TY - JOUR TI - Contingency and selection in mitochondrial genome dynamics AU - Nunn, Christopher J AU - Goyal, Sidhartha A2 - Verstrepen, Kevin J A2 - Barkai, Naama A2 - Verstrepen, Kevin J A2 - Khrapko, Konstantin VL - 11 PY - 2022 DA - 2022/04/11 SP - e76557 C1 - eLife 2022;11:e76557 DO - 10.7554/eLife.76557 UR - https://doi.org/10.7554/eLife.76557 AB - High frequencies of mutant mitochondrial DNA (mtDNA) in human cells lead to cellular defects that are associated with aging and disease. Yet much remains to be understood about the dynamics of the generation of mutant mtDNAs and their relative replicative fitness that informs their fate within cells and tissues. To address this, we utilize long-read single-molecule sequencing to track mutational trajectories of mtDNA in the model organism Saccharomyces cerevisiae. This model has numerous advantages over mammalian systems due to its much larger mtDNA and ease of artificially competing mutant and wild-type mtDNA copies in cells. We show a previously unseen pattern that constrains subsequent excision events in mtDNA fragmentation in yeast. We also provide evidence for the generation of rare and contentious non-periodic mtDNA structures that lead to persistent diversity within individual cells. Finally, we show that measurements of relative fitness of mtDNA fit a phenomenological model that highlights important biophysical parameters governing mtDNA fitness. Altogether, our study provides techniques and insights into the dynamics of large structural changes in genomes that we show are applicable to more complex organisms like humans. KW - multilevel selection KW - mutational trajectories KW - long-read sequencing KW - genome structure dynamics JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -