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      New mtDNA Association Model, MutPred Variant Load, Suggests Individuals With Multiple Mildly Deleterious mtDNA Variants Are More Likely to Suffer From Atherosclerosis

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          Abstract

          The etiology of common complex diseases is multifactorial, involving both genetic, and environmental factors. A role for mitochondrial dysfunction and mitochondrial DNA (mtDNA) variation has been suggested in the pathogenesis of common complex traits. The aim of this study was to investigate a potential role of mtDNA variants in the development of obesity, diabetes, and atherosclerosis in the Polish population. Whole mtDNA sequences from 415 Polish individuals representing three disease cohorts and a control group were obtained using high-throughput sequencing. Two approaches for the assessment of mtDNA variation were applied, traditional mitochondrial haplogroup association analysis and the mutational or variant load model using the MutPred pathogenicity prediction algorithm for amino acid substitutions in humans. We present a possible association between mildly deleterious mtDNA variant load and atherosclerosis that might be due to having more than one likely mildly deleterious non-synonymous substitution. Moreover, it seems largely dependent upon a few common haplogroup associated variants with MutPred score above 0.5.

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          Mutation and cancer: statistical study of retinoblastoma.

          A Knudson (1971)
          Based upon observations on 48 cases of retinoblastoma and published reports, the hypothesis is developed that retinoblastoma is a cancer caused by two mutational events. In the dominantly inherited form, one mutation is inherited via the germinal cells and the second occurs in somatic cells. In the nonhereditary form, both mutations occur in somatic cells. The second mutation produces an average of three retinoblastomas per individual inheriting the first mutation. Using Poisson statistics, one can calculate that this number (three) can explain the occasional gene carrier who gets no tumor, those who develop only unilateral tumors, and those who develop bilateral tumors, as well as explaining instances of multiple tumors in one eye. This value for the mean number of tumors occurring in genetic carriers may be used to estimate the mutation rate for each mutation. The germinal and somatic rates for the first, and the somatic rate for the second, mutation, are approximately equal. The germinal mutation may arise in some instances from a delayed mutation.
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            Automated inference of molecular mechanisms of disease from amino acid substitutions.

            Advances in high-throughput genotyping and next generation sequencing have generated a vast amount of human genetic variation data. Single nucleotide substitutions within protein coding regions are of particular importance owing to their potential to give rise to amino acid substitutions that affect protein structure and function which may ultimately lead to a disease state. Over the last decade, a number of computational methods have been developed to predict whether such amino acid substitutions result in an altered phenotype. Although these methods are useful in practice, and accurate for their intended purpose, they are not well suited for providing probabilistic estimates of the underlying disease mechanism. We have developed a new computational model, MutPred, that is based upon protein sequence, and which models changes of structural features and functional sites between wild-type and mutant sequences. These changes, expressed as probabilities of gain or loss of structure and function, can provide insight into the specific molecular mechanism responsible for the disease state. MutPred also builds on the established SIFT method but offers improved classification accuracy with respect to human disease mutations. Given conservative thresholds on the predicted disruption of molecular function, we propose that MutPred can generate accurate and reliable hypotheses on the molecular basis of disease for approximately 11% of known inherited disease-causing mutations. We also note that the proportion of changes of functionally relevant residues in the sets of cancer-associated somatic mutations is higher than for the inherited lesions in the Human Gene Mutation Database which are instead predicted to be characterized by disruptions of protein structure. http://mutdb.org/mutpred predrag@indiana.edu; smooney@buckinstitute.org.
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              A mitochondrial bioenergetic etiology of disease.

              The classical Mendelian genetic perspective has failed to adequately explain the biology and genetics of common metabolic and degenerative diseases. This is because these diseases are primarily systemic bioenergetic diseases, and the most important energy genes are located in the cytoplasmic mitochondrial DNA (mtDNA). Therefore, to understand these "complex" diseases, we must investigate their bioenergetic pathophysiology and consider the genetics of the thousands of copies of maternally inherited mtDNA, the more than 1,000 nuclear DNA (nDNA) bioenergetic genes, and the epigenomic and signal transduction systems that coordinate these dispersed elements of the mitochondrial genome.
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                Author and article information

                Contributors
                Journal
                Front Genet
                Front Genet
                Front. Genet.
                Frontiers in Genetics
                Frontiers Media S.A.
                1664-8021
                08 January 2019
                2018
                : 9
                : 702
                Affiliations
                [1] 1Faculty of Biology, Institute of Genetics and Biotechnology, University of Warsaw , Warsaw, Poland
                [2] 2Institute of Genetic Medicine, Newcastle University , Newcastle upon Tyne, United Kingdom
                [3] 3Centre for Human Metabolomics, North-West University , Potchefstroom, South Africa
                [4] 4Department of General Biology and Parasitology, Medical University of Warsaw , Warsaw, Poland
                [5] 5Department of Epidemiology, Cardiovascular Disease Prevention and Health Promotion, Institute of Cardiology , Warsaw, Poland
                [6] 6Department of Prevention and Education, Department of Arterial Hypertension and Diabetology, Medical University of Gdansk , Gdansk, Poland
                [7] 7Department of Medical Genetics, Medical University of Warsaw , Warsaw, Poland
                [8] 8Institute of Biochemistry and Biophysics Polish Academy of Sciences , Warsaw, Poland
                Author notes

                Edited by: Nicholas Michael Morton, University of Edinburgh, United Kingdom

                Reviewed by: Federica Cioffi, University of Sannio, Italy; John Mercer, University of Glasgow, United Kingdom

                *Correspondence: Katarzyna Tonska kaska@ 123456igib.uw.edu.pl

                This article was submitted to Genomic Endocrinology, a section of the journal Frontiers in Genetics

                Article
                10.3389/fgene.2018.00702
                6332467
                30671084
                70c7260d-a73f-4857-8192-80ad835e02ad
                Copyright © 2019 Piotrowska-Nowak, Elson, Sobczyk-Kopciol, Piwonska, Puch-Walczak, Drygas, Ploski, Bartnik and Tonska.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 17 September 2018
                : 14 December 2018
                Page count
                Figures: 2, Tables: 6, Equations: 0, References: 43, Pages: 10, Words: 7331
                Funding
                Funded by: Narodowe Centrum Nauki 10.13039/501100004281
                Funded by: Uniwersytet Warszawski 10.13039/501100006445
                Categories
                Genetics
                Original Research

                Genetics
                mtdna variation,mutpred,variant load,common complex diseases,atherosclerosis
                Genetics
                mtdna variation, mutpred, variant load, common complex diseases, atherosclerosis

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