Nick Jones

The advent of single cell data allows us to not only identify distinct cell types but also identify mutations which are invisible in bulk. Through a combination of theory, inference and informatics we show that mtDNA mutations that are unique to individual cells accumulate to high levels by late/mid-life across several species. Cells with these mutations show a gene-expression signature compatible with ageing. We find, through experiments with a variety of sequencing techniques, that similar effects occur in T-cells, with suggestions that levels of mutations, beyond predicting age like a cellular clock, are linked to frailty and mortality. A wide range of cell types appear to have similar amounts of mutation by late life, pointing to physiological relevance. Coupling to subcellular microscopy we provide the first characterization of the dynamics of control of mtDNA in non-replicative cells with evidence that the observed number of mtDNA is a poor read-out of the true genetic number of mtDNA: hinting at new routes to control cellular mtDNA mutation levels. Finally, if time permits, I will discuss how higher carrying capacity, while giving no selective advantage in deterministic genetic models could account for how some mtDNA species can spread through cells even when subject to active negative selection.