High-confidence assessment of functional impact of human mitochondrial non-synonymous genome variations by APOGEE

<div><p>24,189 are all the possible non-synonymous amino acid changes potentially affecting the human mitochondrial DNA. Only a tiny subset was functionally evaluated with certainty so far, while the pathogenicity of the vast majority was only assessed <i>in-silico</i> by software predictors. Since these tools proved to be rather incongruent, we have designed and implemented APOGEE, a machine-learning algorithm that outperforms all existing prediction methods in estimating the harmfulness of mitochondrial non-synonymous genome variations. We provide a detailed description of the underlying algorithm, of the selected and manually curated training and test sets of variants, as well as of its classification ability.</p></div

Performance evaluation calculated on 153 known and unbiased mitochondrial non-synonymous variants.

<p>Performance evaluation calculated on 153 known and unbiased mitochondrial non-synonymous variants.</p

List of assembled predictors and annotations in MitImpact.

<p>List of assembled predictors and annotations in MitImpact.</p

Performance evaluation calculated on 864 known mitochondrial non-synonymous variants.

<p>Number of available predictions in last column.</p

Known variants grouped by mitochondrial gene symbol and OXPHOS complex.

<p>Known variants grouped by mitochondrial gene symbol and OXPHOS complex.</p

Meta-predictors performance comparisons by receiver operating characteristic curves.

<p>Meta-predictors performance comparisons by receiver operating characteristic curves.</p

Analysis of <i>MTNR1B</i> gene polymorphisms in relationship with <i>IRS2</i> gene variants, epicardial fat thickness, glucose homeostasis and cognitive performance in the elderly

<p>Genome-wide association studies pinpointed common variants in or near the <i>MTNR1B</i> gene encoding MT2 melatonin receptor to be strongly associated with fasting glucose levels. <i>IRS2</i> gene polymorphisms impact insulin resistance and epicardial fat (EF) thickness, which in turn is correlated with visceral adiposity, cognitive ability and risk for metabolic plus cardiovascular disease. We aimed to discover the interactions between <i>MTNR1B</i> and <i>IRS2</i> gene polymorphisms, insulin sensitivity, EF thickness and cognitive performance in the elderly. In 60 subjects aged 60 years and older, we evaluated five single nucleotide polymorphisms (SNPs) within the <i>MTNR1B</i> locus (rs10830962, rs4753426, rs12804291, rs10830963, rs3781638), the Gly1057Asp variant of <i>IRS2</i> gene (rs1805097), biochemical parameters, cognitive performance by the Mini Mental State Examination (MMSE) and EF thickness by transthoracic echocardiography. We found that <i>MTNR1B</i> and <i>IRS2</i> gene variants impacted EF thickness, lipid profile and glucose homeostasis. <i>IRS2</i> but not <i>MTNR1B</i> variants impacted MMSE scores. In conclusion, <i>MTNR1B</i> SNPs interact with <i>IRS2</i> gene variant, correlate with the amount of epicardial adipose tissue and impact glucose homeostasis and lipid profile influencing cardiometabolic risk.</p