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Evolution of cell-to-cell variability in stochastic, controlled, heteroplasmic mtDNA populations

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Title: Evolution of cell-to-cell variability in stochastic, controlled, heteroplasmic mtDNA populations
Authors: Johnston, IG
Jones, NS
Item Type: Journal Article
Abstract: Populations of physiologically vital mitochondrial DNA (mtDNA) molecules evolve in cells under control from the nucleus. The evolution of populations of mixed mtDNA types is complicated and poorly understood, and variability of these controlled admixtures plays a central role in the inheritance and onset of genetic disease. Here, we develop a mathematical theory describing the evolution of, and variability in, these stochastic populations for any type of cellular control, showing that cell-to-cell variability in mtDNA and mutant load inevitably increases with time, according to rates that we derive and which are notably independent of the mechanistic details of feedback signaling. We show with a set of experimental case studies that this theory explains disparate quantitative results from classical and modern experimental and computational research on heteroplasmy variance in different species. We demonstrate that our general model provides a host of specific insights, including a modification of the often-used but hard-to-interpret Wright formula to correspond directly to biological observables, the ability to quantify selective and mutational pressure in mtDNA populations, and characterization of the pronounced variability inevitably arising from the action of possible mtDNA quality-control mechanisms. Our general theoretical framework, supported by existing experimental results, thus helps us to understand and predict the evolution of stochastic mtDNA populations in cell biology.
Issue Date: 27-Oct-2016
Date of Acceptance: 22-Sep-2016
URI: http://hdl.handle.net/10044/1/43253
DOI: https://dx.doi.org/10.1016/j.ajhg.2016.09.016
ISSN: 1537-6605
Publisher: Elsevier
Start Page: 1150
End Page: 1162
Journal / Book Title: American Journal of Human Genetics
Volume: 99
Issue: 5
Copyright Statement: © 2016 American Society of Human Genetics.
Sponsor/Funder: Medical Research Council (MRC)
Engineering & Physical Science Research Council (EPSRC)
Funder's Grant Number: MR/J013617/1
EP/N014529/1
Keywords: Science & Technology
Life Sciences & Biomedicine
Genetics & Heredity
RANDOM GENETIC DRIFT
MITOCHONDRIAL-DNA
RAPID SEGREGATION
GERM-CELLS
REPLICATION
EXPRESSION
GENOMES
MODEL
REDUCTION
NETWORKS
06 Biological Sciences
11 Medical And Health Sciences
Publication Status: Published
Appears in Collections:Mathematics
Applied Mathematics and Mathematical Physics