Contingency and selection in mitochondrial genome dynamics

Abstract
Data availability
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Abstract

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.

Data availability

Raw Nanopore sequencing data (that has been demultiplexed and labeled with the corresponding colony name in the main-text) is available alongside sequence alignment code and Python code for primary/alternate structure analysis. The data is available at https://doi.org/10.5061/dryad.vdncjsxwx. The code for analysis is available at https://doi.org/10.5281/zenodo.5851771. Preprocessed data and code to produce the plots in this article are available at https://github.com/javathejhut/ContingencyAndSelection.

The following data sets were generated

1. Nunn CJ
(2022) Data and source code from: Contingency and selection in mitochondrial genome dynamics
Dryad Digital Repository, doi:10.5061/dryad.vdncjsxwx.

https://dx.doi.org/10.5061/dryad.vdncjsxwx

Article and author information

Author details

Christopher J Nunn

Department of Physics, University of Toronto, Toronto, Canada

For correspondence
cnunn@physics.utoronto.ca

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-9598-1045
Sidhartha Goyal

Department of Physics, University of Toronto, Toronto, Canada

For correspondence
goyal@physics.utoronto.ca

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-7452-892X

Funding

Natural Sciences and Engineering Research Council of Canada (RGPIN-2015-0)

Sidhartha Goyal

Simons Foundation (326844)

Sidhartha Goyal

Canada Foundation for Innovation (32708)

Sidhartha Goyal

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.