumulation of selfish mitochondrial clones whose superior fitness ultimately disadvantages the host cell." @default.
- W4382022295 created "2023-06-27" @default.
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- W4382022295 date "2023-06-26" @default.
- W4382022295 modified "2023-10-12" @default.
- W4382022295 title "Mitochondrial mutation, drift and selection during human development and ageing" @default.
- W4382022295 doi "https://doi.org/10.21203/rs.3.rs-3083262/v1" @default.
- W4382022295 hasPublicationYear "2023" @default.
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