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Virus Genes Aug 2023The critical Epstein‒Barr virus (EBV)-encoded latent membrane protein 1 (LMP-1) and BamHI fragment H rightward open reading frame 1 (BHRF-1) genes affect EBV-mediated...
Genetic variability and mutation of Epstein‒Barr virus (EBV)-encoded LMP-1 and BHRF-1 genes in EBV-infected patients: identification of precise targets for development of personalized EBV vaccines.
The critical Epstein‒Barr virus (EBV)-encoded latent membrane protein 1 (LMP-1) and BamHI fragment H rightward open reading frame 1 (BHRF-1) genes affect EBV-mediated malignant transformation and virus replication during EBV infection. Therefore, these two genes are considered ideal targets for EBV vaccine development. However, gene mutations in LMP-1 and BHRF-1 in different cohorts may affect the biological functions of EBV, which would seriously hinder development of personalized vaccines for EBV. In the present study, by performing nested polymerase chain reaction (nested PCR) and DNA sequence techniques, we analyzed the nucleotide variability and phylogeny of LMP-1 containing a 30 bp deletion region (del-LMP-1) and BHRF-1 in EBV-infected patients (N = 382) and healthy persons receiving physical examination (N = 98; defined as the control group) in Yunnan Province, China. Three BHRF-1 subtypes were identified in this study: 79V88V, 79L88L, and 79V88L, with mutation frequencies of 58.59%, 24.24%, and 17.17%, respectively. Compared with the control group, the distribution of BHRF-1 subtypes of the three groups showed no significant difference, suggesting that BHRF-1 is highly conserved in EBV-related samples. In addition, a short fragment of del-LMP-1 was found in 133 cases, and the nucleotide variation rate was 87.50% (133/152). For del-LMP-1, a significant distribution in three groups was detected, as characterized by a high mutation rate. In conclusion, our study illustrates gene variability and mutations of EBV-encoded del-LMP-1 and BHRF-1 in clinical samples. Highly mutated LMP-1 might be associated with various types of EBV-related diseases, indicating that BHRF-1 combined with LMP-1 may be used as an ideal target for development of EBV personalized vaccines.
Topics: Humans; China; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Mutation; Nucleotides; Vaccines; Viral Matrix Proteins; Viral Proteins
PubMed: 37243920
DOI: 10.1007/s11262-023-02006-x -
Mathematical Biosciences Dec 2023Cancer occurs as a consequence of multiple somatic mutations that lead to uncontrolled cell growth. Mutual exclusivity and co-occurrence of mutations imply-but do not...
Cancer occurs as a consequence of multiple somatic mutations that lead to uncontrolled cell growth. Mutual exclusivity and co-occurrence of mutations imply-but do not prove-that mutations exert synergistic or antagonistic epistatic effects on oncogenesis. Knowledge of these interactions, and the consequent trajectories of mutation and selection that lead to cancer has been a longstanding goal within the cancer research community. Recent research has revealed mutation rates and scaled selection coefficients for specific recurrent variants across many cancer types. However, there are no current methods to quantify the strength of selection incorporating pairwise and higher-order epistatic effects on selection within the trajectory of likely cancer genotoypes. Therefore, we have developed a continuous-time Markov chain model that enables the estimation of mutation origination and fixation (flux), dependent on somatic cancer genotype. Coupling this continuous-time Markov chain model with a deconvolution approach provides estimates of underlying mutation rates and selection across the trajectory of oncogenesis. We demonstrate computation of fluxes and selection coefficients in a somatic evolutionary model for the four most frequently variant driver genes (TP53, LRP1B, KRAS and STK11) from 565 cases of lung adenocarcinoma. Our analysis reveals multiple antagonistic epistatic effects that reduce the possible routes of oncogenesis, and inform cancer research regarding viable trajectories of somatic evolution whose progression could be forestalled by precision medicine. Synergistic epistatic effects are also identified, most notably in the somatic genotype TP53 LRP1B for mutations in the KRAS gene, and in somatic genotypes containing KRAS or TP53 mutations for mutations in the STK11 gene. Large positive fluxes of KRAS variants were driven by large selection coefficients, whereas the flux toward LRP1B mutations was substantially aided by a large mutation rate for this gene. The approach enables inference of the most likely routes of site-specific variant evolution and estimation of the strength of selection operating on each step along the route, a key component of what we need to know to develop and implement personalized cancer therapies.
Topics: Humans; Proto-Oncogene Proteins p21(ras); Mutation Rate; Mutation; Carcinogenesis; Genotype
PubMed: 37996064
DOI: 10.1016/j.mbs.2023.109091 -
Genome Medicine Jan 2024Neoadjuvant chemotherapy (NAC) has become a standard treatment strategy for breast cancer (BC). However, owing to the high heterogeneity of these tumors, it is unclear...
BACKGROUND
Neoadjuvant chemotherapy (NAC) has become a standard treatment strategy for breast cancer (BC). However, owing to the high heterogeneity of these tumors, it is unclear which patient population most likely benefit from NAC. Multi-omics offer an improved approach to uncovering genomic and transcriptomic changes before and after NAC in BC and to identifying molecular features associated with NAC sensitivity.
METHODS
We performed whole-exome and RNA sequencing on 233 samples (including matched pre- and post-treatment tumors) from 50 BC patients with rigorously defined responses to NAC and analyzed changes in the multi-omics landscape. Molecular features associated with NAC response were identified and validated in a larger internal, and two external validation cohorts, as well as in vitro experiments.
RESULTS
The most frequently altered genes were TP53, TTN, and MUC16 in both pre- and post-treatment tumors. In comparison with pre-treatment tumors, there was a significant decrease in C > A transversion mutations in post-treatment tumors (P = 0.020). NAC significantly decreased the mutation rate (P = 0.006) of the DNA repair pathway and gene expression levels (FDR = 0.007) in this pathway. NAC also significantly changed the expression level of immune checkpoint genes and the abundance of tumor-infiltrating immune and stroma cells, including B cells, activated dendritic cells, γδT cells, M2 macrophages and endothelial cells. Furthermore, there was a higher rate of C > T substitutions in NAC nonresponsive tumors than responsive ones, especially when the substitution site was flanked by C and G. Importantly, there was a unique amplified region at 8p11.23 (containing ADGRA2 and ADRB3) and a deleted region at 3p13 (harboring FOXP1) in NAC nonresponsive and responsive tumors, respectively. Particularly, the CDKAL1 missense variant P409L (p.Pro409Leu, c.1226C > T) decreased BC cell sensitivity to docetaxel, and ADGRA2 or ADRB3 gene amplifications were associated with worse NAC response and poor prognosis in BC patients.
CONCLUSIONS
Our study has revealed genomic and transcriptomic landscape changes following NAC in BC, and identified novel biomarkers (CDKAL1, ADGRA2 and ADRB3) underlying chemotherapy resistance and poor prognosis, which could guide the development of personalized treatments for BC.
Topics: Humans; Female; Breast Neoplasms; Neoadjuvant Therapy; Endothelial Cells; Gene Expression Profiling; Genomics; Repressor Proteins; Forkhead Transcription Factors; Receptors, Adrenergic, beta-3
PubMed: 38217005
DOI: 10.1186/s13073-024-01286-8 -
Applied Microbiology and Biotechnology Dec 2024Assessing the genomic evolution of Staphylococcus aureus can help us understand how the bacteria adapt to its environment. In this study, we aimed to assess the mutation...
Assessing the genomic evolution of Staphylococcus aureus can help us understand how the bacteria adapt to its environment. In this study, we aimed to assess the mutation rate within 144 methicillin-resistant Staphylococcus aureus (MRSA) carriers with a carriage time from 4 to 11 years, including some carriers who belonged to the same households. We found that 23 of the 144 individuals had completely different MRSA types over time and were therefore not long-term carriers of the same MRSA. From the remaining 121 individuals, we performed whole-genome sequencing (WGS) on 424 isolates and then compared these pairwise using core genome multilocus sequence typing (cgMLST) and single-nucleotide polymorphism (SNP) analyses. We found a median within-host mutation rate in long-term MRSA carriers of 4.9 (3.4-6.9) SNPs/genome/year and 2.7 (1.8-4.2) allelic differences/genome/year, when excluding presumed recombination. Furthermore, we stratified the cohort into subgroups and found no significant difference between the median mutation rate of members of households, individuals with presumed continued exposure, e.g., from travel and persons without known continued exposure. Finally, we found that SNPs occurred at random within the genes in our cohort. KEY POINTS: • Median mutation rate within long-term MRSA carriers of 4.9 (3.4-6.9) SNPs/genome/year • Similar median mutation rates in subgroups (households, travelers) • No hotspots for SNPs within the genome.
Topics: Humans; Methicillin-Resistant Staphylococcus aureus; Staphylococcus aureus; Staphylococcal Infections; Genomics; Multilocus Sequence Typing; Mutation Rate
PubMed: 38212970
DOI: 10.1007/s00253-023-12932-3 -
Nature Communications Sep 2023The transcriptional intermediates of RNAs fold into secondary structures with multiple regulatory roles, yet the details of such cotranscriptional RNA folding are...
The transcriptional intermediates of RNAs fold into secondary structures with multiple regulatory roles, yet the details of such cotranscriptional RNA folding are largely unresolved in eukaryotes. Here, we present eSPET-seq (Structural Probing of Elongating Transcripts in eukaryotes), a method to assess the cotranscriptional RNA folding in Saccharomyces cerevisiae. Our study reveals pervasive structural transitions during cotranscriptional folding and overall structural similarities between nascent and mature RNAs. Furthermore, a combined analysis with genome-wide R-loop and mutation rate approximations provides quantitative evidence for the antimutator effect of nascent RNA folding through competitive inhibition of the R-loops, known to facilitate transcription-associated mutagenesis. Taken together, we present an experimental evaluation of cotranscriptional folding in eukaryotes and demonstrate the antimutator effect of nascent RNA folding. These results suggest genome-wide coupling between the processing and transmission of genetic information through RNA folding.
Topics: Antimutagenic Agents; Eukaryotic Cells; Mutagenesis; RNA; Saccharomyces cerevisiae
PubMed: 37730811
DOI: 10.1038/s41467-023-41550-w -
Genome Biology and Evolution Aug 2023Coding sequence evolution is influenced by both natural selection and neutral evolutionary forces. In many species, the effects of mutation bias, codon usage, and...
Coding sequence evolution is influenced by both natural selection and neutral evolutionary forces. In many species, the effects of mutation bias, codon usage, and GC-biased gene conversion (gBGC) on gene sequence evolution have not been detailed. Quantification of how these forces shape substitution patterns is therefore necessary to understand the strength and direction of natural selection. Here, we used comparative genomics to investigate the association between base composition and codon usage bias on gene sequence evolution in butterflies and moths (Lepidoptera), including an in-depth analysis of underlying patterns and processes in one species, Leptidea sinapis. The data revealed significant G/C to A/T substitution bias at third codon position with some variation in the strength among different butterfly lineages. However, the substitution bias was lower than expected from previously estimated mutation rate ratios, partly due to the influence of gBGC. We found that A/T-ending codons were overrepresented in most species, but there was a positive association between the magnitude of codon usage bias and GC-content in third codon positions. In addition, the tRNA-gene population in L. sinapis showed higher GC-content at third codon positions compared to coding sequences in general and less overrepresentation of A/T-ending codons. There was an inverse relationship between synonymous substitutions and codon usage bias indicating selection on synonymous sites. We conclude that the evolutionary rate in Lepidoptera is affected by a complex interaction between underlying G/C -> A/T mutation bias and partly counteracting fixation biases, predominantly conferred by overall purifying selection, gBGC, and selection on codon usage.
Topics: Animals; Butterflies; Codon Usage; Base Composition; Codon; Gene Conversion; Selection, Genetic; Evolution, Molecular
PubMed: 37565492
DOI: 10.1093/gbe/evad150 -
Nucleic Acids Research Jun 2024AT-rich interaction domain protein 1A (ARID1A), a SWI/SNF chromatin remodeling complex subunit, is frequently mutated across various cancer entities. Loss of ARID1A...
AT-rich interaction domain protein 1A (ARID1A), a SWI/SNF chromatin remodeling complex subunit, is frequently mutated across various cancer entities. Loss of ARID1A leads to DNA repair defects. Here, we show that ARID1A plays epigenetic roles to promote both DNA double-strand breaks (DSBs) repair pathways, non-homologous end-joining (NHEJ) and homologous recombination (HR). ARID1A is accumulated at DSBs after DNA damage and regulates chromatin loops formation by recruiting RAD21 and CTCF to DSBs. Simultaneously, ARID1A facilitates transcription silencing at DSBs in transcriptionally active chromatin by recruiting HDAC1 and RSF1 to control the distribution of activating histone marks, chromatin accessibility, and eviction of RNAPII. ARID1A depletion resulted in enhanced accumulation of micronuclei, activation of cGAS-STING pathway, and an increased expression of immunomodulatory cytokines upon ionizing radiation. Furthermore, low ARID1A expression in cancer patients receiving radiotherapy was associated with higher infiltration of several immune cells. The high mutation rate of ARID1A in various cancer types highlights its clinical relevance as a promising biomarker that correlates with the level of immune regulatory cytokines and estimates the levels of tumor-infiltrating immune cells, which can predict the response to the combination of radio- and immunotherapy.
Topics: Humans; Cell Line, Tumor; Chromatin; Chromatin Assembly and Disassembly; DNA Breaks, Double-Stranded; DNA Repair; DNA-Binding Proteins; Histone Deacetylase 1; Homologous Recombination; Immunity; Neoplasms; Nuclear Proteins; Nucleotidyltransferases; Trans-Activators; Transcription Factors
PubMed: 38587186
DOI: 10.1093/nar/gkae233 -
Bioinformatics Advances 2023Compared to eukaryotes, prokaryote genomes are more diverse through different mechanisms, including a higher mutation rate and horizontal gene transfer. Therefore, using...
MOTIVATION
Compared to eukaryotes, prokaryote genomes are more diverse through different mechanisms, including a higher mutation rate and horizontal gene transfer. Therefore, using a linear representative reference can cause a reference bias. Graph-based pangenome methods have been developed to tackle this problem. However, comparisons in DNA space are still challenging due to this high diversity. In contrast, amino acid sequences have higher similarity due to evolutionary constraints, whereby a single amino acid may be encoded by several synonymous codons. Coding regions cover the majority of the genome in prokaryotes. Thus, panproteomes present an attractive alternative leveraging the higher sequence similarity while not losing much of the genome in non-coding regions.
RESULTS
We present PanPA, a method that takes a set of multiple sequence alignments of protein sequences, indexes them, and builds a graph for each multiple sequence alignment. In the querying step, it can align DNA or amino acid sequences back to these graphs. We first showcase that PanPA generates correct alignments on a panproteome from 1350 . To demonstrate that panproteomes allow comparisons at longer phylogenetic distances, we compare DNA and protein alignments from 1073 assemblies against reference genome, pangenome, and panproteome using BWA, GraphAligner, and PanPA, respectively; with PanPA aligning around 22% more sequences. We also aligned a DNA short-reads whole genome sequencing (WGS) sample from against the reference with BWA and the panproteome with PanPA, where PanPA was able to find alignment for 68% of the reads compared to 5% with BWA.
AVAILALABILITY AND IMPLEMENTATION
PanPA is available at https://github.com/fawaz-dabbaghieh/PanPA.
PubMed: 38145107
DOI: 10.1093/bioadv/vbad167 -
World Journal of Gastrointestinal... Jul 2023The carcinogenesis of stomach adenocarcinoma (STAD) involves many different molecules and multiple pathways, including the NOTCH signaling pathway. As a key factor that...
BACKGROUND
The carcinogenesis of stomach adenocarcinoma (STAD) involves many different molecules and multiple pathways, including the NOTCH signaling pathway. As a key factor that functions as a critical link in the NOTCH pathway, mind bomb 1 () is upregulated in various tumors and has been reported to promote cell metastasis and invasion. However, studies on the role of in STAD are limited. Here, we evaluated the prognostic value of in STAD and its association with immune infiltration and copy number variation.
AIM
To elucidate the relationship between gene and gastric cancer (GC) and provide a new idea for the treatment of GC.
METHODS
We identified mutations in the gene by searching the cBioPortal database and then analyzed their relationship with the overall survival rate and disease-free survival rate using the Kaplan-Meier method. The Cancer Genome Atlas (TCGA) database provided transcript levels for in STADs and normal tissues. As a method of distinguishing the STAD tissues from adjacent normal tissues, a receiver operating characteristic (ROC) curve was generated. Kaplan-Meier plotter was used to determine the effect of expression on survival. Based on the LinkedOmics database, we were able to identify the coexpressed genes of the gene, the top 50 positively correlated genes, and the top 50 negatively correlated genes. STRING was used to construct protein-protein interaction networks related to the gene. An analysis of functional enrichment was carried out using the R package "Cluster Profiler". The relationships between mRNA expression of and immune infiltrates were assessed by Tumor IMmune Estimation Resource (TIMER) and the "GSVA package" in R.
RESULTS
According to the cBioPortal database, the mutation rate in 287 patients in the TCGA dataset was approximately 6%. Kaplan-Meier survival analysis showed that patients with STAD in the mutated group had a worse prognosis than those in the unmutated group ( = 0.0156). There was a significant upregulation of expression in STAD tissues compared to adjacent normal tissues. A high T stage was associated with increased mRNA expression. The ROC curve analysis revealed 59.4% sensitivity and 85.6% specificity of for differentiating STAD tissues from adjacent normal tissues at a truncation level of 2.248. Kaplan-Meier plotter indicated that patients with higher levels had a worse prognosis than those with lower levels (26.4 mo 56.2 mo, = 0.0330). A correlation analysis demonstrated an association between immune infiltrates and mRNA expression.
CONCLUSION
Upregulation of expression is significantly associated with poor survival rate and immune infiltration in gastric adenocarcinoma. may be a biomarker for the poor prognosis of STAD patients and a potential immunotherapeutic target.
PubMed: 37546549
DOI: 10.4251/wjgo.v15.i7.1295 -
PloS One 2023Monkeypox is a double-stranded DNA virus with an envelope and is a member of the Poxviridae family's Orthopoxvirus genus. This virus can transmit from human to human...
Monkeypox is a double-stranded DNA virus with an envelope and is a member of the Poxviridae family's Orthopoxvirus genus. This virus can transmit from human to human through direct contact with respiratory secretions, infected animals and humans, or contaminated objects and causing mutations in the human body. In May 2022, several monkeypox affected cases were found in many countries. Because of its transmitting characteristics, on July 23, 2022, a nationwide public health emergency was proclaimed by WHO due to the monkeypox virus. This study analyzed the gene mutation rate that is collected from the most recent NCBI monkeypox dataset. The collected data is prepared to independently identify the nucleotide and codon mutation. Additionally, depending on the size and availability of the gene dataset, the computed mutation rate is split into three categories: Canada, Germany, and the rest of the world. In this study, the genome mutation rate of the monkeypox virus is predicted using a deep learning-based Long Short-Term Memory (LSTM) model and compared with Gated Recurrent Unit (GRU) model. The LSTM model shows "Root Mean Square Error" (RMSE) values of 0.09 and 0.08 for testing and training, respectively. Using this time series analysis method, the prospective mutation rate of the 50th patient has been predicted. Note that this is a new report on the monkeypox gene mutation. It is found that the nucleotide mutation rates are decreasing, and the balance between bi-directional rates are maintained.
Topics: Animals; Humans; Mpox (monkeypox); Memory, Short-Term; Prospective Studies; Monkeypox virus; Mutation
PubMed: 37611023
DOI: 10.1371/journal.pone.0290045