Dataset Information

Substitutions into amino acids that are pathogenic in human mitochondrial proteins are more frequent in lineages closely related to human than in distant lineages.

ABSTRACT: Propensities for different amino acids within a protein site change in the course of evolution, so that an amino acid deleterious in a particular species may be acceptable at the same site in a different species. Here, we study the amino acid-changing variants in human mitochondrial genes, and analyze their occurrence in non-human species. We show that substitutions giving rise to such variants tend to occur in lineages closely related to human more frequently than in more distantly related lineages, indicating that a human variant is more likely to be deleterious in more distant species. Unexpectedly, substitutions giving rise to amino acids that correspond to alleles pathogenic in humans also more frequently occur in more closely related lineages. Therefore, a pathogenic variant still tends to be more acceptable in human mitochondria than a variant that may only be fit after a substantial perturbation of the protein structure.

SUBMITTER: Klink GV

PROVIDER: S-EPMC5731343 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Substitutions into amino acids that are pathogenic in human mitochondrial proteins are more frequent in lineages closely related to human than in distant lineages.

Klink Galya V GV Golovin Andrey V AV Bazykin Georgii A GA

PeerJ 20171212

Propensities for different amino acids within a protein site change in the course of evolution, so that an amino acid deleterious in a particular species may be acceptable at the same site in a different species. Here, we study the amino acid-changing variants in human mitochondrial genes, and analyze their occurrence in non-human species. We show that substitutions giving rise to such variants tend to occur in lineages closely related to human more frequently than in more distantly related line ...[more]

PMID: 29250469

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Project description:MotivationNext Generation Sequencing technologies make it possible to detect rare genetic variants in individual patients. Currently, more than a dozen software and web services have been created to predict the pathogenicity of variants related with changing of amino acid residues. Despite considerable efforts in this area, at the moment there is no ideal method to classify pathogenic and harmless variants, and the assessment of the pathogenicity is often contradictory. In this article, we propose to use peptides structural formulas of proteins as an amino acid residues substitutions description, rather than a single-letter code. This allowed us to investigate the effectiveness of chemoinformatics approach to assess the pathogenicity of variants associated with amino acid substitutions.ResultsThe structure-activity relationships analysis relying on protein-specific data and atom centric substructural multilevel neighborhoods of atoms (MNA) descriptors of molecular fragments appeared to be suitable for predicting the pathogenic effect of single amino acid variants. MNA-based Naïve Bayes classifier algorithm, ClinVar and humsavar data were used for the creation of structure-activity relationships models for 10 proteins. The performance of the models was compared with 11 different predicting tools: 8 individual (SIFT 4G, Polyphen2 HDIV, MutationAssessor, PROVEAN, FATHMM, MVP, LIST-S2, MutPred) and 3 consensus (M-CAP, MetaSVM, MetaLR). The accuracy of MNA-based method varies for the proteins (AUC: 0.631-0.993; MCC: 0.191-0.891). It was similar for both the results of comparisons with the other individual predictors and third-party protein-specific predictors. For several proteins (BRCA1, BRCA2, COL1A2, and RYR1), the performance of the MNA-based method was outstanding, capable of capturing the pathogenic effect of structural changes in amino acid substitutions.Availability and implementationThe datasets are available as supplemental data at Bioinformatics online. A python script to convert amino acid and nucleotide sequences from single-letter codes to SD files is available at https://github.com/SmirnygaTotoshka/SequenceToSDF. The authors provide trial licenses for MultiPASS software to interested readers upon request.

Dataset Information

Substitutions into amino acids that are pathogenic in human mitochondrial proteins are more frequent in lineages closely related to human than in distant lineages.

Publications

Substitutions into amino acids that are pathogenic in human mitochondrial proteins are more frequent in lineages closely related to human than in distant lineages.

Similar Datasets

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