Dottorato in BIOLOGIA UMANA E GENETICA MEDICA

Titolo della tesi: APOGEE 2: multi-layer machine-learning model for the interpretable prediction of mitochondrial missense variants

In multicellular organisms, mitochondria are essential for producing energy metabolism; their dysfunction has pleiotropic effects and is a common cause of genetic diseases. The failure of the oxidative phosphorylation system is frequently caused by mitochondrial DNA mutations. Their significant variability in terms of clinical manifestations and onset of symptoms, which involve multiple tissues, their heteroplasmic levels, and mutational load in tissues, all contribute to the challenging task of the pathogenicity interpretation. Here, we present APOGEE 2, the latest release of a mitochondrially-centered ensemble method designed to improve the accuracy of pathogenicity predictions for interpreting missense mitochondrial variants. In 2020, It was included in the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP)’s joint consensus recommendations as being specifically tailored for mitochondrial variants classification. APOGEE 2 features an improved machine learning method and a curated training set for enhanced performance metrics. It offers region-wise assessments of genome fragility and mechanistic analyses of specific amino acids that cause perceptible long-range effects on protein structure. With clinical and research use in mind, APOGEE 2 scores and pathogenicity probabilities are precompiled and available in MitImpact, an online collection of genomic, clinical and functional annotations for all nucleotide changes that cause non-synonymous substitutions in human mitochondrial protein coding genes, developed by our group. APOGEE 2’s ability to address challenges in interpreting mitochondrial missense variants makes it a valuable tool in the field of mitochondrial genetics, aiding mtDNA variants genotype-phenotype correlations, improving diagnostic accuracy, and supporting the development of potential therapeutic interventions.