Point Mutations
Recently Published Documents





2021 ◽  
R. Shyama Prasad Rao ◽  
Nagib Ahsan ◽  
Chunhui Xu ◽  
Lingtao Su ◽  
Jacob Verburgt ◽  

SARS-CoV-2, responsible for the current COVID-19 pandemic that claimed over 4.2 million lives, belongs to a class of enveloped viruses that undergo quick evolutionary adjustments under selection pressure. Numerous variants have emerged in SARS-CoV-2 that are currently posing a serious challenge to the global vaccination effort and COVID-19 management. The evolutionary dynamics of this virus are only beginning to be explored. In this work, we have analysed 1.79 million spike glycoprotein sequences of SARS-CoV-2 and found that the virus is fine-tuning the spike with numerous amino acid insertions and deletions (indels). Indels seem to have a selective advantage as the proportions of sequences with indels were steadily increasing over time, currently at over 89%, with similar trends across countries/variants. There were as many as 420 unique indel positions and 447 unique combinations of indels. Despite their high frequency, indels resulted in only minimal alteration, including both gain and loss, of N-glycosylation sites. As indels and point mutations are positively correlated and sequences with indels have significantly more point mutations, they have implications in the context of evolutionary dynamics of the SARS-CoV-2 spike glycoprotein.

Viruses ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1514
Matteo Castelli ◽  
Andreina Baj ◽  
Elena Criscuolo ◽  
Roberto Ferrarese ◽  
Roberta A. Diotti ◽  

SARS-CoV-2 spike is evolving to maximize transmissibility and evade the humoral response. The massive genomic sequencing of SARS-CoV-2 isolates has led to the identification of single-point mutations and deletions, often having the recurrence of hotspots, associated with advantageous phenotypes. We report the isolation and molecular characterization of a SARS-CoV-2 strain, belonging to a lineage (C.36) not previously associated with concerning traits, which shows decreased susceptibility to vaccine sera neutralization.

2021 ◽  
Vol 11 (1) ◽  
pp. 26-36
Vladimir Chechetkin ◽  
Vasily Lobzin

A method of Transitional Automorphic Mapping of the Genome on Itself (TAMGI) is aimed at combining detection and reconstruction of correlational and quasi-periodic motifs in the viral genomic RNA/DNA sequences. The motifs reconstructed by TAMGI are robust with respect to indels and point mutations and can be tried as putative therapeutic targets. We developed and tested the relevant theory and statistical criteria for TAMGI applications. The applications of TAMGI are illustrated by the study of motifs in the genomes of the severe acute respiratory syndrome coronaviruses SARS-CoV and SARS-CoV-2 (the latter coronavirus SARS-CoV-2 being responsible for the COVID-19 pandemic) packaged within filament-like helical capsid. Such ribonucleocapsid is transported into spherical membrane envelope with incorporated spike glycoproteins. Two other examples concern the genomes of viruses with icosahedral capsids, satellite tobacco mosaic virus (STMV) and bacteriophage PHIX174. A part of the quasi-periodic motifs in these viral genomes was evolved due to weakly specific cooperative interaction between genomic ssRNA/ssDNA and nucleocapsid proteins. The symmetry of the capsids leads to the natural selection of specific quasi-periodic motifs in the related genomic sequences. Generally, TAMGI provides a convenient tool for the study of numerous molecular mechanisms with participation of both quasi-periodic motifs and complete repeats, the genome organization, contextual analysis of cis/trans regulatory elements, data mining, and correlations in the genomic sequences.

2021 ◽  
Josep Rizo ◽  
Marcial Camacho ◽  
Bradley Quade ◽  
Thorsten Trimbuch ◽  
Junjie Xu ◽  

Munc13-1 plays a central role in neurotransmitter release through its conserved C-terminal region, which includes a diacyglycerol (DAG)-binding C1 domain, a Ca2+/PIP2-binding C2B domain, a MUN domain and a C2C domain. Munc13-1 was proposed to bridge synaptic vesicles to the plasma membrane in two different orientations mediated by distinct interactions of the C1C2B region with the plasma membrane: i) one involving a polybasic face that yields a perpendicular orientation of Munc13-1 and hinders release; and ii) another involving the DAG-Ca2+-PIP2-binding face that induces a slanted orientation and facilitates release. Here we have tested this model and investigated the role of the C1C2B region in neurotransmitter release. We find that K603E or R769E point mutations in the polybasic face severely impair synaptic vesicle priming in primary murine hippocampal cultures, and Ca2+-independent liposome bridging and fusion in in vitro reconstitution assays. A K720E mutation in the polybasic face and a K706E mutation in the C2B domain Ca2+-binding loops have milder effects in reconstitution assays and do not affect vesicle priming, but enhance or impair Ca2+-evoked release, respectively. The phenotypes caused by combining these mutations are dominated by the K603E and R769E mutations. Our results show that the C1-C2B region of Munc13-1 plays a central role in vesicle priming and support the notion that re-orientation of Munc13-1 controls neurotransmitter release and short-term presynaptic plasticity.

2021 ◽  
Junjie Zhang ◽  
Ran Xu ◽  
qiang lu ◽  
zhenzhou Xu ◽  
jianye Liu ◽  

Abstract Background: Previously, our team identified a seven-gene mutation panel in urine sediment to discriminate UBC from benign urological diseases. In the present study, we aimed to validate the panel in an expanded and close to natural population cohort of hematuria. Also, we tried to optimize the panel by incorporating methylation biomarkers. We performed external validation to investigate the robustness and stability of the novel panel. Methods: Patients with urothelial carcinomas and controls were prospectively recruited in clinical trial ChiCTR2000029980. The mutation panel was validated in the expanded cohort(n=333) from Hunan multicenter. Several UBC-specific methylation biomarkers were identified by comprehensive analyses of a series of TCGA, GEO and an independent cohorts, and examined in the expanded cohort. Random Forest algorithm was used to construct an optimal panel. External validation of the optimal panel was carried out in Beijing single center cohort(n=89). NGS technique was used to analyze the DNA point mutations and MS-PCR for methylation.Results: The AUC, sensitivity and specificity of the mutation panel in expanded cohort were 0.81, 0.67 and 0.90, respectively. After screening, only cg16966315, cg17945976 and cg24720571 were left for further analysis. The optimal panel consisted of cg24720571 and 8 point mutations, including TERT 228(G_A), FGFR3 568(C_T), TERT 250(G_A), FGFR3 099(A_G), PIK3CA 091(G_A), PIK3CA 085(A_G), PIK3CA 082 (G_A) and HRAS 874(T_C). The AUC, sensitivity and specificity of the optimal panel in training group were 0.89, 0.84 and 0.79, respectively, and in test group were 0.95, 0.91 and 0.95, respectively. In the external validation, the AUC, sensitivity and specificity were 0.98, 0.93 and 0.93, respectively.Conclusions: The optimal panel was obviously superior to previous mutation panel and showed a highly specific and robust performance. The optimal panel may be used as a replaceable approach for early detection of UC.Trial registration: This research was registered in Chinese Clinical Trial Registry(ChiCTR2000029980).

2021 ◽  
pp. jmedgenet-2021-107884
Michal Yechieli ◽  
Suleyman Gulsuner ◽  
Hilla Ben-Pazi ◽  
Aviva Fattal ◽  
Adi Aran ◽  

ObjectiveTo determine the yield of genetic diagnoses using chromosomal microarray (CMA) and trio whole exome sequencing (WES), separately and combined, among patients with cryptogenic cerebral palsy (CP).MethodsTrio WES of patients with prior CMA analysis for cryptogenic CP, defined as disabling, non-progressive motor symptoms beginning before the age of 3 years without known cause.ResultsGiven both CMA analysis and trio WES, clinically significant genetic findings were identified for 58% of patients (26 of 45). Diagnoses were eight large CNVs detected by CMA and 18 point mutations detected by trio WES. None had more than one severe mutation. Approximately half of events (14 of 26) were de novo. Yield was significantly higher in patients with CP with comorbidities (69%, 22 of 32) than in those with pure motor CP (31%, 4 of 13; p=0.02). Among patients with genetic diagnoses, CNVs were more frequent than point mutations among patients with congenital anomalies (OR 7.8, 95% CI 1.2 to 52.4) or major dysmorphic features (OR 10.5, 95% CI 1.4 to 73.7). Clinically significant mutations were identified in 18 different genes: 14 with known involvement in CP-related disorders and 4 responsible for other neurodevelopmental conditions. Three possible new candidate genes for CP were ARGEF10, RTF1 and TAOK3.ConclusionsCryptogenic CP is genetically highly heterogeneous. Genomic analysis has a high yield and is warranted in all these patients. Trio WES has higher yield than CMA, except in patients with congenital anomalies or major dysmorphic features, but these methods are complementary. Patients with negative results with one approach should also be tested by the other.

Insects ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 676
Valentina Mastrantonio ◽  
Daniele Porretta ◽  
Valentina Lucchesi ◽  
Nurper Güz ◽  
Naciye Sena Çağatay ◽  

Insecticide resistance is an informative model for studying the appearance of adaptive traits. Simultaneously, understanding how many times resistance mutations originate is essential to design effective resistance management. In the mosquito Culex pipiens, target–site resistance to the insecticide diflubenzuron (DFB) has been recently found in Italian and Turkish populations. Three point mutations confer it at the codon 1043 of the chitin synthase 1 gene (chs-1): I1043L, I1043M, and I1043F. Whether the resistant mutations originated independently from different susceptible alleles or sequentially from resistant alleles and whether resistant alleles from Italy and Turkey have originated once or multiple times remain unresolved. Here, we sequenced a fragment of the chs-1 gene carrying the resistant mutations and inferred the phylogenetic relationships among susceptible and resistant alleles. Confirming previous findings, we found the three mutations in Italy and the I1043M in Turkey. Notably, the I1043F was also found for the first time in Turkish samples, highlighting the need for extensive monitoring activities. Phylogenetic analyses are consistent with an independent origin of the I1043F, I1043M, and I1043L mutations from different susceptible alleles and with multiple independent origins of the Italian and Turkish I1043M and I1043F alleles.

Diagnostics ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1341
Antonios Revythis ◽  
Sidrah Shah ◽  
Mikolaj Kutka ◽  
Michele Moschetta ◽  
Mehmet Akif Ozturk ◽  

The use of biomarkers in medicine has become essential in clinical practice in order to help with diagnosis, prognostication and prediction of treatment response. Since Alexander Breslow’s original report on “melanoma and prognostic values of thickness”, providing the first biomarker for melanoma, many promising new biomarkers have followed. These include serum markers, such as lactate dehydrogenase and S100 calcium-binding protein B. However, as our understanding of the DNA mutational profile progresses, new gene targets and proteins have been identified. These include point mutations, such as mutations of the BRAF gene and tumour suppressor gene tP53. At present, only a small number of the available biomarkers are being utilised, but this may soon change as more studies are published. The aim of this article is to provide a comprehensive review of melanoma biomarkers and their utility for current and, potentially, future clinical practice.

2021 ◽  
Vol 8 ◽  
Tanushree Tunstall ◽  
Jody Phelan ◽  
Charlotte Eccleston ◽  
Taane G. Clark ◽  
Nicholas Furnham

Resistance to drugs used to treat tuberculosis disease (TB) continues to remain a public health burden, with missense point mutations in the underlying Mycobacterium tuberculosis bacteria described for nearly all anti-TB drugs. The post-genomics era along with advances in computational and structural biology provide opportunities to understand the interrelationships between the genetic basis and the structural consequences of M. tuberculosis mutations linked to drug resistance. Pyrazinamide (PZA) is a crucial first line antibiotic currently used in TB treatment regimens. The mutational promiscuity exhibited by the pncA gene (target for PZA) necessitates computational approaches to investigate the genetic and structural basis for PZA resistance development. We analysed 424 missense point mutations linked to PZA resistance derived from ∼35K M. tuberculosis clinical isolates sourced globally, which comprised the four main M. tuberculosis lineages (Lineage 1–4). Mutations were annotated to reflect their association with PZA resistance. Genomic measures (minor allele frequency and odds ratio), structural features (surface area, residue depth and hydrophobicity) and biophysical effects (change in stability and ligand affinity) of point mutations on pncA protein stability and ligand affinity were assessed. Missense point mutations within pncA were distributed throughout the gene, with the majority (>80%) of mutations with a destabilising effect on protomer stability and on ligand affinity. Active site residues involved in PZA binding were associated with multiple point mutations highlighting mutational diversity due to selection pressures at these functionally important sites. There were weak associations between genomic measures and biophysical effect of mutations. However, mutations associated with PZA resistance showed statistically significant differences between structural features (surface area and residue depth), but not hydrophobicity score for mutational sites. Most interestingly M. tuberculosis lineage 1 (ancient lineage) exhibited a distinct protein stability profile for mutations associated with PZA resistance, compared to modern lineages.

Export Citation Format

Share Document