Disease-associated mitochondrial mutations and the evolution of primate mitogenomes.

William Corrêa Tavares,Héctor N Seuánez,Roscoe Stanyon

doi:10.1371/journal.pone.0177403

William Corrêa Tavares, Héctor N Seuánez + Show 1 more

Open Access

https://doi.org/10.1371/journal.pone.0177403

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Abstract

Several human diseases have been associated with mutations in mitochondrial genes comprising a set of confirmed and reported mutations according to the MITOMAP database. An analysis of complete mitogenomes across 139 primate species showed that most confirmed disease-associated mutations occurred in aligned codon positions and gene regions under strong purifying selection resulting in a strong evolutionary conservation. Only two confirmed variants (7.1%), coding for the same amino acids accounting for severe human diseases, were identified without apparent pathogenicity in non-human primates, like the closely related Bornean orangutan. Conversely, reported disease-associated mutations were not especially concentrated in conserved codon positions, and a large fraction of them occurred in highly variable ones. Additionally, 88 (45.8%) of reported mutations showed similar variants in several non-human primates and some of them have been present in extinct species of the genus Homo. Considering that recurrent mutations leading to persistent variants throughout the evolutionary diversification of primates are less likely to be severely damaging to fitness, we suggest that these 88 mutations are less likely to be pathogenic. Conversely, 69 (35.9%) of reported disease-associated mutations occurred in extremely conserved aligned codon positions which makes them more likely to damage the primate mitochondrial physiology.

Highlights

The mammalian mitogenome comprises a set of 13 genes coding for proteins of the electron transport chain, two genes specifying for 12S- and 16S rRNAs, 22 for tRNAs, and a non-coding D-loop region, altogether encompassing approximately 16,600 bp [1]
The mt-proteins of the electron transport chain together with other 80 proteins encoded by nuclear genes [2] comprise the oxidative phosphorylation (OXPHOS) machinery consisting of five multimeric protein complexes, one exclusively containing nuclear proteins and four other (I, III, IV and V) with nuclear and mitochondrial proteins [3]
Separate alignments of the 13 protein-coding mt-genes were run with Muscle [23] and checked manually with Mega v.6.0 [24]. These alignments were subsequently concatenated in a single dataset with 11,406 bp for Maximum Likelihood (ML) phylogenetic reconstructions

Summary

Introduction

The mammalian mitogenome comprises a set of 13 genes coding for proteins of the electron transport chain, two genes specifying for 12S- and 16S rRNAs, 22 for tRNAs, and a non-coding D-loop region, altogether encompassing approximately 16,600 bp [1]. The mt-proteins of the electron transport chain together with other 80 proteins encoded by nuclear genes [2] comprise the oxidative phosphorylation (OXPHOS) machinery consisting of five multimeric protein complexes, one exclusively containing nuclear proteins (complex II) and four other (I, III, IV and V) with nuclear and mitochondrial proteins [3]. As OXPHOS dysfunction accounts for serious impairments in energy production, mt-genes have been subject to strong evolutionary constraints and a drastically restricted variability. Mitochondrial mutations, disease, and primate evolution study design, data collection and analysis, decision to publish, or preparation of the manuscript

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