Machine learning classifier for identification of damaging missense mutations exclusive to human mitochondrial DNA-encoded polypeptides

Martín-Navarro, Antonio; Gaudioso-Simón, Andrés; Álvarez-Jarreta, Jorge; Montoya, Julio; Mayordomo, Elvira; Ruiz‐Pesini, Eduardo

doi:10.1186/s12859-017-1562-7

Cited by 30 publications

(22 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…As a final test of the model that negative selection acts against deleterious mtDNA variants, we used the MutPred algorithm [36] to compare the pathogenicity of nonsynonymous mutations found in mutator flies to a distribution of MutPred scores created from Monte Carlo simulations of random mutagenesis. The MutPred algorithm uses the structural and functional properties of a protein to predict the functional consequence of a nonsynonymous amino acid substitution, and previous work has established the validity of the MutPred algorithm to predict the consequences of mtDNA mutations [37–39]. MutPred assigns scores ranging from 0 to 1 to quantify the pathogenicity of a particular variant, with higher scores indicating a greater likelihood of pathogenicity.…”

Section: Resultsmentioning

confidence: 99%

Deleterious mitochondrial DNA point mutations are overrepresented in Drosophila expressing a proofreading-defective DNA polymerase γ

et al. 2018

View full text Add to dashboard Cite

Mitochondrial DNA (mtDNA) mutations cause severe maternally inherited syndromes and the accumulation of somatic mtDNA mutations is implicated in aging and common diseases. However, the mechanisms that influence the frequency and pathogenicity of mtDNA mutations are poorly understood. To address this matter, we created a Drosophila mtDNA mutator strain expressing a proofreading-deficient form of the mitochondrial DNA polymerase. Mutator flies have a dramatically increased somatic mtDNA mutation frequency that correlates with the dosage of the proofreading-deficient polymerase. Mutator flies also exhibit mitochondrial dysfunction, shortened lifespan, a progressive locomotor deficit, and loss of dopaminergic neurons. Surprisingly, the frequency of nonsynonymous, pathogenic, and conserved-site mutations in mutator flies exceeded predictions of a neutral mutational model, indicating the existence of a positive selection mechanism that favors deleterious mtDNA variants. We propose from these findings that deleterious mtDNA mutations are overrepresented because they selectively evade quality control surveillance or because they are amplified through compensatory mitochondrial biogenesis.

show abstract

Section: Resultsmentioning

confidence: 99%

Deleterious mitochondrial DNA point mutations are overrepresented in Drosophila expressing a proofreading-defective DNA polymerase γ

et al. 2018

View full text Add to dashboard Cite

show abstract

“…This proline is conserved in 94.7% of 4,988 eukaryotic (from protists to mammals) p.MT-CYB sequences (Martin-Navarro et al, 2017 ). Pathogenicity predictors, such as MutPred (Pereira et al, 2011 ), PolyPhen-2 and Mitoclass.1 (Martin-Navarro et al, 2017 ), consider this amino acid substitution as a pathogenic mutation. The m.13094T>C mutation has not been reported in these 37,545 human sequences.…”

Section: Resultsmentioning

confidence: 99%

“…This m.13094T>C transition provokes a valine to alanine change in p.MT-ND5 position 253 (Figure 2D ). The valine is conserved in 99.7% of 5,159 eukaryotic p.MT-ND5 sequences (Martin-Navarro et al, 2017 ). This Val253 is located in the p.MT-ND5 transmembrane helix 8 (TMH8), following a serine pair (Ser249 and Ser250) that distorts TMH8 (Zhu et al, 2016 ), and a key His248 sit on a flexible loop of the discontinuous TMH8.…”

Section: Resultsmentioning

confidence: 99%

The Decrease in Mitochondrial DNA Mutation Load Parallels Visual Recovery in a Leber Hereditary Optic Neuropathy Patient

et al. 2018

Self Cite

View full text Add to dashboard Cite

The onset of Leber hereditary optic neuropathy is relatively rare in childhood and, interestingly, the rate of spontaneous visual recovery is very high in this group of patients. Here, we report a child harboring a rare pathological mitochondrial DNA mutation, present in heteroplasmy, associated with the disease. A patient follow-up showed a rapid recovery of the vision accompanied by a decrease of the percentage of mutated mtDNA. A retrospective study on the age of recovery of all childhood-onset Leber hereditary optic neuropathy patients reported in the literature suggested that this process was probably related with pubertal changes.

show abstract

“…For instance, more than 70% of the confirmed pathogenic mutations were predicted to be benign with SIFT, whereas about 15% of the pathogenic variants were not predicted as such by Polyphen2, highlighting that the tools developed for nDNA are barely suitable for mtDNA. Conversely, recent tools developed for mtDNA using machine learning based approaches (Table 1D) show better performances (Figure 2), as MToolBox (Calabrese et al, 2014), the meta-predictor APOGEE (Castellana et al, 2017), or Mitoclass.1 (Martin-Navarro et al, 2017), confirming the need to pursue the development of tools dedicated to mitochondrial genetics.…”

Section: Mtdna Variant Annotationmentioning

confidence: 93%

Bioinformatics Tools and Databases to Assess the Pathogenicity of Mitochondrial DNA Variants in the Field of Next Generation Sequencing

et al. 2018

View full text Add to dashboard Cite

The development of next generation sequencing (NGS) has greatly enhanced the diagnosis of mitochondrial disorders, with a systematic analysis of the whole mitochondrial DNA (mtDNA) sequence and better detection sensitivity. However, the exponential growth of sequencing data renders complex the interpretation of the identified variants, thereby posing new challenges for the molecular diagnosis of mitochondrial diseases. Indeed, mtDNA sequencing by NGS requires specific bioinformatics tools and the adaptation of those developed for nuclear DNA, for the detection and quantification of mtDNA variants from sequence alignment to the calling steps, in order to manage the specific features of the mitochondrial genome including heteroplasmy, i.e., coexistence of mutant and wildtype mtDNA copies. The prioritization of mtDNA variants remains difficult, relying on a limited number of specific resources: population and clinical databases, and in silico tools providing a prediction of the variant pathogenicity. An evaluation of the most prominent bioinformatics tools showed that their ability to predict the pathogenicity was highly variable indicating that special efforts should be directed at developing new bioinformatics tools dedicated to the mitochondrial genome. In addition, massive parallel sequencing raised several issues related to the interpretation of very low mtDNA mutational loads, discovery of variants of unknown significance, and mutations unrelated to patient phenotype or the co-occurrence of mtDNA variants. This review provides an overview of the current strategies and bioinformatics tools for accurate annotation, prioritization and reporting of mtDNA variations from NGS data, in order to carry out accurate genetic counseling in individuals with primary mitochondrial diseases.

show abstract

Machine learning classifier for identification of damaging missense mutations exclusive to human mitochondrial DNA-encoded polypeptides

Cited by 30 publications

References 47 publications

Deleterious mitochondrial DNA point mutations are overrepresented in Drosophila expressing a proofreading-defective DNA polymerase γ

Deleterious mitochondrial DNA point mutations are overrepresented in Drosophila expressing a proofreading-defective DNA polymerase γ

The Decrease in Mitochondrial DNA Mutation Load Parallels Visual Recovery in a Leber Hereditary Optic Neuropathy Patient

Bioinformatics Tools and Databases to Assess the Pathogenicity of Mitochondrial DNA Variants in the Field of Next Generation Sequencing

Contact Info

Product

Resources

About