Predicting the pathogenicity of novel variants in mitochondrial tRNA with MitoTIP

Abstract

Novel or rare variants in mitochondrial tRNA sequences may be observed after mitochondrial DNA analysis. Determining whether these variants are pathogenic is critical, but confirmation of the effect of a variant on mitochondrial function can be challenging. We have used available databases of benign and pathogenic variants, alignment between diverse tRNAs, structural information and comparative genomics to predict the impact of all possible single-base variants and deletions. The Mitochondrial tRNA Informatics Predictor (MitoTIP) is available through MITOMAP at www.mitomap.org. The source code for MitoTIP is available at www.github.com/sonneysa/MitoTIP.

Fig 1. Position and stem penalties for pathogenicity prediction.

(A) The variant history and conservation scores at the analogous positions of every mitochondrial tRNA were averaged and used to score a generic tRNA structure. This identifies the regions of the tRNA that are most vulnerable to pathogenic variants. (B) Variants at base pairing regions are assessed based on the steric hindrance they induce, with the highest scores assigned at the ends of the stems region as shown in the scoring heat map for the phenylalanine tRNA.

Fig 2. Separation of benign and pathogenic variants by MitoTIP.

(A) Pathogenicity scores from naïve evaluations of known pathogenic (n = 38) and described benign (n = 651) variants plotted using box and whiskers at 5–95% (p<0.0001 by Mann Whitney test). Negative scoring is possible when polymorphisms improve Watson-Crick pairing in stems. (B) Sensitivity and specificity plot of these data at a range of pathogenicity scores. The crossover pathogenicity score was 12.8.