Phylogeny of the Hominidae, showing two disease-associated mutations in modern humans (<i>Homo sapiens</i>) with similar counterparts in other hominids.

<p>A. Confirmed, disease-associated A132T mutation in mt-<i>ND1</i> showing its occurrence in the Bornean orangutans (<i>Pongo pygmaeus</i>). B. Reported, disease-associated, A64S mutation in mt-<i>ND1</i>, showing that all hominids show serine in residue 64 of NADH1, except modern humans and closely related Neanderthals.</p

Disease-associated mitochondrial mutations and the evolution of primate mitogenomes

<div><p>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 <i>Homo</i>. 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.</p></div

Indices of evolutionary conservation.

<p>Frequency distributions of Ind 1 (left), Ind2 (middle) Ind3 (right) of three groups of aligned codon positions (all positions, positions with confirmed disease-associated mutations and positions with reported disease-associated mutations).</p

Overlapping mutations in mt-<i>ATP6</i> and mt-<i>ATP8</i>.

<p>Comparison between a confirmed disease-associated missense mutation in humans (m.8528T>C; left) and a mutation in an adjacent region (m.8527A>G, right) in two non-human primates, <i>Tarsius wallacei</i> and <i>Lepilemur hubbardorum</i>. These mutations affected nucleotide positions in overlapping coding regions of mt-<i>ATP6</i> (in blue, above) and mt-<i>ATP8</i> (in red, below). m.8528T>C is a missense mutation in both genes, while m.8527A>G is a missense mutation only in mt-<i>ATP6</i>.</p

Comparisons of Ind1, Ind2 and Ind2 distributions.

<p>Comparisons of Ind1, Ind2 and Ind2 distributions.</p

Reported, disease-associated missense mutations in aligned codons positions with variable amino acid residues along primate evolution resulting in amino acid changes with similar physicochemical properties according to TreeSAAP.

<p>Reported, disease-associated missense mutations in aligned codons positions with variable amino acid residues along primate evolution resulting in amino acid changes with similar physicochemical properties according to TreeSAAP.</p

Number of aligned codon positions occupied by disease-associated mutations.

<p>Number of aligned codon positions occupied by disease-associated mutations.</p

Gene size, genetic distance and codons under negative selection.

<p>(A) Significant, positive correlation between mitochondrial gene size and mean GTR+Γ+I distance (r² = 0. 461; p = 0.011). (B) Non-significant, negative correlation between gene size and percentage of codons under negative selection (r² = 0.136; p = 0.214).</p

Recurrence of reported disease-associated mutations in the human across primate phylogeny.

<p>Left: Number of independent occurrences, per codon position, of amino acids accounting for reported disease-associated mutations in the human across primate phylogeny. Right: Number of species with amino acids accounting for reported disease-associated mutations in the human.</p

Predicted pathogenicity scores.

<p>Significant difference between means of predicted pathogenicity scores between confirmed disease-associated mutations and reported disease-associated mutations (t = 2.956; d.f. = 226; p = 0.003).</p