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Scientific Reports Mar 2019Allelic imbalance is a common phenomenon in mammals that plays an important role in gene regulation. An Allele Specific Expression (ASE) approach can be used to detect...
Allelic imbalance is a common phenomenon in mammals that plays an important role in gene regulation. An Allele Specific Expression (ASE) approach can be used to detect variants with a cis-regulatory effect on gene expression. In cattle, this type of study has only been done once in Holstein. In our study we performed a genome-wide analysis of ASE in 19 Limousine muscle samples. We identified 5,658 ASE SNPs (Single Nucleotide Polymorphisms showing allele specific expression) in 13% of genes with detectable expression in the Longissimus thoraci muscle. Interestingly we found allelic imbalance in AOX1, PALLD and CAST genes. We also found 2,107 ASE SNPs located within genomic regions associated with meat or carcass traits. In order to identify causative cis-regulatory variants explaining ASE we searched for SNPs altering binding sites of transcription factors or microRNAs. We identified one SNP in the 3'UTR region of PRNP that could be a causal regulatory variant modifying binding sites of several miRNAs. We showed that ASE is frequent within our muscle samples. Our data could be used to elucidate the molecular mechanisms underlying gene expression imbalance.
Topics: 3' Untranslated Regions; Alleles; Allelic Imbalance; Animals; Cattle; Genome-Wide Association Study; Genotype; Muscle, Skeletal; Phenotype; Polymorphism, Single Nucleotide; Quantitative Trait Loci
PubMed: 30862965
DOI: 10.1038/s41598-019-40781-6 -
Journal of Hepatology Oct 2008Liver transplantation usually cures hepatocellular carcinoma when the Milan selection criteria are applied, whereas there is substantial risk of posttransplant...
BACKGROUND/AIMS
Liver transplantation usually cures hepatocellular carcinoma when the Milan selection criteria are applied, whereas there is substantial risk of posttransplant recurrence with tumors beyond these criteria. This study uses molecular data to identify a subgroup of patients who, despite having hepatocellular carcinoma beyond Milan criteria, have favorable outcomes.
METHODS
Allelic imbalance of 18 microsatellites was analyzed in 70 consecutive patients (35 within Milan, 35 beyond Milan criteria) transplanted for hepatocellular carcinoma of whom 24 had recurrence and 46 survived at least 5 years recurrence-free. Fractional allelic imbalance (the fraction of significant microsatellites that demonstrated allelic imbalance) and relevant clinical/pathological variables were tested for correlation with time to recurrence.
RESULTS
Allelic imbalance in 9/18 microsatellites correlated with recurrence. Fractional allelic imbalance > 0.27 and macrovascular invasion were independent predictors of recurrence in patients with tumors beyond Milan criteria; the probability of recurrence at 5 years was 85% with fractional allelic imbalance > or = 0.27 vs. 10% when < 0.27 (p=0.0002). An algorithm including Milan criteria and fractional allelic imbalance status is 89% accurate in predicting tumor recurrence after transplantation.
CONCLUSION
Analysis of allelic imbalance of 9 microsatellites identifies a subgroup of patients who, despite having hepatocellular carcinoma beyond Milan criteria, have a low risk of posttransplant recurrence.
Topics: Aged; Algorithms; Biomarkers, Tumor; Carcinoma, Hepatocellular; DNA, Neoplasm; Female; Gene Frequency; Humans; Liver Neoplasms; Liver Transplantation; Loss of Heterozygosity; Male; Microsatellite Repeats; Middle Aged; Neoplasm Recurrence, Local; ROC Curve; Retrospective Studies; Risk Factors; Sensitivity and Specificity; Treatment Outcome
PubMed: 18602719
DOI: 10.1016/j.jhep.2008.03.032 -
Seminars in Oncology Oct 2011The 5q-syndrome is a subtype of myelodysplastic syndrome (MDS) with a defined clinical phenotype associated with heterozygous deletions of chromosome 5q. While no genes... (Review)
Review
The 5q-syndrome is a subtype of myelodysplastic syndrome (MDS) with a defined clinical phenotype associated with heterozygous deletions of chromosome 5q. While no genes have been identified that undergo recurrent homozygous inactivation, functional studies have revealed individual genes that contribute to the clinical phenotype of MDS through haplo-insufficient gene expression. Heterozygous loss of the RPS14 gene on 5q leads to activation of p53 in the erythroid lineage and the macrocytic anemia characteristic of the 5q-syndrome. The megakaryocytic and platelet phenotype of the 5q-syndrome has been attributed to heterozygous deletion of miR145 and miR146a. Murine models have implicated heterozygous loss of APC, EGR1, DIAPH1, and NPM1 in the pathophysiology of del(5q) MDS. These findings indicate that the phenotype of MDS patients with deletions of chromosome 5q is due to haplo-insufficiency of multiple genes.
Topics: Anemia, Macrocytic; Chromosome Deletion; Chromosomes, Human, Pair 5; Disease Progression; Haploinsufficiency; Humans; Myelodysplastic Syndromes; Nucleophosmin; Phenotype
PubMed: 21943668
DOI: 10.1053/j.seminoncol.2011.04.010 -
Journal of Muscle Research and Cell... Aug 2017HCM, the most common inherited cardiac disease, is mainly caused by mutations in sarcomeric genes. More than a third of the patients are heterozygous for mutations in...
HCM, the most common inherited cardiac disease, is mainly caused by mutations in sarcomeric genes. More than a third of the patients are heterozygous for mutations in the MYH7 gene encoding for the β-myosin heavy chain. In HCM-patients, expression of the mutant and the wildtype allele can be unequal, thus leading to fractions of mutant and wildtype mRNA and protein which deviate from 1:1. This so-called allelic imbalance was detected in whole tissue samples but also in individual cells. There is evidence that the severity of HCM not only depends on the functional effect of the mutation itself, but also on the fraction of mutant protein in the myocardial tissue. Allelic imbalance has been shown to occur in a broad range of genes. Therefore, we aimed to examine whether the MYH7-alleles are intrinsically expressed imbalanced or whether the allelic imbalance is solely associated with the disease. We compared the expression of MYH7-alleles in non-HCM donors and in HCM-patients with different MYH7-missense mutations. In the HCM-patients, we identified imbalanced as well as equal expression of both alleles. Also at the protein level, allelic imbalance was determined. Most interestingly, we also discovered allelic imbalance and balance in non-HCM donors. Our findings therefore strongly indicate that apart from mutation-specific mechanisms, also non-HCM associated allelic-mRNA expression regulation may account for the allelic imbalance of the MYH7 gene in HCM-patients. Since the relative amount of mutant mRNA and protein or the extent of allelic imbalance has been associated with the severity of HCM, individual analysis of the MYH7-allelic expression may provide valuable information for the prognosis of each patient.
Topics: Adult; Alleles; Allelic Imbalance; Cardiac Myosins; Cardiomyopathy, Hypertrophic; Female; Gene Expression Regulation, Enzymologic; Humans; Male; Middle Aged; Mutation; Myosin Heavy Chains; Sarcomeres
PubMed: 29101517
DOI: 10.1007/s10974-017-9486-4 -
G3 (Bethesda, Md.) Feb 2018Allelic imbalance (AI) indicates the presence of functional variation in regulatory regions. Detecting regulatory differences using AI is widespread, yet there is no...
Allelic imbalance (AI) indicates the presence of functional variation in regulatory regions. Detecting regulatory differences using AI is widespread, yet there is no formal statistical methodology that tests whether AI differs between conditions. Here, we present a novel model and formally test differences in AI across conditions using Bayesian credible intervals. The approach tests AI by environment (G×E) interactions, and can be used to test AI between environments, genotypes, sex, and any other condition. We incorporate bias into the modeling process. Bias is allowed to vary between conditions, making the formulation of the model general. As gene expression affects power for detection of AI, and, as expression may vary between conditions, the model explicitly takes coverage into account. The proposed model has low type I and II error under several scenarios, and is robust to large differences in coverage between conditions. We reanalyze RNA-seq data from a population panel, with F1 genotypes, to compare levels of AI between mated and virgin female flies, and we show that AI × genotype interactions can also be tested. To demonstrate the use of the model to test genetic differences and interactions, a formal test between two F1s was performed, showing the expected 20% difference in AI. The proposed model allows a formal test of G×E and G×G, and reaffirms a previous finding that regulation is robust between environments.
Topics: Algorithms; Alleles; Allelic Imbalance; Animals; Bayes Theorem; Drosophila melanogaster; Female; Gene Expression Regulation; Gene-Environment Interaction; Genotype; Male; Models, Genetic; Polymorphism, Single Nucleotide; Regulatory Sequences, Nucleic Acid
PubMed: 29167272
DOI: 10.1534/g3.117.300139 -
Cell Nov 1986
Review
Topics: Bacteriophage mu; Chromosome Deletion; DNA Replication; DNA Transposable Elements; DNA, Bacterial; DNA, Viral; Methylation
PubMed: 3021339
DOI: 10.1016/0092-8674(86)90586-6 -
Physiological Genomics Jul 2013Type 2 diabetes (T2D)-associated SNPs are more likely to be expression quantitative trait loci (eQTLs). The allelic expression imbalance (AEI) analysis is the measure of...
Type 2 diabetes (T2D)-associated SNPs are more likely to be expression quantitative trait loci (eQTLs). The allelic expression imbalance (AEI) analysis is the measure of relative expression between two allelic transcripts and is the most sensitive measurement to detect cis-regulatory effects. We performed AEI screening to detect cis-regulators for genes expressed in transformed lymphocytes of 190 Caucasian (CA) and African American (AA) subjects to identify functional variants for T2D susceptibility in the chromosome 1q21-24 region of linkage. Among transcribed SNPs studied in 115 genes, significant AEI (P < 0.001) occurred in 28 and 30 genes in CA and AA subjects, respectively. Analysis of the effect of selected AEI-SNPs (≥10% mean AEI) on total gene expression further established the cis-eQTLs in thioesterase superfamily member-4 (THEM4) (rs13320, P = 0.027), and IGSF8 (rs1131891, P = 0.02). Examination of published genome-wide association data identified significant associations (P < 0.01) of three AEI-SNPs with T2D in the DIAGRAM-v3 dataset. Six AEI single nucleotide polymorphisms, including rs13320 (P = 1.35E-04) in THEM4, were associated with glucose homeostasis traits in the MAGIC dataset. Evaluation of AEI-SNPs for association with glucose homeostasis traits in 611 nondiabetic subjects showed lower AIRG (P = 0.005) in those with TT/TC genotype for rs13320. THEM4 expression in adipose was higher (P = 0.005) in subjects carrying the T allele; in vitro analysis with luciferase construct confirmed the higher expression of the T allele. Resequencing of THEM4 exons in 192 CA subjects revealed four coding nonsynonymous variants, but did not explain transmission of T2D in 718 subjects from 67 Caucasian pedigrees. Our study indicates the role of a cis-regulatory SNP in THEM4 that may influence T2D predisposition by modulating glucose homeostasis.
Topics: 3' Untranslated Regions; Adaptor Proteins, Signal Transducing; Black or African American; Allelic Imbalance; Case-Control Studies; Chromosomes, Human, Pair 1; Diabetes Mellitus, Type 2; Gene Expression Regulation; Genetic Predisposition to Disease; Genetic Testing; Genome-Wide Association Study; Glucose; HEK293 Cells; Homeostasis; Humans; Luciferases; Membrane Proteins; Phenotype; Polymorphism, Single Nucleotide; Quantitative Trait, Heritable; Receptors, Immunologic; Thiolester Hydrolases; White People
PubMed: 23673729
DOI: 10.1152/physiolgenomics.00048.2013 -
BMC Cancer Dec 2022We evaluated the performance of single-nucleotide polymorphism (SNP) genotyping arrays OncoScan (Thermo Fisher Scientific, San Diego, CA) and Infinium CytoSNP-850K...
BACKGROUND
We evaluated the performance of single-nucleotide polymorphism (SNP) genotyping arrays OncoScan (Thermo Fisher Scientific, San Diego, CA) and Infinium CytoSNP-850K (CytoSNP; Illumina, Waltham, MA) for assessing homologous recombination deficiency (HRD) genomic instability.
METHODS
DNA (pretreatment samples) across 20 tumor types was evaluated with OncoScan, CytoSNP, and the clinically validated HRD test. Copy number variation (CNV) and loss of heterozygosity (LOH) analyses were performed with ASCATv2.5.1. Aggregate HRD genomic metrics included LOH, telomeric-allelic imbalance number (TAI), and large-scale state transition (LST). Associations between BRCA mutation (BRCAm) status and the clinically validated HRD test metric (dichotomized at a clinical cut-off) were evaluated using area under the receiver operating characteristic (AUROC); Spearman ρ was calculated for continuous metrics. CNV segmentation and HRD genomic metrics were calculated (n = 120, n = 106, and n = 126 for OncoScan, CytoSNP and clinically validated HRD test, respectively).
RESULTS
When assessed by SNP arrays, the genomic metric demonstrated good association with BRCAm (AUROC of HRD: OncoScan, 0.87; CytoSNP, 0.75) and the clinically validated test (cut-off, 42; AUROC of HRD: OncoScan, 0.92; CytoSNP, 0.91). The genomic metrics demonstrated good correlation with the clinically validated aggregate HRD test metric (ρ: OncoScan, 0.82; CytoSNP, 0.81) and for each component (ρ: OncoScan, 0.68 [LOH], 0.76 [TAI], and 0.78 [LST]; CytoSNP, 0.59 [LOH], 0.77 [TAI], and 0.82 [LST]). HRD assessed by SNP genotyping arrays and the clinically validated test showed good correlation.
CONCLUSION
OncoScan and CytoSNP may potentially identify most HRD-positive tumors with appropriate clinically relevant cut-offs.
Topics: Humans; Loss of Heterozygosity; DNA Copy Number Variations; Polymorphism, Single Nucleotide; Homologous Recombination; High-Throughput Nucleotide Sequencing; Genomic Instability
PubMed: 36517748
DOI: 10.1186/s12885-022-10197-z -
Journal of the American Society of... Nov 2017
Topics: Animals; Haploinsufficiency; Hypertension; Kidney; Rats; Rats, Inbred Dahl; Sodium Chloride, Dietary; Transcription Factors
PubMed: 29038288
DOI: 10.1681/ASN.2017080917 -
Gene Feb 2015Trypanosoma brucei is a vector borne, lethal protistan parasite of humans and livestock in sub-Saharan Africa. Antigenic variation of its cell surface coat enables the... (Review)
Review
Trypanosoma brucei is a vector borne, lethal protistan parasite of humans and livestock in sub-Saharan Africa. Antigenic variation of its cell surface coat enables the parasite to evade adaptive immune responses and to live freely in the blood of its mammalian hosts. The coat consists of ten million copies of variant surface glycoprotein (VSG) that is expressed from a single VSG gene, drawn from a large repertoire and located near the telomere at one of fifteen so-called bloodstream expression sites (BESs). Thus, antigenic variation is achieved by switching to the expression of a different VSG gene. A BES is a tandem array of expression site-associated genes and a terminal VSG gene. It is polycistronically transcribed by a multifunctional RNA polymerase I (RNAPI) from a short promoter that is located 45-60 kb upstream of the VSG gene. The mechanism(s) restricting VSG expression to a single BES are not well understood. There is convincing evidence that epigenetic silencing and transcription attenuation play important roles. Furthermore, recent data indicated that there is regulation at the level of transcription initiation and that, surprisingly, the VSG mRNA appears to have a role in restricting VSG expression to a single gene. Here, we review BES expression regulation and propose a model in which telomere-directed, epigenetic BES silencing is opposed by BES promoter-directed, activated RNAPI transcription.
Topics: Alleles; Allelic Imbalance; Gene Expression Regulation; Gene Silencing; Genes, Protozoan; Promoter Regions, Genetic; RNA Polymerase I; Telomere; Transcription Initiation Site; Trypanosoma brucei brucei; Variant Surface Glycoproteins, Trypanosoma
PubMed: 25261847
DOI: 10.1016/j.gene.2014.09.047