Gene-specific function prediction for non-synonymous mutations in monogenic diabetes genes.
Ontology highlight
ABSTRACT:
SUBMITTER: Li Q
PROVIDER: S-EPMC4138110 | biostudies-literature | 2014
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:BACKGROUND: Complete genome sequences of the Astroviridae include human, non-human mammalian and avian species. A consensus topology of astroviruses has been derived from nucleotide substitutions in the full-length genomes and from non-synonymous nucleotide substitutions in each of the three ORFs. Analyses of synonymous substitutions displayed a loss of tree structure, suggesting either saturation of the substitution model or a deviant pattern of synonymous substitutions in certain virus species. RESULTS: We analyzed the complete Astroviridae family for the inference of adaptive molecular evolution at sites and in branches. High rates of synonymous mutations are observed among the non-human virus species. Deviant patterns of synonymous substitutions are found in the capsid structural genes. Purifying selection is a dominant force among all astrovirus genes and only few codon sites showed values for the dN/dS ratio that may indicate site-specific molecular adaptation during virus evolution. One of these sites is the glycine residue of a RGD motif in ORF2 of human astrovirus serotype 1. RGD or similar integrin recognition motifs are present in nearly all astrovirus species. CONCLUSION: Phylogenetic analysis directed by maximum likelihood approximation allows the inclusion of significantly more evolutionary history and thereby, improves the estimation of dN and dS. Sites with enhanced values for dN/dS are prominent at domains in charge of environmental communication (f.i. VP27 and domain 4 in ORF1a) more than at domains dedicated to intrinsic virus functions (f.i. VP34 and ORF1b (the virus polymerase)). Integrin recognition may play a key role in astrovirus to target cell attachment.
| S-EPMC1828050 | biostudies-literature
Project description:Synonymous mutations in protein-coding genes do not alter protein sequences and are thus generally presumed to be neutral or nearly neutral1-5. Here, to experimentally verify this presumption, we constructed 8,341 yeast mutants each carrying a synonymous, nonsynonymous or nonsense mutation in one of 21 endogenous genes with diverse functions and expression levels and measured their fitness relative to the wild type in a rich medium. Three-quarters of synonymous mutations resulted in a significant reduction in fitness, and the distribution of fitness effects was overall similar-albeit nonidentical-between synonymous and nonsynonymous mutations. Both synonymous and nonsynonymous mutations frequently disturbed the level of mRNA expression of the mutated gene, and the extent of the disturbance partially predicted the fitness effect. Investigations in additional environments revealed greater across-environment fitness variations for nonsynonymous mutants than for synonymous mutants despite their similar fitness distributions in each environment, suggesting that a smaller proportion of nonsynonymous mutants than synonymous mutants are always non-deleterious in a changing environment to permit fixation, potentially explaining the common observation of substantially lower nonsynonymous than synonymous substitution rates. The strong non-neutrality of most synonymous mutations, if it holds true for other genes and in other organisms, would require re-examination of numerous biological conclusions about mutation, selection, effective population size, divergence time and disease mechanisms that rely on the assumption that synoymous mutations are neutral.
| S-EPMC9650438 | biostudies-literature
Project description:BackgroundCodon pair usage (codon context) is a species specific gene primary structure feature whose evolutionary and functional roles are poorly understood. The data available show that codon-context has direct impact on both translation accuracy and efficiency, but one does not yet understand how it affects these two translation variables or whether context biases shape gene evolution.Methodologies/principal findingsHere we study codon-context biases using a set of 72 orthologous highly conserved genes from bacteria, archaea, fungi and high eukaryotes to identify 7 distinct groups of codon context rules. We show that synonymous mutations, i.e., neutral mutations that occur in synonymous codons of codon-pairs, are selected to maintain context biases and that non-synonymous mutations, i.e., non-neutral mutations that alter protein amino acid sequences, are also under selective pressure to preserve codon-context biases.ConclusionsSince in vivo studies provide evidence for a role of codon context on decoding fidelity in E. coli and for decoding efficiency in mammalian cells, our data support the hypothesis that, like codon usage, codon context modulates the evolution of gene primary structure and fine tunes the structure of open reading frames for high genome translational fidelity and efficiency in the 3 domains of life.
| S-EPMC3202573 | biostudies-literature
Project description:To evaluate the heterogeneity in the clinical expression in a family with glucokinase mature-onset diabetes of the young (GCK-MODY).Members (three generations) of the same family presented either with overt neonatal hyperglycemia, marked postprandial hyperglycemia, or glucosuria. Homeostasis model assessment of insulin resistance (HOMA(IR)) and insulinogenic and disposition indexes were calculated. Oral glucose tolerance test (OGTT) results in the GCK mutation carriers from this family were compared with those from other subjects with GCK mutations in the same codon (GCK(261)), with other missense and other types of GCK mutations in different codons from the European MODY Consortium database (GCK(m)).Mutation G261R was found in the GCK gene. During the OGTT, glucose (P = 0.02) and insulin (P = 0.009) response at 2 h as well as at the 2-h glucose increment (GCK(261) versus other missense GCK mutations, P = 0.003) were significantly higher in GCK(261) than in GCK(m) carriers.Differing from other GCK(m) carriers, the glucose and insulin response to oral glucose was significantly higher in GCK(261) carriers, indicating clinical heterogeneity in GCK-MODY.
| S-EPMC2809268 | biostudies-other
Project description:Type 1 diabetes (T1D) has a multifactorial autoimmune etiology, involving environmental prompts and polygenic predisposition. We hypothesized that pancreata from individuals with and at risk for T1D would exhibit dysregulated expression of genes associated with monogenic forms of diabetes caused by nonredundant single-gene mutations. Using a "monogenetic transcriptomic strategy," we measured the expression of these genes in human T1D, autoantibody-positive (autoantibody+), and control pancreas tissues with real-time quantitative PCR in accordance with the Minimum Information for Publication of Quantitative Real-Time PCR Experiments (MIQE) guidelines. Gene and protein expression was visualized in situ with use of immunofluorescence, RNAscope, and confocal microscopy. Two dozen monogenic diabetes genes showed altered expression in human pancreata from individuals with T1D versus unaffected control subjects. Six of these genes also saw dysregulation in pancreata from autoantibody+ individuals at increased risk for T1D. As a subset of these genes are related to cellular stress responses, we measured integrated stress response (ISR) genes and identified 20 with altered expression in T1D pancreata, including three of the four eIF2α-dependent kinases. Equally intriguing, we observed significant repression of the three arms of the ISR in autoantibody+ pancreata. Collectively, these efforts suggest monogenic diabetes and ISR genes are dysregulated early in the T1D disease process and likely contribute to the disorder's pathogenesis.
| S-EPMC8385619 | biostudies-literature
Project description:UDP glucuronosyltransferases (UGTs) are an important class of Phase II enzymes involved in the metabolism and detoxification of numerous xenobiotics including therapeutic drugs and endogenous compounds (e.g. bilirubin). To date, there are 21 human UGT genes identified, and most of them contain single-nucleotide polymorphisms (SNPs). Non-synonymous SNPs (nsSNPs) of the human UGT genes may cause absent or reduced enzyme activity and polymorphisms of UGT have been found to be closely related to altered drug clearance and/or drug response, hyperbilirubinemia, Gilbert's syndrome, and Crigler-Najjar syndrome. However, it is unlikely to study the functional impact of all identified nsSNPs in humans using laboratory approach due to its giant number. We have investigated the potential for bioinformatics approach for the prediction of phenotype based on known nsSNPs. We have identified a total of 248 nsSNPs from human UGT genes. The two algorithms tools, sorting intolerant from tolerant (SIFT) and polymorphism phenotyping (PolyPhen), were used to predict the impact of these nsSNPs on protein function. SIFT classified 35.5% of the UGT nsSNPs as "deleterious"; while PolyPhen identified 46.0% of the UGT nsSNPs as "potentially damaging" and "damaging". The results from the two algorithms were highly associated. Among 63 functionally characterized nsSNPs in the UGTs, 24 showed altered enzyme expression/activities and 45 were associated with disease susceptibility. SIFT and Polyphen had a correct prediction rate of 57.1% and 66.7%, respectively. These findings demonstrate the potential use of bioinformatics techniques to predict genotype-phenotype relationships which may constitute the basis for future functional studies.
| S-EPMC2758119 | biostudies-literature
Project description:Diagnosis of monogenic as well as atypical forms of diabetes mellitus has important clinical implications for their specific diagnosis, prognosis, and targeted treatment. Single gene mutations that affect beta-cell function represent 1-2% of all cases of diabetes. However, phenotypic heterogeneity and lack of family history of diabetes can limit the diagnosis of monogenic forms of diabetes. Next-generation sequencing technologies provide an excellent opportunity to screen large numbers of individuals with a diagnosis of diabetes for mutations in disease-associated genes.We utilized a targeted sequencing approach using the Illumina HiSeq to perform a case-control sequencing study of 22 monogenic diabetes genes in 4016 individuals with type 2 diabetes (including 1346 individuals diagnosed before the age of 40 years) and 2872 controls. We analyzed protein-coding variants identified from the sequence data and compared the frequencies of pathogenic variants (protein-truncating variants and missense variants) between the cases and controls.A total of 40 individuals with diabetes (1.8% of early onset sub-group and 0.6% of adult onset sub-group) were carriers of known pathogenic missense variants in the GCK, HNF1A, HNF4A, ABCC8, and INS genes. In addition, heterozygous protein truncating mutations were detected in the GCK, HNF1A, and HNF1B genes in seven individuals with diabetes. Rare missense mutations in the GCK gene were significantly over-represented in individuals with diabetes (0.5% carrier frequency) compared to controls (0.035%). One individual with early onset diabetes was homozygous for a rare pathogenic missense variant in the WFS1 gene but did not have the additional phenotypes associated with Wolfram syndrome.Targeted sequencing of genes linked with monogenic diabetes can identify disease-relevant mutations in individuals diagnosed with type 2 diabetes not suspected of having monogenic forms of the disease. Our data suggests that GCK-MODY frequently masquerades as classical type 2 diabetes. The results confirm that MODY is under-diagnosed, particularly in individuals presenting with early onset diabetes and clinically labeled as type 2 diabetes; thus, sequencing of all monogenic diabetes genes should be routinely considered in such individuals. Genetic information can provide a specific diagnosis, inform disease prognosis and may help to better stratify treatment plans.
| S-EPMC5717832 | biostudies-literature
Project description:The melanocortin 1 receptor (MC1R) is involved in the control of melanogenesis. Polymorphisms in this gene have been associated with variation in skin and hair color and with elevated risk for the development of melanoma. Here we used 11 computational tools based on different approaches to predict the damage-associated non-synonymous single nucleotide polymorphisms (nsSNPs) in the coding region of the human MC1R gene. Among the 92 nsSNPs arranged according to the predictions 62% were classified as damaging in more than five tools. The classification was significantly correlated with the scores of two consensus programs. Alleles associated with the red hair color (RHC) phenotype and with the risk of melanoma were examined. The R variants D84E, R142H, R151C, I155T, R160W and D294H were classified as damaging by the majority of the tools while the r variants V60L, V92M and R163Q have been predicted as neutral in most of the programs The combination of the prediction tools results in 14 nsSNPs indicated as the most damaging mutations in MC1R (L48P, R67W, H70Y, P72L, S83P, R151H, S172I, L206P, T242I, G255R, P256S, C273Y, C289R and R306H); C273Y showed to be highly damaging in SIFT, Polyphen-2, MutPred, PANTHER and PROVEAN scores. The computational analysis proved capable of identifying the potentially damaging nsSNPs in MC1R, which are candidates for further laboratory studies of the functional and pharmacological significance of the alterations in the receptor and the phenotypic outcomes.
| S-EPMC4368538 | biostudies-literature
Project description:In the NCBI database, as on June 6, 2020, total number of available complete genome sequences of SARS-CoV2 across the world is 3617. The envelope protein of SARS-CoV2 possesses several non-synonymous mutations over the transmembrane domain and (C)-terminus in 15 (0.414%) genomes among 3617 available SARS-CoV2 genomes. More precisely, it is to be mentioned that 10(0.386%) out of 2588 genomes from the USA, 3(0.806%) from Asia, 1 (0.348%) from Europe and 1 (0.274%) from Oceania contain the missense mutations over the envelope proteins of SARS-CoV2 genomes. The C-terminus motif DLLV has been changed to DFLV and YLLV in the proteins QJR88103 (Australia: Victoria) and QKI36831 (China: Guangzhou) respectively, which might affect the binding of this motif with the host protein PALS1.
| S-EPMC7335631 | biostudies-literature