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PloS One 2013Copy number alterations (CNA) are common events occurring in leukaemias and solid tumors. Comparative Genome Hybridization (CGH) is actually the gold standard technique...
Copy number alterations (CNA) are common events occurring in leukaemias and solid tumors. Comparative Genome Hybridization (CGH) is actually the gold standard technique to analyze CNAs; however, CGH analysis requires dedicated instruments and is able to perform only low resolution Loss of Heterozygosity (LOH) analyses. Here we present CEQer (Comparative Exome Quantification analyzer), a new graphical, event-driven tool for CNA/allelic-imbalance (AI) coupled analysis of exome sequencing data. By using case-control matched exome data, CEQer performs a comparative digital exonic quantification to generate CNA data and couples this information with exome-wide LOH and allelic imbalance detection. This data is used to build mixed statistical/heuristic models allowing the identification of CNA/AI events. To test our tool, we initially used in silico generated data, then we performed whole-exome sequencing from 20 leukemic specimens and corresponding matched controls and we analyzed the results using CEQer. Taken globally, these analyses showed that the combined use of comparative digital exon quantification and LOH/AI allows generating very accurate CNA data. Therefore, we propose CEQer as an efficient, robust and user-friendly graphical tool for the identification of CNA/AI in the context of whole-exome sequencing data.
Topics: Allelic Imbalance; Comparative Genomic Hybridization; DNA Copy Number Variations; Exome; Exons; Humans
PubMed: 24124457
DOI: 10.1371/journal.pone.0074825 -
Cell Cycle (Georgetown, Tex.) Nov 2016
Topics: Chromosome Deletion; Chromosomes, Human, Pair 8; Humans; Loss of Heterozygosity; Neoplasms
PubMed: 27458787
DOI: 10.1080/15548627.2016.1204869 -
Molecular Biology and Evolution Dec 2021Hybridization and genome duplication have played crucial roles in the evolution of many animal and plant taxa. The subgenomes of parental species undergo considerable...
Hybridization and genome duplication have played crucial roles in the evolution of many animal and plant taxa. The subgenomes of parental species undergo considerable changes in hybrids and polyploids, which often selectively eliminate segments of one subgenome. However, the mechanisms underlying these changes are not well understood, particularly when the hybridization is linked with asexual reproduction that opens up unexpected evolutionary pathways. To elucidate this problem, we compared published cytogenetic and RNAseq data with exome sequences of asexual diploid and polyploid hybrids between three fish species; Cobitis elongatoides, C. taenia, and C. tanaitica. Clonal genomes remained generally static at chromosome-scale levels but their heterozygosity gradually deteriorated at the level of individual genes owing to allelic deletions and conversions. Interestingly, the impact of both processes varies among animals and genomic regions depending on ploidy level and the properties of affected genes. Namely, polyploids were more tolerant to deletions than diploid asexuals where conversions prevailed, and genomic restructuring events accumulated preferentially in genes characterized by high transcription levels and GC-content, strong purifying selection and specific functions like interacting with intracellular membranes. Although hybrids were phenotypically more similar to C. taenia, we found that they preferentially retained C. elongatoides alleles. This demonstrates that favored subgenome is not necessarily the transcriptionally dominant one. This study demonstrated that subgenomes in asexual hybrids and polyploids evolve under a complex interplay of selection and several molecular mechanisms whose efficiency depends on the organism's ploidy level, as well as functional properties and parental ancestry of the genomic region.
Topics: Animals; Cypriniformes; Diploidy; Evolution, Molecular; Genome, Plant; Hybridization, Genetic; Loss of Heterozygosity; Polyploidy
PubMed: 34410426
DOI: 10.1093/molbev/msab249 -
Annals of Surgery Dec 2001To investigate the relationship between number and location of allelic imbalances (AI) and local tumor progression according to Astler-Coller classification.
OBJECTIVE
To investigate the relationship between number and location of allelic imbalances (AI) and local tumor progression according to Astler-Coller classification.
SUMMARY BACKGROUND DATA
Spontaneous errors in DNA replication (i.e., allelic imbalance or microsatellite instability) have been suggested to play an important role in carcinomatous transformation as reflecting alterations of gene function.
METHODS
One hundred two consecutive patients with colorectal carcinoma undergoing surgical resection were included in this study. Patients were distributed according to the Astler-Coller classification as stages A (n = 7), B1 (n = 15), B2 (n = 24), C (n = 31), and D (n = 25). Fluorescent polymerase chain reaction was performed on frozen tumor, normal colon mucosa, and blood DNA at 35 microsatellite markers. Allelic imbalance frequency was compared with tumor staging.
RESULTS
The percentage of AI was significantly higher in stage D than in A/B1 and B2. In addition, the percentage of AI was significantly higher in 10 synchronous colorectal liver metastases than in stage A/B1 and B2 tumors. However, the allelotyping revealed a subgroup of A/B1 tumors with a high AI frequency. Statistical analysis showed that the presence of AI at microsatellites D1S305, D2S138, D3S1282, D17S790, and D22S928 presented a significantly positive correlation with stages.
CONCLUSION
The frequency of AI significantly correlates with tumor progression of colorectal cancer. Primary tumors with synchronous colorectal liver metastases showed a higher percentage of AI, suggesting that a frequency of AI greater than 35% with this selection of markers indicates a high risk of local progression and of development of metastases.
Topics: Adult; Aged; Aged, 80 and over; Allelic Imbalance; Colorectal Neoplasms; Disease Progression; Female; Gene Frequency; Humans; Liver Neoplasms; Male; Microsatellite Repeats; Middle Aged; Polymerase Chain Reaction; Prognosis
PubMed: 11729386
DOI: 10.1097/00000658-200112000-00011 -
Head & Neck Oct 2008Genetic aberrations, such as DNA copy number variation (CNV) and loss of heterozygosity (LOH), have been implicated in head and neck squamous cell carcinoma (HNSCC)... (Review)
Review
Genetic aberrations, such as DNA copy number variation (CNV) and loss of heterozygosity (LOH), have been implicated in head and neck squamous cell carcinoma (HNSCC) initiation and progression. This review examines CNV and LOH as predictors of HNSCC recurrence and mortality. We searched PubMed for relevant publications and compared and discussed results from the articles. Certain CNV and LOH events have consistently been associated with HNSCC recurrence and survival. The recent high-resolution single nucleotide polymorphism (SNP) arrays have the potential to identify many more genetic changes and concurrent genome-wide CNV, copy-neutral and/or allelic imbalance LOH in HNSCC that may bear on prognosis. Our review confirms that outcome in HNSCC can be predicted to a considerable extent by the presence of tumor cell genetic aberrations. It points out the limitations of some methodologies that were used in the past and discusses the advantages and challenges of using genome-wide SNP arrays.
Topics: Carcinoma, Squamous Cell; DNA, Neoplasm; Gene Expression Profiling; Head and Neck Neoplasms; Humans; Loss of Heterozygosity; Neoplasm Recurrence, Local; Neoplasm Staging; Oligonucleotide Array Sequence Analysis; Polymorphism, Single Nucleotide; Prognosis; Survival Analysis
PubMed: 18642290
DOI: 10.1002/hed.20861 -
Genes Nov 2022The (nuclear factor I/A) gene encodes for a transcription factor belonging to the nuclear factor I family and has key roles in various embryonic differentiation... (Review)
Review
The (nuclear factor I/A) gene encodes for a transcription factor belonging to the nuclear factor I family and has key roles in various embryonic differentiation pathways. In humans, is the major contributor to the phenotypic traits of "Chromosome 1p32p31 deletion syndrome". We report on two new cases with deletions involving without any other pathogenic protein-coding gene alterations. A cohort of 24 patients with haploinsufficiency as the sole anomaly was selected by reviewing the literature and public databases in order to analyze all clinical features reported and their relative frequencies. This process was useful because it provided an overall picture of the phenotypic outcome of haploinsufficiency and helped to define a cluster of phenotypic traits that can facilitate clinicians in identifying affected patients. haploinsufficiency can be suspected by a careful observation of the dysmorphisms (macrocephaly, craniofacial, and first-finger anomalies), and this potential diagnosis is strengthened by the presence of intellectual and developmental disabilities or other neurodevelopmental disorders. Further clues of haploinsufficiency can be provided by instrumental tests such as MRI and kidney urinary tract ultrasound and confirmed by genetic testing.
Topics: Humans; NFI Transcription Factors; Haploinsufficiency; Megalencephaly; Chromosome Deletion; Urinary Tract
PubMed: 36553517
DOI: 10.3390/genes13122249 -
Indian Pediatrics Aug 20133p deletion is a rare cytogenetic finding. Here we describe a 3 months old male with congenital malformations. His karyotype revealed 3p deletion 46,XY,del(3)(p25-pter)....
3p deletion is a rare cytogenetic finding. Here we describe a 3 months old male with congenital malformations. His karyotype revealed 3p deletion 46,XY,del(3)(p25-pter). The child had flexion deformity of wrist and elbow which has never been reported before.
Topics: Abnormalities, Multiple; Chromosome Deletion; Chromosomes, Human, Pair 3; Humans; Infant; Male
PubMed: 24036645
DOI: No ID Found -
Bioinformatics (Oxford, England) Mar 2018The majority of the human genome is composed of non-coding regions containing regulatory elements such as enhancers, which are crucial for controlling gene expression....
MOTIVATION
The majority of the human genome is composed of non-coding regions containing regulatory elements such as enhancers, which are crucial for controlling gene expression. Many variants associated with complex traits are in these regions, and may disrupt gene regulatory sequences. Consequently, it is important to not only identify true enhancers but also to test if a variant within an enhancer affects gene regulation. Recently, allele-specific analysis in high-throughput reporter assays, such as massively parallel reporter assays (MPRAs), have been used to functionally validate non-coding variants. However, we are still missing high-quality and robust data analysis tools for these datasets.
RESULTS
We have further developed our method for allele-specific analysis QuASAR (quantitative allele-specific analysis of reads) to analyze allele-specific signals in barcoded read counts data from MPRA. Using this approach, we can take into account the uncertainty on the original plasmid proportions, over-dispersion, and sequencing errors. The provided allelic skew estimate and its standard error also simplifies meta-analysis of replicate experiments. Additionally, we show that a beta-binomial distribution better models the variability present in the allelic imbalance of these synthetic reporters and results in a test that is statistically well calibrated under the null. Applying this approach to the MPRA data, we found 602 SNPs with significant (false discovery rate 10%) allele-specific regulatory function in LCLs. We also show that we can combine MPRA with QuASAR estimates to validate existing experimental and computational annotations of regulatory variants. Our study shows that with appropriate data analysis tools, we can improve the power to detect allelic effects in high-throughput reporter assays.
AVAILABILITY AND IMPLEMENTATION
http://github.com/piquelab/QuASAR/tree/master/mpra.
CONTACT
[email protected] or [email protected].
SUPPLEMENTARY INFORMATION
Supplementary data are available online at Bioinformatics.
Topics: Alleles; Allelic Imbalance; Computational Biology; Gene Expression Regulation; Genome, Human; Humans; Polymorphism, Single Nucleotide; Regulatory Sequences, Nucleic Acid; Software
PubMed: 29028988
DOI: 10.1093/bioinformatics/btx598 -
Annals of Surgical Oncology Oct 2009Combined treatment with 5-fluorouracil and cisplatin (FP chemotherapy) is an effective neoadjuvant regimen for gastric carcinoma. However, it is ineffective in half of...
BACKGROUND
Combined treatment with 5-fluorouracil and cisplatin (FP chemotherapy) is an effective neoadjuvant regimen for gastric carcinoma. However, it is ineffective in half of all patients. This study tests the hypothesis that genetic markers might identify those patients with gastric cancer who would respond to neoadjuvant FP chemotherapy.
MATERIALS AND METHODS
A total of 23 patients with gastric carcinoma were treated with neoadjuvant chemotherapy. Pretreatment biopsy specimens before neoadjuvant chemotherapy were obtained from 15 of 23 patients, and resected tumors were obtained from all 23. Genetic studies were performed to detect allelic imbalance (AI), microsatellite instability (MSI), and K-ras mutation.
RESULTS
A clinical response was observed in 13 of 23 patients. Kaplan-Meier survival curve showed that clinical responder group had a significantly higher likelihood of overall survival (P = 0.0165), compared with nonresponder group. In 23 resection specimens, 10 of 23 tumors presented AI at the p53 locus and/or MSI; 8 of the 10 tumors were nonresponders, while 12 of 13 tumors without p53 AI or MSI were responders (P = 0.0007). In 15 pretreatment biopsy specimens, 8 tumors had p53 AI and/or MSI; 7 of the 8 tumors were nonresponders, while 6 of 7 tumors without p53 AI or MSI were responders to preoperative chemotherapy (P = 0.008). Tumors with AI at the p53 locus and/or MSI were significantly more resistant to neoadjuvant chemotherapy. No relationship was found between K-ras mutations and responses.
CONCLUSIONS
Analysis for p53 AI and MSI might represent a clinically useful approach to predicting the response to neoadjuvant FP chemotherapy in gastric carcinoma.
Topics: Aged; Aged, 80 and over; Allelic Imbalance; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Cisplatin; Drug Resistance, Neoplasm; Female; Fluorouracil; Genes, ras; Humans; Male; Microsatellite Instability; Middle Aged; Mutation; Neoadjuvant Therapy; Neoplasm Staging; Polymerase Chain Reaction; Prognosis; Stomach Neoplasms; Survival Rate; Tumor Suppressor Protein p53
PubMed: 19597886
DOI: 10.1245/s10434-009-0590-6 -
F1000Research 2019Allelic imbalance occurs when the two alleles of a gene are differentially expressed within a diploid organism and can indicate important differences in cis-regulation...
Allelic imbalance occurs when the two alleles of a gene are differentially expressed within a diploid organism and can indicate important differences in cis-regulation and epigenetic state across the two chromosomes. Because of this, the ability to accurately quantify the proportion at which each allele of a gene is expressed is of great interest to researchers. This becomes challenging in the presence of small read counts and/or sample sizes, which can cause estimators for allelic expression proportions to have high variance. Investigators have traditionally dealt with this problem by filtering out genes with small counts and samples. However, this may inadvertently remove important genes that have truly large allelic imbalances. Another option is to use pseudocounts or Bayesian estimators to reduce the variance. To this end, we evaluated the accuracy of four different estimators, the latter two of which are Bayesian shrinkage estimators: maximum likelihood, adding a pseudocount to each allele, approximate posterior estimation of GLM coefficients (apeglm) and adaptive shrinkage (ash). We also wrote C++ code to quickly calculate ML and apeglm estimates and integrated it into the package. The four methods were evaluated on two simulations and one real data set. Apeglm consistently performed better than ML according to a variety of criteria, and generally outperformed use of pseudocounts as well. Ash also performed better than ML in one of the simulations, but in the other performance was more mixed. Finally, when compared to five other packages that also fit beta-binomial models, the package was substantially faster and more numerically reliable, making our package useful for quick and reliable analyses of allelic imbalance. is available as an R/Bioconductor package at http://bioconductor.org/packages/apeglm.
Topics: Alleles; Allelic Imbalance; Bayes Theorem; Models, Statistical; Software
PubMed: 33796271
DOI: 10.12688/f1000research.20916.2