A Genome-wide Screen Reveals that Reducing Mitochondrial DNA Polymerase Can Promote Elimination of Deleterious Mitochondrial Mutations.
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Publication Date
2019-12Journal Title
Current biology : CB
ISSN
0960-9822
Publisher
Elsevier
Volume
29
Issue
24
Pages
4330-4336.e3
Language
eng
Type
Article
This Version
AM
Physical Medium
Print-Electronic
Metadata
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Chiang, A. C., McCartney, E., O'Farrell, P. H., & Ma, H. (2019). A Genome-wide Screen Reveals that Reducing Mitochondrial DNA Polymerase Can Promote Elimination of Deleterious Mitochondrial Mutations.. Current biology : CB, 29 (24), 4330-4336.e3. https://doi.org/10.1016/j.cub.2019.10.060
Abstract
A mutant mitochondrial genome arising amid the pool of mitochondrial genomes within a cell must compete with existing genomes to survive to the next generation. Even weak selective forces can bias transmission of one genome over another to impact the inheritance of mitochondrial diseases and guide the evolution of mitochondrial DNA (mtDNA). Studies in several systems suggested that purifying selection in the female germline reduces transmission of detrimental mitochondrial mutations[1-7].
In contrast, some selfish genomes can take over despite a cost to host fitness[8-13]. Within individuals, the outcome of competition is therefore influenced by multiple selective forces. The nuclear genome, which encodes most proteins within mitochondria, and all external regulators of mitochondrial biogenesis and dynamics can influence the competition between mitochondrial genomes[14-18]. Yet, little is known about how this works. Previously, we established a Drosophila line transmitting two mitochondrial genomes in a stable ratio enforced by purifying selection benefiting one genome and a selfish advantage favouring the other[8]. To find nuclear genes that impact mtDNA competition, here we screened heterozygous deletions tiling ~70% of the euchromatic regions and examined their influence on this ratio. This genome-wide screen detected many nuclear modifiers of this ratio and identified one as the catalytic subunit of mtDNA polymerase gene (POLG), tam. A reduced dose of tam drove elimination of defective mitochondrial genomes. This study suggests that our approach will uncover targets for interventions that would block propagation of pathogenic mitochondrial mutations.
Keywords
Mitochondria, Animals, Drosophila melanogaster, Drosophila Proteins, DNA, Mitochondrial, Evolution, Molecular, Mutation, Genome, Mitochondrial, Selection, Genetic, DNA Polymerase gamma
Sponsorship
Wellcome Trust (202269/Z/16/Z)
BBSRC (1943886)
Identifiers
External DOI: https://doi.org/10.1016/j.cub.2019.10.060
This record's URL: https://www.repository.cam.ac.uk/handle/1810/298672
Rights
Attribution-NonCommercial-NoDerivatives 4.0 International
Licence URL: https://creativecommons.org/licenses/by-nc-nd/4.0/