A multi-parametric workflow for the prioritization of mitochondrial DNA variants of clinical interest

Mariangela Santorsola, Claudia Calabrese, Giulia Girolimetti, Maria Angela Diroma, Giuseppe Gasparre, Marcella Attimonelli, Mariangela Santorsola, Claudia Calabrese, Giulia Girolimetti, Maria Angela Diroma, Giuseppe Gasparre, Marcella Attimonelli

Abstract

Assigning a pathogenic role to mitochondrial DNA (mtDNA) variants and unveiling the potential involvement of the mitochondrial genome in diseases are challenging tasks in human medicine. Assuming that rare variants are more likely to be damaging, we designed a phylogeny-based prioritization workflow to obtain a reliable pool of candidate variants for further investigations. The prioritization workflow relies on an exhaustive functional annotation through the mtDNA extraction pipeline MToolBox and includes Macro Haplogroup Consensus Sequences to filter out fixed evolutionary variants and report rare or private variants, the nucleotide variability as reported in HmtDB and the disease score based on several predictors of pathogenicity for non-synonymous variants. Cutoffs for both the disease score as well as for the nucleotide variability index were established with the aim to discriminate sequence variants contributing to defective phenotypes. The workflow was validated on mitochondrial sequences from Leber's Hereditary Optic Neuropathy affected individuals, successfully identifying 23 variants including the majority of the known causative ones. The application of the prioritization workflow to cancer datasets allowed to trim down the number of candidate for subsequent functional analyses, unveiling among these a high percentage of somatic variants. Prioritization criteria were implemented in both standalone ( http://sourceforge.net/projects/mtoolbox/ ) and web version ( https://mseqdr.org/mtoolbox.php ) of MToolBox.

Figures

Fig. 1
Fig. 1
a The histogram graphs the bimodal distribution of disease scores associated to 1872 non-synonymous variants (HmtDB, May 2014) observed in mtDNA sequences from healthy individuals and stored in HmtDB. The solid lines indicate the two gaussian components of the mixture model (McLachlan and Peel 2000) (46 and 54 %, respectively). The first component of the mixture model with the lowest disease score values included the most benign non-synonymous variants. The vertical dashed line is drawn at the selected Disease Score Threshold, DST, defined as 0.4311; non-synonymous variants featuring a DS above 0.4311 may, therefore, be considered potentially affecting function. bBox-plot diagram shows the disease scores of non-synonymous variants by class of ‘Neutral’ or ‘Disease’ prediction (disease scores ranging from 0.05 to 0.4311 and from 0.6565 to 0.9162, respectively, for each class) as returned by all six pathogenicity predictors implemented in MToolBox. Circles represent the outliers. c Empirical cumulative distribution function of nucleotide variability associated with the 816 non-synonymous variants, featuring a disease score above the established DST. Dashes vertical line indicates the nucleotide variability cutoff, NVC = 0.0026, defined as the third quartile of such distribution. Non-synonymous variants showing variability values below the NVC are filtered by the variant prioritization workflow
Fig. 2
Fig. 2
The stepwise prioritization workflow and the related number of mitochondrial variants filtered in any step performed on the full lists of any detected variants annotated in A LHON and B ovarian datasets from Sanger sequencing
Fig. 3
Fig. 3
The stepwise prioritization workflow and the related number of mitochondrial variants filtered in any step performed on the full lists of any detected A tumor-specific and B germline variants annotated in the COAD dataset from Whole Exome Sequencing (WXS). The number of blood-specific variants is also shown

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