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. 2017 Nov 21;12(11):e0187862.
doi: 10.1371/journal.pone.0187862. eCollection 2017.

Mitochondrial DNA sequence context in the penetrance of mitochondrial t-RNA mutations: A study across multiple lineages with diagnostic implications

Rachel A Queen  1 , Jannetta S Steyn  1 , Phillip Lord  2 , Joanna L Elson  1   3
Affiliations

Mitochondrial DNA sequence context in the penetrance of mitochondrial t-RNA mutations: A study across multiple lineages with diagnostic implications

Rachel A Queen et al. PLoS One. .

Abstract

Mitochondrial DNA (mtDNA) mutations are well recognized as an important cause of inherited disease. Diseases caused by mtDNA mutations exhibit a high degree of clinical heterogeneity with a complex genotype-phenotype relationship, with many such mutations exhibiting incomplete penetrance. There is evidence that the spectrum of mutations causing mitochondrial disease might differ between different mitochondrial lineages (haplogroups) seen in different global populations. This would point to the importance of sequence context in the expression of mutations. To explore this possibility, we looked for mutations which are known to cause disease in humans, in animals of other species unaffected by mtDNA disease. The mt-tRNA genes are the location of many pathogenic mutations, with the m.3243A>G mutation on the mt-tRNA-Leu(UUR) being the most frequently seen mutation in humans. This study looked for the presence of m.3243A>G in 2784 sequences from 33 species, as well as any of the other mutations reported in association with disease located on mt-tRNA-Leu(UUR). We report a number of disease associated variations found on mt-tRNA-Leu(UUR) in other chordates, as the major population variant, with m.3243A>G being seen in 6 species. In these, we also found a number of mutations which appear compensatory and which could prevent the pathogenicity associated with this change in humans. This work has important implications for the discovery and diagnosis of mtDNA mutations in non-European populations. In addition, it might provide a partial explanation for the conflicting results in the literature that examines the role of mtDNA variants in complex traits.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Species from the phylum Chordata with over 30 complete mitochondrial sequences.
Fig 2
Fig 2. Classification of variants with reports of disease association within mt-tRNA-Leu (UUR) gene.
Fig 3
Fig 3
(A) Alignment of 6 unique mt-tRNA-Leu (UUR) sequences from Canis lupus familiaris with the rCRS. Reticulation indicates one of the variants observed at positions 3239, and 3243 has occurred more than once in Canis lupus familiaris. (B) A phylogenetic network, created using Canis lupus familiaris mt-tRNA-Leu (UUR) sequences. The first structure shows the positions of polymorphisms between all of the sequences studied from Canis lupus familiaris and humans. The second two structures show the tRNA molecule where the 3243 A>G polymorphism was observed in Canis lupus familiaris. (C) The secondary structure of the mt-tRNA-Leu (UUR) from Canis lupus familiaris.
Fig 4
Fig 4
(A) The secondary structure of mt-tRNA-Leu molecules carrying the 3243 A>G mutation. (B) Alignments of tRNA’s D-Loop of from carnivore and primates carrying the 3243 A>G mutation.
Fig 5
Fig 5. Mutations which are classified as definitely pathogenic in humans that are found to be fixed in other species.
See this image and copyright information in PMC

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