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Background sequence characteristics influence the occurrence and severity of disease-causing mtDNA mutations

Lookup NU author(s): Dr Wei Wei, Dr Aurora Gomez Duran, Dr Gavin Hudson, Professor Patrick Chinnery



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2017 Wei et al. Inherited mitochondrial DNA (mtDNA) mutations have emerged as a common cause of human disease, with mutations occurring multiple times in the world population. The clinical presentation of three pathogenic mtDNA mutations is strongly associated with a background mtDNA haplogroup, but it is not clear whether this is limited to a handful of examples or is a more general phenomenon. To address this, we determined the characteristics of 30,506 mtDNA sequences sampled globally. After performing several quality control steps, we ascribed an established pathogenicity score to the major alleles for each sequence. The mean pathogenicity score for known disease-causing mutations was significantly different between mtDNA macro-haplogroups. Several mutations were observed across all haplogroup backgrounds, whereas others were only observed on specific clades. In some instances this reflected a founder effect, but in others, the mutation recurred but only within the same phylogenetic cluster. Sequence diversity estimates showed that disease-causing mutations were more frequent on young sequences, and genomes with two or more disease-causing mutations were more common than expected by chance. These findings implicate the mtDNA background more generally in recurrent mutation events that have been purified through natural selection in older populations. This provides an explanation for the low frequency of mtDNA disease reported in specific ethnic groups.

Publication metadata

Author(s): Wei W, Gomez-Duran A, Hudson G, Chinnery PF

Publication type: Article

Publication status: Published

Journal: PLoS Genetics

Year: 2017

Volume: 13

Issue: 12

Print publication date: 31/12/2017

Online publication date: 18/12/2017

Acceptance date: 26/11/2017

Date deposited: 16/01/2018

ISSN (print): 1553-7390

ISSN (electronic): 1553-7404

Publisher: Public Library of Science


DOI: 10.1371/journal.pgen.1007126


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