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Signs of Selection in Synonymous Sites of the Mitochondrial Cytochrome b Gene of Baikal Oilfish (Comephoridae) by mRNA Secondary Structure Alterations.

ABSTRACT: Studies over the past decade have shown a significant role of synonymous mutations in posttranscriptional regulation of gene expression, which is particularly associated with messenger RNA (mRNA) secondary structure alterations. Most studies focused on prokaryote genomes and the nuclear genomes of eukaryotes while little is known about the regulation of mitochondrial DNA (mtDNA) gene expression. This paper reveals signs of selection in synonymous sites of the mitochondrial cytochrome b gene (Cytb) of Baikal oilfish or golomyankas (Comephoridae) directed towards altering the secondary structure of the mRNA and probably altering the character of mtDNA gene expression. Our findings are based on comparisons of intraspecific genetic variation patterns of small golomyanka (Comephorus dybowski) and two genetic groups of big golomyanka (Comephorus dybowskii). Two approaches were used: (i) analysis of the distribution of synonymous mutations between weak-AT (W) and strong-GC (S) nucleotides within species and groups in accordance with mutation directions from central to peripheral haplotypes and (ii) approaches based on the predicted mRNA secondary structure.

SUBMITTER: Teterina VI

PROVIDER: S-EPMC4465659 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Signs of Selection in Synonymous Sites of the Mitochondrial Cytochrome b Gene of Baikal Oilfish (Comephoridae) by mRNA Secondary Structure Alterations.

Teterina Veronika I VI Mamontov Anatoliy M AM Sukhanova Lyubov V LV Kirilchik Sergei V SV

BioMed research international 20150531

Studies over the past decade have shown a significant role of synonymous mutations in posttranscriptional regulation of gene expression, which is particularly associated with messenger RNA (mRNA) secondary structure alterations. Most studies focused on prokaryote genomes and the nuclear genomes of eukaryotes while little is known about the regulation of mitochondrial DNA (mtDNA) gene expression. This paper reveals signs of selection in synonymous sites of the mitochondrial cytochrome b gene (Cyt ...[more]

PMID: 26114105

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Project description:Evolution of protein sequences is largely governed by purifying selection, with a small fraction of proteins evolving under positive selection. The evolution at synonymous positions in protein-coding genes is not nearly as well understood, with the extent and types of selection remaining, largely, unclear. A statistical test to identify purifying and positive selection at synonymous sites in protein-coding genes was developed. The method compares the rate of evolution at synonymous sites (Ks) to that in intron sequences of the same gene after sampling the aligned intron sequences to mimic the statistical properties of coding sequences. We detected purifying selection at synonymous sites in approximately 28% of the 1,562 analyzed orthologous genes from mouse and rat, and positive selection in approximately 12% of the genes. Thus, the fraction of genes with readily detectable positive selection at synonymous sites is much greater than the fraction of genes with comparable positive selection at nonsynonymous sites, i.e., at the level of the protein sequence. Unlike other genes, the genes with positive selection at synonymous sites showed no correlation between Ks and the rate of evolution in nonsynonymous sites (Ka), indicating that evolution of synonymous sites under positive selection is decoupled from protein evolution. The genes with purifying selection at synonymous sites showed significant anticorrelation between Ks and expression level and breadth, indicating that highly expressed genes evolve slowly. The genes with positive selection at synonymous sites showed the opposite trend, i.e., highly expressed genes had, on average, higher Ks. For the genes with positive selection at synonymous sites, a significantly lower mRNA stability is predicted compared to the genes with negative selection. Thus, mRNA destabilization could be an important factor driving positive selection in nonsynonymous sites, probably, through regulation of expression at the level of mRNA degradation and, possibly, also translation rate. So, unexpectedly, we found that positive selection at synonymous sites of mammalian genes is substantially more common than positive selection at the level of protein sequences. Positive selection at synonymous sites might act through mRNA destabilization affecting mRNA levels and translation.

Project description:BackgroundSirtuins are NAD+ dependent deacetylases, which regulate mitochondrial energy metabolism as well as cellular response to stress. The NAD/NADH-system plays a crucial role in oxidative phosphorylation linking sirtuins and the mitochondrial respiratory chain. Furthermore, sirtuins are able to directly deacetylate and activate different complexes of the respiratory chain. This prompted us to analyse sirtuin levels in skin fibroblasts from patients with cytochrome c-oxidase (COX) deficiency and to test the impact of different pharmaceutical activators of sirtuins (SRT1720, paeonol) to modulate sirtuins and possibly respiratory chain enzymes in patient cells in vitro.MethodsWe assayed intracellular levels of sirtuin 1 and the mitochondrial sirtuins SIRT3 and SIRT4 in human fibroblasts from patients with COX- deficiency. Furthermore, sirtuins were measured after inhibiting complex IV in healthy control fibroblasts by cyanide and after incubation with activators SRT1720 and paeonol. To determine the effect of sirtuin inhibition at the cellular level we measured total cellular acetylation (control and patient cells, with and without treatment) by Western blot.ResultsWe observed a significant decrease in cellular levels of all three sirtuins at the activity, protein and transcriptional level (by 15% to 50%) in COX-deficient cells. Additionally, the intracellular concentration of NAD+ was reduced in patient cells. We mimicked the biochemical phenotype of COX- deficiency by incubating healthy fibroblasts with cyanide and observed reduced sirtuin levels. A pharmacological activation of sirtuins resulted in normalized sirtuin levels in patient cells. Hyper acetylation was also reversible after treatment with sirtuin activators. Pharmacological modulation of sirtuins resulted in altered respiratory chain complex activities.ConclusionsWe found inhibition of situins 1, 3 and 4 at activity, protein and transcriptional levels in fibroblasts from patient with COX-deficiency. Pharmacological activators were able to restore reduced sirtuin levels and thereby modulate respiratory chain activities.

Dataset Information

Signs of Selection in Synonymous Sites of the Mitochondrial Cytochrome b Gene of Baikal Oilfish (Comephoridae) by mRNA Secondary Structure Alterations.

Publications

Signs of Selection in Synonymous Sites of the Mitochondrial Cytochrome b Gene of Baikal Oilfish (Comephoridae) by mRNA Secondary Structure Alterations.

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