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Contingency and selection in mitochondrial genome dynamics

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...

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Autores principales: Nunn, Christopher J, Goyal, Sidhartha
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9054137/
https://www.ncbi.nlm.nih.gov/pubmed/35404229
http://dx.doi.org/10.7554/eLife.76557
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author Nunn, Christopher J
Goyal, Sidhartha
author_facet Nunn, Christopher J
Goyal, Sidhartha
author_sort Nunn, Christopher J
collection PubMed
description 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.
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spelling pubmed-90541372022-04-30 Contingency and selection in mitochondrial genome dynamics Nunn, Christopher J Goyal, Sidhartha eLife Computational and Systems Biology 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. eLife Sciences Publications, Ltd 2022-04-11 /pmc/articles/PMC9054137/ /pubmed/35404229 http://dx.doi.org/10.7554/eLife.76557 Text en © 2022, Nunn and Goyal https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Computational and Systems Biology
Nunn, Christopher J
Goyal, Sidhartha
Contingency and selection in mitochondrial genome dynamics
title Contingency and selection in mitochondrial genome dynamics
title_full Contingency and selection in mitochondrial genome dynamics
title_fullStr Contingency and selection in mitochondrial genome dynamics
title_full_unstemmed Contingency and selection in mitochondrial genome dynamics
title_short Contingency and selection in mitochondrial genome dynamics
title_sort contingency and selection in mitochondrial genome dynamics
topic Computational and Systems Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9054137/
https://www.ncbi.nlm.nih.gov/pubmed/35404229
http://dx.doi.org/10.7554/eLife.76557
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