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Journal of Biosciences 2022A major presumption of the neutral theory of evolution proposed by Kimura in the late 1960s is that synonymous mutations (mutations that do not alter the primary...
A major presumption of the neutral theory of evolution proposed by Kimura in the late 1960s is that synonymous mutations (mutations that do not alter the primary sequence of a protein due to the redundancy of the genetic code) are supposed to be selectively neutral or nearly neutral (Kimura 1968). However, Shen et al. (2022) have recently demonstrated that 75.9% of synonymous mutations in genes involved in important cellular functions in the haploid yeast show reduced fitness in different environments examined. Based on their analyses of fitness effects in different growth conditions, the authors argue that non-synonymous mutants show a more significant fitness variation across growth environments compared with synonymous mutants, although the two mutant classes have similar patterns of fitness susceptibility in the same environment. They propose that a larger proportion of synonymous mutants reach fixation compared with their non-synonymous counterparts because more of them survive environmental challenges. In this Clipboard article, I examine the evidence provided by the authors to evaluate whether their evidence is sufficient to substantiate this claim and explore possible consequences of these observations.
Topics: Silent Mutation; Mutation; Saccharomyces cerevisiae; Evolution, Molecular; Genetic Fitness
PubMed: 36510436
DOI: No ID Found -
Frontiers in Pediatrics 2022Glanzmann thrombasthenia (GT) is a rare inherited disease characterized by mucocutaneous bleeding due to the abnormalities in quantity or quality of platelet membrane GP...
Glanzmann thrombasthenia (GT) is a rare inherited disease characterized by mucocutaneous bleeding due to the abnormalities in quantity or quality of platelet membrane GP IIb (CD41) or GP IIIa (CD61). GP IIb and GP IIIa are encoded by the and genes, respectively. Herein, we described a 7-year-old Chinese boy of the consanguineous couple who was diagnosed with GT based on the typical clinical manifestations, absence of blood clot retraction and the reduced expression of CD41 and CD61 in platelets. A homozygous silent variant c.1431C > T (p. G477=) of the gene was identified by the Whole-exome sequencing and confirmed by Sanger sequencing. The variant was predicted to affect the splicing. RT-PCR and sequencing revealed that the variant caused a deletion of 95 base pairs and frameshift, and subsequently created a premature stop codon in exon 10 of (p. G477Afs*30). It was indicated that the variant c.1431C > T (p. G477=) of was the cause for Glanzmann thrombasthenia. Our findings expanded the mutation spectrum and provided the information for the genetic counseling, prenatal diagnosis and preimplantation genetic testing (PGT).
PubMed: 36704147
DOI: 10.3389/fped.2022.1062900 -
Genes Apr 2022Synonymous single nucleotide variants (sSNVs) are often considered functionally silent, but a few cases of cancer-causing sSNVs have been reported. From available...
Synonymous single nucleotide variants (sSNVs) are often considered functionally silent, but a few cases of cancer-causing sSNVs have been reported. From available databases, we collected four categories of sSNVs: germline, somatic in normal tissues, somatic in cancerous tissues, and putative cancer drivers. We found that screening sSNVs for recurrence among patients, conservation of the affected genomic position, and synVep prediction (synVep is a machine learning-based sSNV effect predictor) recovers cancer driver variants (termed ) and previously unknown putative cancer genes. Of the 2.9 million somatic sSNVs found in the COSMIC database, we identified 2111 proposed cancer driver sSNVs. Of these, 326 sSNVs could be further tagged for possible RNA splicing effects, RNA structural changes, and affected RBP motifs. This list of proposed cancer driver sSNVs provides computational guidance in prioritizing the experimental evaluation of synonymous mutations found in cancers. Furthermore, our list of novel potential cancer genes, galvanized by synonymous mutations, may highlight yet unexplored cancer mechanisms.
Topics: Genomics; Humans; Neoplasms; Oncogenes; RNA Splicing; Silent Mutation
PubMed: 35627162
DOI: 10.3390/genes13050778 -
PloS One 2022Colorectal cancer (CRC) needs several mutations to occur in various genes, and can vary widely in different individuals; hence it is essential to be discovered in a...
BACKGROUND
Colorectal cancer (CRC) needs several mutations to occur in various genes, and can vary widely in different individuals; hence it is essential to be discovered in a specific population. Until recently, there has been no known study describing APC, TP53, PIK3CA, KRAS, and MLH1 of CRC in Indonesian population. This study describes the nature and location of mutation in CRC patients treated at three different hospitals in Jakarta.
METHODS
This descriptive study was conducted on CRC patients who underwent neoadjuvant, surgical, and adjuvant therapy at RSCM, RSKJ, and MRCCC in 2017-2018. DNA analysis was performed using next-generation sequencing and aligned against GRCh38. The pathogenic variant was identified using ACMG classification and FATHMM score. Data related to behavior and survival were collected from medical records.
RESULTS
Twenty-two subjects in which APC, TP53, and PIKCA were mutated. KRAS mutation occurred in 64%, while MLH1 in 45%. There were five mutation types: nonsense, missense, frameshift, splice-site, and silent mutation. There are four groups of co-occurring mutations: APC, TP53, PIK3CA (triple mutation/TM) alone; TM+KRAS; TM+MLH1; and TM+KRAS+MLH1, presenting different nature and survival.
CONCLUSION
Indonesia has a distinct profile of pathogenic mutation, mainly presenting with locally-advanced stage with various outcomes and survival rate.
Topics: Class I Phosphatidylinositol 3-Kinases; Colorectal Neoplasms; Genomics; Humans; Indonesia; MutL Protein Homolog 1; Mutation; Proto-Oncogene Proteins p21(ras); Tumor Suppressor Protein p53
PubMed: 35709138
DOI: 10.1371/journal.pone.0267090 -
Biomolecules Nov 2020The bacterial RNA polymerase (RNAP) is a multi-subunit protein complex (α2ββ'ω σ) containing the smallest subunit, ω. Although identified early in RNAP research,... (Review)
Review
The bacterial RNA polymerase (RNAP) is a multi-subunit protein complex (α2ββ'ω σ) containing the smallest subunit, ω. Although identified early in RNAP research, its function remained ambiguous and shrouded with controversy for a considerable period. It was shown before that the protein has a structural role in maintaining the conformation of the largest subunit, β', and its recruitment in the enzyme assembly. Despite evolutionary conservation of ω and its role in the assembly of RNAP, mutants lacking (codes for ω) are viable due to the association of the global chaperone protein GroEL with RNAP. To get a better insight into the structure and functional role of ω during transcription, several dominant lethal mutants of ω were isolated. The mutants showed higher binding affinity compared to that of native ω to the α2ββ' subassembly. We observed that the interaction between α2ββ' and these lethal mutants is driven by mostly favorable enthalpy and a small but unfavorable negative entropy term. However, during the isolation of these mutants we isolated a silent mutant serendipitously, which showed a lethal phenotype. Silent mutant of a given protein is defined as a protein having the same sequence of amino acids as that of wild type but having mutation in the gene with alteration in base sequence from more frequent code to less frequent one due to codon degeneracy. Eventually, many silent mutants were generated to understand the role of rare codons at various positions in . We observed that the dominant lethal mutants of ω having either point mutation or silent in nature are more structured in comparison to the native ω. However, the silent code's position in the reading frame of plays a role in the structural alteration of the translated protein. This structural alteration in ω makes it more rigid, which affects the plasticity of the interacting domain formed by ω and α2ββ'. Here, we attempted to describe how the conformational flexibility of the ω helps in maintaining the plasticity of the active site of RNA polymerase. The dominant lethal mutant of ω has a suppressor mapped near the catalytic center of the β' subunit, and it is the same for both types of mutants.
Topics: Bacterial Proteins; DNA-Directed RNA Polymerases; Mutant Proteins; Protein Subunits; Structure-Activity Relationship; Transcription Factors
PubMed: 33238579
DOI: 10.3390/biom10111588 -
Trends in Pharmacological Sciences Dec 2017Identifying the direct physiological targets of drugs and chemical probes remains challenging. Here we describe how resistance can be used to achieve 'gold-standard'... (Review)
Review
Identifying the direct physiological targets of drugs and chemical probes remains challenging. Here we describe how resistance can be used to achieve 'gold-standard' validation of a chemical inhibitor's direct target in human cells. This involves demonstrating that a silent mutation in the target that suppresses inhibitor activity in cell-based assays can also reduce inhibitor potency in biochemical assays. Further, phenotypes due to target inhibition can be identified as those observed in the inhibitor-sensitive cells, across a range of inhibitor concentrations, but not in genetically matched cells with a silent resistance-conferring mutation in the target. We propose that chemotype-specific resistance, which is generally considered to be a limitation of molecularly targeted agents, can be leveraged to deconvolve the mechanism of action of drugs and to properly use chemical probes.
Topics: Antineoplastic Agents; Drug Resistance, Neoplasm; Humans; Molecular Targeted Therapy; Neoplasms
PubMed: 29037508
DOI: 10.1016/j.tips.2017.09.003 -
Virus Research Jan 2022COVID-19 has posed unforeseen circumstances and throttled major economies worldwide. India has witnessed two waves affecting around 31 million people representing 16% of...
BACKGROUND
COVID-19 has posed unforeseen circumstances and throttled major economies worldwide. India has witnessed two waves affecting around 31 million people representing 16% of the cases globally. To date, the epidemic waves have not been comprehensively investigated to understand pandemic progress in India.
OBJECTIVE
Here, we aim for pan Indian cross-sectional evolutionary analysis since inception of SARS-CoV-2.
METHODS
High quality genomes, along with their collection date till 26th July 2021, were downloaded. Whole genome-based phylogeny was obtained. Further, the mutational analysis was performed using SARS-CoV-2 first reported from Wuhan (NC_045512.2) as reference.
RESULTS
Based on reported cases and mutation rates, we could divide the Indian epidemic into seven phases. The average mutation rate for the pre-first wave was <11, which elevated to 17 in the first wave and doubled in the second wave (∼34). In accordance with mutation rate, VOCs and VOIs started appearing in the first wave (1.5%), which dominated the second (∼96%) and post-second wave (100%). Nation-wide mutational analysis depicted >0.5 million mutation events with four major mutations in >19,300 genomes, including two mutations in coding (spike (D614G), and NSP 12b (P314L) of rdrp), one silent mutation (NSP3 F106F) and one extragenic mutation (5' UTR 241).
CONCLUSION
Whole genome-based phylogeny could demarcate post-first wave isolates from previous ones by point of diversification leading to incidences of VOCs and VOIs in India. Such analysis is crucial in the timely management of pandemic.
Topics: 5' Untranslated Regions; COVID-19; Cross-Sectional Studies; Epidemics; Genome, Viral; Genomics; Humans; India; Mutation; Phylogeny; SARS-CoV-2; Spike Glycoprotein, Coronavirus
PubMed: 34822953
DOI: 10.1016/j.virusres.2021.198642 -
Journal of Dental Research Apr 2020Amelogenesis imperfecta (AI) is a collection of genetic disorders affecting the quality and/or quantity of tooth enamel. More than 20 genes are, so far, known to be...
Amelogenesis imperfecta (AI) is a collection of genetic disorders affecting the quality and/or quantity of tooth enamel. More than 20 genes are, so far, known to be responsible for this condition. In this study, we recruited 3 Turkish families with hypomaturation AI. Whole-exome sequence analyses identified disease-causing mutations in each proband, and these mutations cosegregated with the AI phenotype in all recruited members of each family. The AI-causing mutations in family 1 were a novel mutation [NM_182680.1:c.143T>C, p.(Leu48Ser)] in the proband and a novel homozygous mutation [NM_004771.3:c.616G>A, p.(Asp206Asn)] in the mother of the proband. Previously reported compound heterozygous mutations [NM_004771.3:c.103A>C, p.(Arg35=) and c.389C>T, p.(Thr130Ile)] caused the AI in family 2 and family 3. Minigene splicing analyses revealed that the missense mutation increased exonic definition of exon 4 and the synonymous mutation decreased exonic definition of exon 1. These mutations would trigger an alteration of exon usage during RNA splicing, causing the enamel malformations. These results broaden our understanding of molecular genetic pathology of tooth enamel formation.
Topics: Amelogenesis Imperfecta; Dental Enamel; Exons; Humans; Mutation; Pedigree
PubMed: 31999931
DOI: 10.1177/0022034520901708 -
Frontiers in Immunology 2022Phosphatidylinositol-4-kinase alpha (PI4KIIIα), encoded by the gene, can synthesize phosphatidylinositol-4-phosphate (PI-4-P), which serves as a specific membrane...
Phosphatidylinositol-4-kinase alpha (PI4KIIIα), encoded by the gene, can synthesize phosphatidylinositol-4-phosphate (PI-4-P), which serves as a specific membrane marker and is instrumental in signal transduction. mutations can cause autosomal recessive diseases involving neurological, intestinal, and immunological conditions (OMIM:619621, 616531, 619708). We detected sepsis, severe diarrhea, and decreased immunoglobulin levels in one neonate. Two novel compound heterozygous mutations, c.5846T>C (p.Leu1949Pro) and c.3453C>T (p.Gly1151=), were identified in the neonate from the father and the mother, respectively. Sanger sequencing and reverse transcription polymerase chain reaction (RT-PCR) for peripheral blood and minigene splicing assays showed a deletion of five bases (GTGAG) with the c.3453C>T variant at the mRNA level, which could result in a truncated protein (p.Gly1151GlyfsTer17). The missense mutation c.5846T>C (p.Leu1949Pro) kinase activity was measured, and little or no catalytic activity was detected. According to the clinical characteristics and gene mutations with functional verification, our pediatricians diagnosed the child with a combined immunodeficiency and intestinal disorder close to gastrointestinal defects and immunodeficiency syndrome 2 (GIDID2; OMIM: 619708). Medicines such as immunomodulators are prescribed to balance immune dysregulation. This study is the first report of a synonymous mutation in the gene that influences alternative splicing. Our findings expand the mutation spectrum leading to PI4KIIIa deficiency-related diseases and provide exact information for genetic counseling.
Topics: Child; Infant, Newborn; Humans; Silent Mutation; RNA Splicing; Alternative Splicing; Mutation; Gene Expression
PubMed: 36341355
DOI: 10.3389/fimmu.2022.987666 -
Scientific Reports May 2023Recent studies have shown that some silent mutations can be harmful to various processes. In this study, we performed a comprehensive in silico analysis to elucidate the...
Recent studies have shown that some silent mutations can be harmful to various processes. In this study, we performed a comprehensive in silico analysis to elucidate the effects of silent mutations on cancer pathogenesis using exome sequencing data derived from the Cancer Genome Atlas. We focused on the codon optimality scores of silent mutations, which were defined as the difference between the optimality of synonymous codons, calculated using the codon usage table. The relationship between cancer evolution and silent mutations showed that the codon optimality score of the mutations that occurred later in carcinogenesis was significantly higher than of those that occurred earlier. In addition, mutations with higher scores were enriched in genes involved in the cell cycle and cell division, while those with lower scores were enriched in genes involved in apoptosis and cellular senescence. Our results demonstrate that some silent mutations can be involved in cancer pathogenesis.
Topics: Humans; Silent Mutation; Evolution, Molecular; Mutation; Codon; Neoplasms
PubMed: 37165041
DOI: 10.1038/s41598-023-34452-w