scholarly journals Synonymous variants in holoprosencephaly alter codon usage and impact the Sonic Hedgehog protein

Brain ◽  
2020 ◽  
Vol 143 (7) ◽  
pp. 2027-2038
Author(s):  
Artem Kim ◽  
Jérôme Le Douce ◽  
Farah Diab ◽  
Monika Ferovova ◽  
Christèle Dubourg ◽  
...  
Keyword(s):  
Codon Usage ◽  
Sonic Hedgehog ◽  
In Silico ◽  
Synonymous Codon ◽  
Critical Role ◽  
Protein Translation ◽  
Mirna Regulation ◽  
Single Nucleotide Variants ◽  
Mrna Structure ◽  
The Impact

Abstract Synonymous single nucleotide variants (sSNVs) have been implicated in various genetic disorders through alterations of pre-mRNA splicing, mRNA structure and miRNA regulation. However, their impact on synonymous codon usage and protein translation remains to be elucidated in clinical context. Here, we explore the functional impact of sSNVs in the Sonic Hedgehog (SHH) gene, identified in patients affected by holoprosencephaly, a congenital brain defect resulting from incomplete forebrain cleavage. We identified eight sSNVs in SHH, selectively enriched in holoprosencephaly patients as compared to healthy individuals, and systematically assessed their effect at both transcriptional and translational levels using a series of in silico and in vitro approaches. Although no evidence of impact of these sSNVs on splicing, mRNA structure or miRNA regulation was found, five sSNVs introduced significant changes in codon usage and were predicted to impact protein translation. Cell assays demonstrated that these five sSNVs are associated with a significantly reduced amount of the resulting protein, ranging from 5% to 23%. Inhibition of the proteasome rescued the protein levels for four out of five sSNVs, confirming their impact on protein stability and folding. Remarkably, we found a significant correlation between experimental values of protein reduction and computational measures of codon usage, indicating the relevance of in silico models in predicting the impact of sSNVs on translation. Considering the critical role of SHH in brain development, our findings highlight the clinical relevance of sSNVs in holoprosencephaly and underline the importance of investigating their impact on translation in human pathologies.

The Synonymous V107V Mutation In Factor IX Is Not So Silent and May Cause Hemophilia B In Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2197-2197 ◽  
Author(s):  
Chava Kimchi-Sarfaty ◽  
Vijaya L Simhadri ◽  
David Kopelman ◽  
Adam Friedman ◽  
Nathan Edwards ◽  
...  
Keyword(s):  
Codon Usage ◽  
In Silico ◽  
Synonymous Codon ◽  
Protein Translation ◽  
Factor Ix ◽  
Hemophilia B ◽  
Structure Stability ◽  
Synonymous Mutation ◽  
Codon Substitution ◽  
In Silico Analyses

Abstract Abstract 2197 Hemophilia B is characterized by structural and functional defects in coagulation factor IX (FIX) caused by mutations in the F9 gene. Various mutations (nonsense, missense, etc.) are known to be associated with the disease, including a synonymous V107V mutation reported recently by Knobe and colleagues (Knobe et al., Hemophilia, 2008). However the mechanism by which this synonymous mutation contributes to the disease has not yet been elucidated. Earlier we have shown that synonymous codon substitutions in the mRNA of the multidrug resistance protein (MDR1) may change the conformation of the protein and result in altered functionality (Kimchi-Sarfaty et al., Science, 2008). Here we have performed in silico analyses of the synonymous codon substitution (GTGàGTA) leading to the V107V polymorphism and found that it may change the mRNA structure, stability, codon usage, and 3D structure of the encoded protein. We hypothesize that changes in codon usage might affect the rhythm of protein translation and thus result in slightly altered FIX conformation. In vitro analyses of FIX mRNA and protein expression supported our in silico analyses. The GTGàGTA (V107V) synonymous mutation results in reduced expression levels as well as an encoded protein with a slightly different conformation compared to wild-type FIX. These results show that the V107V polymorphism is not silent and might cause mild hemophilia B. This work sheds further light on ways in which synonymous mutations impact disease. The findings and conclusions in this article have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any Agency determination policy Disclosures: No relevant conflicts of interest to declare.

scholarly journals Intragenomic variation in mutation biases causes underestimation of selection on synonymous codon usage

2021 ◽  
Author(s):  
Alexander L Cope ◽  
Premal Shah
Keyword(s):  
Population Genetics ◽  
Natural Selection ◽  
Codon Usage ◽  
Codon Bias ◽  
Synonymous Codon ◽  
Synonymous Codon Usage ◽  
Mutation Bias ◽  
Biased Gene Conversion ◽  
Intragenomic Variation ◽  
The Impact

Patterns of non-uniform usage of synonymous codons (codon bias) varies across genes in an organism and across species from all domains of life. The bias in codon usage is due to a combination of both non-adaptive (e.g. mutation biases) and adaptive (e.g. natural selection for translation efficiency/accuracy) evolutionary forces. Most population genetics models quantify the effects of mutation bias and selection on shaping codon usage patterns assuming a uniform mutation bias across the genome. However, mutation biases can vary both along and across chromosomes due to processes such as biased gene conversion, potentially obfuscating signals of translational selection. Moreover, estimates of variation in genomic mutation biases are often lacking for non-model organisms. Here, we combine an unsupervised learning method with a population genetics model of synonymous codon bias evolution to assess the impact of intragenomic variation in mutation bias on the strength and direction of natural selection on synonymous codon usage across 49 Saccharomycotina budding yeasts. We find that in the absence of a priori information, unsupervised learning approaches can be used to identify regions evolving under different mutation biases. We find that the impact of intragenomic variation in mutation bias varies widely, even among closely-related species. We show that the overall strength and direction of selection on codon usage can be underestimated by failing to account for intragenomic variation in mutation biases. Interestingly, genes falling into clusters identified by machine learning are also often physically clustered across chromosomes, consistent with processes such as biased gene conversion. Our results indicate the need for more nuanced models of sequence evolution that systematically incorporate the effects of variable mutation biases on codon frequencies.

scholarly journals Analysis of computational codon usage models and their association with translationally slow codons

2020 ◽  
Author(s):  
Gabriel Wright ◽  
Anabel Rodriguez ◽  
Jun Li ◽  
Patricia L. Clark ◽  
Tijana Milenković ◽  
...  
Keyword(s):  
Codon Usage ◽  
Computational Models ◽  
Selective Pressure ◽  
Synonymous Codon ◽  
Ground Truth ◽  
Protein Translation ◽  
Weak Correlation ◽  
Experimental Conditions ◽  
Synonymous Codons ◽  
Genome Wide

AbstractImproved computational modeling of protein translation rates, including better prediction of where translational slowdowns along an mRNA sequence may occur, is critical for understanding co-translational folding. Because codons within a synonymous codon group are translated at different rates, many computational translation models rely on analyzing synonymous codons. Some models rely on genome-wide codon usage bias (CUB), believing that globally rare and common codons are the most informative of slow and fast translation, respectively. Others use the CUB observed only in highly expressed genes, which should be under selective pressure to be translated efficiently (and whose CUB may therefore be more indicative of translation rates). No prior work has analyzed these models for their ability to predict translational slowdowns. Here, we evaluate five models for their association with slowly translated positions as denoted by two independent ribosome footprint (RFP) count experiments from S. cerevisiae, because RFP data is often considered as a “ground truth” for translation rates across mRNA sequences. We show that all five considered models strongly associate with the RFP data and therefore have potential for estimating translational slowdowns. However, we also show that there is a weak correlation between RFP counts for the same genes originating from independent experiments, even when their experimental conditions are similar. This raises concerns about the efficacy of using current RFP experimental data for estimating translation rates and highlights a potential advantage of using computational models to understand translation rates instead.

scholarly journals Meta analysis of variant predictions in congenital adrenal hyperplasia caused by mutations in CYP21A2.

2021 ◽  
Author(s):  
Mayara Jorgens Prado ◽  
Rodrigo Ligabue-Braun ◽  
Arnaldo Zaha ◽  
Maria Lucia Rosa Rossetti ◽  
Amit V Pandey
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
In Silico ◽  
Meta Analysis ◽  
Genetic Disorders ◽  
In Silico Prediction ◽  
Adrenal Hyperplasia ◽  
Single Nucleotide Variants ◽  
Mild Phenotype ◽  
The Impact

Context: CYP21A2 deficiency represents 95% of congenital adrenal hyperplasia cases (CAH), a group of genetic disorders that affect steroid biosynthesis. The genetic and functional analysis provides critical tools to elucidate complex CAH cases. One of the most accessible tools to infer the pathogenicity of new variants is in silico prediction. Objective: Analyze the performance of in silico prediction tools to categorize missense single nucleotide variants (SNVs) of the CYP21A2. Methods: SNVs of the CYP21A2 characterized in vitro by functional assays were selected to assess the performance of online single and meta predictors. SNVs were tested separately or in combination with the related phenotype (severe or mild CAH form). In total, 103 SNVs of the CYP21A2 (90 pathogenic and 13 neutral) were used to test the performance of 13 single-predictors and four meta-predictors. Results: SNVs associated with the severe phenotypes were well categorized by all tools, with an accuracy between 0.69 (PredictSNP2) and 0.97 (CADD), and Matthews' correlation coefficient (MCC) between 0.49 (PoredicSNP2) and 0.90 (CADD). However, SNVs related to the mild phenotype had more variation, with the accuracy between 0.47 (S3Ds&GO and MAPP) and 0.88 (CADD), and MCC between 0.18 (MAPP) and 0.71 (CADD). Conclusion: From our analysis, we identified four predictors of CYP21A2 pathogenicity with good performance. These results can be used for future analysis to infer the impact of uncharacterized SNVs' in CYP21A2.

scholarly journals Construction of anti-codon table of the plant kingdom and evolution of tRNA selenocysteine (tRNASec)

BMC Genomics ◽  
2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Tapan Kumar Mohanta ◽  
Awdhesh Kumar Mishra ◽  
Abeer Hashem ◽  
Elsayed Fathi Abd_Allah ◽  
Abdul Latif Khan ◽  
...  
Keyword(s):  
Amino Acids ◽  
Zea Mays ◽  
Amino Acid ◽  
Codon Usage ◽  
Synonymous Codon ◽  
Protein Translation ◽  
Synonymous Codon Usage ◽  
Papaver Somniferum ◽  
Plant Kingdom ◽  
Ostreococcus Tauri

Abstract Background The tRNAs act as a bridge between the coding mRNA and incoming amino acids during protein translation. The anti-codon of tRNA recognizes the codon of the mRNA and deliver the amino acid into the protein translation chain. However, we did not know about the exact abundance of anti-codons in the genome and whether the frequency of abundance remains same across the plant lineage or not. Results Therefore, we analysed the tRNAnome of 128 plant species and reported an anti-codon table of the plant kingdom. We found that CAU anti-codon of tRNAMet has highest (5.039%) whereas GCG anti-codon of tRNAArg has lowest (0.004%) abundance. However, when we compared the anti-codon frequencies according to the tRNA isotypes, we found tRNALeu (7.808%) has highest abundance followed by tRNASer (7.668%) and tRNAGly (7.523%). Similarly, suppressor tRNA (0.036%) has lowest abundance followed by tRNASec (0.066%) and tRNAHis (2.109). The genome of Ipomoea nil, Papaver somniferum, and Zea mays encoded the highest number of anti-codons (isoacceptor) at 59 each whereas the genome of Ostreococcus tauri was found to encode only 18 isoacceptors. The tRNASec genes undergone losses more frequently than duplication and we found that tRNASec showed anti-codon switch during the course of evolution. Conclusion The anti-codon table of the plant tRNA will enable us to understand the synonymous codon usage of the plant kingdom and can be very helpful to understand which codon is preferred over other during the translation.

scholarly journals Non-optimal codon usage is critical for protein structure and function of the master general amino acid control regulator CPC-1

2020 ◽  
Author(s):  
Xueliang Lyu ◽  
Yi Liu
Keyword(s):  
Protein Structure ◽  
Amino Acid ◽  
Codon Usage ◽  
Synonymous Codon ◽  
Critical Role ◽  
Amino Acid Starvation ◽  
General Amino Acid Control ◽  
Acid Control ◽  
Control Response ◽  
And Function

ABSTRACTUnder amino acid starvation condition, eukaryotic organisms activate a general amino acid control response. In Neurospora crassa, Cross Pathway Control-1 (CPC-1), the ortholog of the Saccharomyces cerevisiae bZIP transcription factor GCN4, functions as the master regulator of the general amino acid control response. Codon usage biases are a universal feature of eukaryotic genomes and are critical for regulation of gene expression. Although codon usage has also been implicated in the regulation of protein structure and function, genetic evidence supporting this conclusion is very limited. Here we show that Neurospora cpc-1 has a non-optimal NNU-rich codon usage profile that contrasts with the strong NNC codon preference in the genome. Although substitution of the cpc-1 NNU codons with synonymous NNC codons elevated CPC-1 expression in Neurospora, it altered CPC-1 degradation rate and abolished its amino acid starvation-induced protein stabilization. The codon-manipulated CPC-1 protein also exhibited different sensitivity to limited protease digestion. Furthermore, CPC-1 functions in rescuing the cell growth of the cpc-1 deletion mutant and activating the expression of its target genes were impaired by the synonymous codon changes. Together, these results reveal the critical role of codon usage in regulating of CPC-1 expression and function, and establish a genetic example of the importance of codon usage in protein structure.Abstract importanceGeneral amino acid control response is critical for organisms to adapt to amino acid starvation condition. The preference to use certain synonymous codons are a universal feature of all genomes. Synonymous codon changes were previously thought to be silent mutations. In this study, we show that the Neurospora cpc-1 gene has an unusual codon usage profile compared to other genes in the genome. We found that codon optimization of the cpc-1 gene without changing its amino acid sequence resulted in elevated CPC-1 expression, altered protein degradation rate and impaired protein functions due to changes in protein structure. Together, these results reveal the critical role of synonymous codon usage in regulating of CPC-1 expression and function, and establish a genetic example of the importance of codon usage in protein structure.

scholarly journals Construction of Anti-codon Table of the Plant Kingdom and Evolution of tRNA Selenocysteine (tRNAsec)

2020 ◽  
Author(s):  
Tapan Kumar Kumar Mohanta ◽  
Awdhesh Kumar Mishra ◽  
Abeer Hashem ◽  
Elsayed Fathi Abd_Allah ◽  
Ahmed Al-Harrasi
Keyword(s):  
Amino Acids ◽  
Zea Mays ◽  
Amino Acid ◽  
Codon Usage ◽  
Synonymous Codon ◽  
Protein Translation ◽  
Synonymous Codon Usage ◽  
Papaver Somniferum ◽  
Plant Kingdom ◽  
Ostreococcus Tauri

Abstract Background The tRNAs act as a bridge between the coding mRNA and incoming amino acids during protein translation. The anti-codon of tRNA recognizes the codon of the mRNA and deliver the amino acid into the protein translation chain. However, we did not know about the exact abundance of anti-codons in the genome and whether the frequency of abundance remains same across the plant lineage or not. Results Therefore, we analysed the tRNAnome of 128 species and reported an anti-codon table of the plant kingdom. We found that CAU anti-codon of tRNAMet has highest (5.039%) whereas CGC anti-codon of tRNAArg has lowest (0.004%) abundance. However, when we compared the anti-codon frequencies according to the tRNA isotypes, we found tRNALeu (7.808%) has highest abundance followed by tRNASer (7.668%) and tRNAGly (7.523%). Similarly, suppressor tRNA (0.036%) has lowest abundance followed by tRNASec (0.066%) and tRNAHis (2.109). The genome of Ipomoea nil, Papaver somniferum, and Zea mays encoded the highest number of anti-codons at 59 each whereas the genome of Ostreococcus tauri was found to encode only 18 isoacceptors. The tRNASec genes undergone losses more frequently than duplication and it has undergone anti-codon switch during the course of evolution. Conclusion The anti-codon table of the plant tRNA will enable us to understand the synonymous codon usage of the plant kingdom and can be very helpful to understand which codon is preferred over other during the translation.

In silico Analysis of Synonymous Codon Usage Pattern of Rhizobium etli CFN 42

2014 ◽  
Vol 86 (2) ◽  
pp. 385-393
Author(s):  
Mohammad Samir Farooqi ◽  
R. K. Sanjukta ◽  
Dwijesh Chandra Mishra ◽  
Dhananjaya Pratap Singh ◽  
Anil Rai ◽  
...  
Keyword(s):  
Codon Usage ◽  
In Silico ◽  
Synonymous Codon ◽  
In Silico Analysis ◽  
Synonymous Codon Usage ◽  
Codon Usage Pattern ◽  
Usage Pattern ◽  
Rhizobium Etli ◽  
Silico Analysis

scholarly journals Nonoptimal Codon Usage Is Critical for Protein Structure and Function of the Master General Amino Acid Control Regulator CPC-1

mBio ◽  
2020 ◽  
Vol 11 (5) ◽  
Author(s):  
Xueliang Lyu ◽  
Yi Liu
Keyword(s):  
Protein Structure ◽  
Amino Acid ◽  
Codon Usage ◽  
Synonymous Codon ◽  
Critical Role ◽  
Amino Acid Starvation ◽  
General Amino Acid Control ◽  
Acid Control ◽  
Control Response ◽  
And Function

ABSTRACT Under amino acid starvation conditions, eukaryotic organisms activate a general amino acid control response. In Neurospora crassa, Cross Pathway Control Protein 1 (CPC-1), the ortholog of the Saccharomyces cerevisiae bZIP transcription factor GCN4, functions as the master regulator of the general amino acid control response. Codon usage biases are a universal feature of eukaryotic genomes and are critical for regulation of gene expression. Although codon usage has also been implicated in the regulation of protein structure and function, genetic evidence supporting this conclusion is very limited. Here, we show that Neurospora cpc-1 has a nonoptimal NNU-rich codon usage profile that contrasts with the strong NNC codon preference in the genome. Although substitution of the cpc-1 NNU codons with synonymous NNC codons elevated CPC-1 expression in Neurospora, it altered the CPC-1 degradation rate and abolished its amino acid starvation-induced protein stabilization. The codon-manipulated CPC-1 protein also exhibited different sensitivity to limited protease digestion. Furthermore, CPC-1 functions in rescuing the cell growth of the cpc-1 deletion mutant and activation of the expression of its target genes were impaired by the synonymous codon changes. Together, these results reveal the critical role of codon usage in regulation of CPC-1 expression and function and establish a genetic example of the importance of codon usage in protein folding. IMPORTANCE The general amino acid control response is critical for adaptation of organisms to amino acid starvation conditions. The preference to use certain synonymous codons is a universal feature of all genomes. Synonymous codon changes were previously thought to be silent mutations. In this study, we showed that the Neurospora cpc-1 gene has an unusual codon usage profile compared to other genes in the genome. We found that codon optimization of the cpc-1 gene without changing its amino acid sequence resulted in elevated CPC-1 expression, an altered protein degradation rate, and impaired protein functions due to changes in protein structure. Together, these results reveal the critical role of synonymous codon usage in regulation of CPC-1 expression and function and establish a genetic example of the importance of codon usage in protein structure.

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