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PSAP-Genomic-Regions: A Method Leveraging Population Data to Prioritize coding and non-coding variants in Whole Genome Sequencing for Rare Disease Diagnosis

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GENETIC EPIDEMIOLOGY 2025年第1期49卷 e22593页

作者： Ogloblinsky, Marie-Sophie C. Bocher, Ozvan Aloui, Chaker Leutenegger, Anne-Louise Ozisik, Ozan Baudot, Anais Tournier-Lasserve, Elisabeth Castillo-Madeen, Helen Lewinsohn, Daniel Conrad, Donald F. Genin, Emmanuelle Marenne, Gaelle Univ Brest Inserm EFS UMR 1078GGB Brest France Helmholtz Zentrum Munchen Inst Translat Genom Munich Germany Univ Paris Cite Unite Mixte Rech Inserm NeuroDiderot Paris France Aix Marseille Univ INSERM Marseille Med Genet MMG Marseille France Hop St Louis AP HP Serv Genet Mol Neurovasc Paris France Oregon Hlth & Sci Univ Oregon Natl Primate Res Ctr Div Genet Portland OR USA Ctr Hosp Reg Univ Brest Brest France

The introduction of Next-Generation Sequencing technologies in the clinics has improved rare disease diagnosis. nonetheless, for very heterogeneous or very rare diseases, more than half of cases still lack molecular diagnosis. Novel strategies are needed to prioritize variants within a single individual. The Population Sampling Probability (PSAP) method was developed to meet this aim but only for coding variants in exome data. Here, we propose an extension of the PSAP method to the non-coding genome called PSAP-genomic-regions. In this extension, instead of considering genes as testing units (PSAP-genes strategy), we use genomic regions defined over the whole genome that pinpoint potential functional constraints. We conceived an evaluation protocol for our method using artificially generated disease exomes and genomes, by inserting coding and non-coding pathogenic ClinVar variants in large data sets of exomes and genomes from the general population. PSAP-genomic-regions significantly improves the ranking of these variants compared to using a pathogenicity score alone. Using PSAP-genomic-regions, more than 50% of non-coding ClinVar variants were among the top 10 variants of the genome. On real sequencing data from six patients with Cerebral Small Vessel Disease and nine patients with male infertility, all causal variants were ranked in the top 100 variants with PSAP-genomic-regions. By revisiting the testing units used in the PSAP method to include non-coding variants, we have developed PSAP-genomic-regions, an efficient whole-genome prioritization tool which offers promising results for the diagnosis of unresolved rare diseases.

关键词： non-coding variants rare diseases variant prioritization whole-genome sequencing

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Role of non-coding variants in cardiovascular disease

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JOURNAL OF CELLULAR AND MOLECULAR MEDICINE 2023年第12期27卷 1621-1636页

作者： Heshmatzad, Katayoun Naderi, Niloofar Maleki, Majid Abbasi, Shiva Ghasemi, Serwa Ashrafi, Nooshin Fazelifar, Amir Farjam Mahdavi, Mohammad Kalayinia, Samira Iran Univ Med Sci Rajaie Cardiovasc Med & Res Ctr Tehran Iran Iran Univ Med Sci Cardiogenet Res Ctr Rajaie Cardiovasc Med & Res Ctr Tehran Iran

Cardiovascular diseases (CVDs) constitute one of the significant causes of death worldwide. Different pathological states are linked to CVDs, which despite interventions and treatments, still have poor prognoses. The genetic component, as a beneficial tool in the risk stratification of CVD development, plays a role in the pathogenesis of this group of diseases. The emergence of genome-wide association studies (GWAS) have led to the identification of non-coding parts associated with cardiovascular traits and disorders. variants located in functional non-coding regions, including promoters/enhancers, introns, miRNAs and 5 '/3 ' UTRs, account for 90% of all identified single-nucleotide polymorphisms associated with CVDs. Here, for the first time, we conducted a comprehensive review on the reported non-coding variants for different CVDs, including hypercholesterolemia, cardiomyopathies, congenital heart diseases, thoracic aortic aneurysms/dissections and coronary artery diseases. Additionally, we present the most commonly reported genes involved in each CVD. In total, 1469 non-coding variants constitute most reports on familial hypercholesterolemia, hypertrophic cardiomyopathy and dilated cardiomyopathy. The application and identification of non-coding variants are beneficial for the genetic diagnosis and better therapeutic management of CVDs.

关键词： arrhythmia cardiomyopathy cardiovascular diseases congenital heart disease hypercholesterolemia hypertension non-coding variants

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Understanding V(D)J recombination initiator RAG1 gene using molecular phylogenetic and genetic variant analyses and upgrading missense and non-coding variants of clinical importance

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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 2015年第4期462卷 301-313页

作者： Kumar, Abhishek Bhandari, Anita Sarde, Sandeep J. Muppavarapu, Sekhar Tandon, Ravi Univ Kiel Inst Bot Dept Genet & Mol Biol Bot Kiel Germany German Canc Res Ctr Div Mol Genet Epidemiol Heidelberg Germany Univ Kiel Inst Zool Mol Physiol D-24098 Kiel Germany Univ Kiel Agrigen Program Kiel Germany Jawaharlal Nehru Univ Sch Biotechnol New Delhi 110067 India

The recombination-activating genes (RAGs) encode for V(D)J recombinases responsible for rearrangements of antigen-receptor genes during T and B cell development, and RAG expression is known to correlate strictly with the process of rearrangement. There have been several studies of RAG1 illustrating biochemical, physiological and immunological properties. Hitherto, there are limited studies on RAG1 focusing molecular phylogenetic analyses, evolutionary traits, and genetic variants in human populations. Hence, there is a need of a comprehensive study on this topic. In the current report, we have shed light into insights of evolutionary traits and genetic variants of human RAG1 gene using 1092 genomes from human populations. Syntenic analyses revealed that two RAG genes are physically linked and conserved on the same locus in head-to-head orientation from sea urchin to human for about 550 MY. Spliceosomal introns have been in invaded in fishes and sea urchin, whereas gene structures of RAG1 gene from tetrapods remained single exon architecture. We compiled 751 genetic variants in human RAG1 gene using 1092 human genomes;where major stockholders of variant classes are 79% single nucleotide polymorphisms (SNPs), 12.2% somatic single nucleotide variants (somatic SNVs) and 6.8% deletion. Out of 267 missense variants, 140 are deleterious mutations. We identified 284 non-coding variants with 94% regulatory in nature. (C) 2015 Elsevier Inc. All rights reserved.

关键词： RAG1 Ancestral locus Phylogenetic analysis RAG1 variants Missense variants non-coding variants

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Identifying functional non-coding variants in APOA5/A4/C3/A1 gene cluster associated with coronary heart disease

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JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY 2020年 144卷 54-62页

作者： Cui, Guanglin Tian, Min Hu, Senlin Wang, Yan Wang, Dao Wen Huazhong Univ Sci & Technol Tongji Hosp Tongji Med Coll Inst HypertensDiv Cardiol Wuhan 430030 Peoples R China Huazhong Univ Sci & Technol Tongji Hosp Tongji Med Coll Dept Internal Med Wuhan 430030 Peoples R China Hubei Prov Key Lab Genet & Mol Mech Cardiol Disor Wuhan 430030 Peoples R China Harvard TH Chan Sch Publ Hlth Dept Nutr Boston MA USA Harvard TH Chan Sch Publ Hlth Dept Epidemiol Boston MA USA

Recent genome-wide association studies identified several polymorphisms in the APOA5/A4/C3/A1 gene cluster influencing lipids level and risk of coronary heart disease (CHD). However, few studies explored the molecular mechanism. The purposes of this study were to fine-map noncoding region between APOA1 and APOC3 and then explore the clinical relevance in CHD and potential underlying mechanisms. In this study, a 2.7-kb length of the non-coding region between APOA1 and APOC3 was screened and five polymorphisms were investigated in the case-control study. The molecular mechanism was explored. Our data confirmed the association between rs7123454, rs12721030, rs10750098, and rs12721028 with CHD in 828 patients and 828 controls and replicated it in an independent population of 405 patients and 405 controls. In addition, the rs10750098 and rs12721030 are significantly associated with decreased serum APOA1 levels (P = 4.2 x 10(-4) and P = 3.2 x 10(-5), combined analysis), while a significant association was observed between serum APOA1 level and CHD (OR: 0.43, 95% CI: 0.28-0.64, P < .01) with adjustment for clinical covariates and different population sets. In vitro evaluation of potential function of non-coding variants between APOA1 and APOC3 demonstrated that rs10750098 as being the most sufficient to confer the haplotype-specific effect on the regulation of APOs gene transcription. Our results strongly implicate the involvement of common noncoding DNA variants in APOA5/A4/C3/A1 gene cluster in the pathogenesis of dyslipidemia and the risk of CHD.

关键词： APOA5/A4/C3/A1 non-coding variants Lipoprotein Coronary heart disease

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Quantifying the Impact of non-coding variants on Transcription Factor-DNA Binding 21st

Quantifying the Impact of Non-coding Variants on Transcripti...

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21st Annual International Conference on Research in Computational Molecular Biology (RECOMB)

作者： Zhao, Jingkang Li, Dongshunyi Seo, Jungkyun Allen, Andrew S. Gordan, Raluca Duke Univ Ctr Genom & Computat Biol Durham NC 27708 USA Duke Univ Program Computat Biol & Bioinformat Durham NC 27708 USA Duke Univ Dept Biostat & Bioinformat Durham NC 27708 USA Duke Univ Dept Comp Sci Durham NC 27708 USA

ISBN: (纸本)9783319569703;9783319569697

Many recent studies have emphasized the importance of genetic variants and mutations in cancer and other complex human diseases. The overwhelming majority of these variants occur in non-coding portions of the genome, where they can have a functional impact by disrupting regulatory interactions between transcription factors (TFs) and DNA. Here, we present a method for assessing the impact of non coding mutations on TF-DNA interactions, based on regression models of DNA-binding specificity trained on high-throughput in vitro data. We use ordinary least squares (OLS) to estimate the parameters of the binding model for each TF, and we show that our predictions of TF binding changes due to DNA mutations correlate well with measured changes in gene expression. In addition, by leveraging distributional results associated with OLS estimation, for each predicted change in TF binding we also compute a normalized score (z-score) and a significance value (p value) reflecting our confidence that the mutation affects TF binding. We use this approach to analyze a large set of pathogenic non-coding variants, and we show that these variants lead to significant differences in TF binding between alleles, compared to a control set of common variants. Thus, our results indicate that there is a strong regulatory component to the pathogenic non-coding variants identified thus far.

关键词： TF-DNA binding non-coding variants Regression models

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non-coding variants in VAMP2 and SNAP25 affect gene expression: potential implications in migraine susceptibility

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JOURNAL OF HEADACHE AND PAIN 2023年第1期24卷 78-78页

作者： Felicio, Daniela Dias, Andreia Martins, Sandra Carvalho, Estefania Lopes, Alexandra M. Pinto, Nadia Lemos, Carolina Santos, Mariana Alves-Ferreira, Miguel Inst Invest & Inovacao Saude i3S P-4200135 Porto Portugal Univ Porto IPATIMUP Inst Mol Pathol & Immunol P-4200135 Porto Portugal Univ Porto ICBAS Sch Med & Biomed Sci P-4050313 Porto Portugal Univ Porto Unit Genet & Epidemiol Res Neurol Dis UnIGENe Inst Biol Mol & Celular IBMC P-4200135 Porto Portugal Univ Porto Ctr Predict & Prevent Genet CGPP Inst Biol Mol & Celular IBMC P-4200135 Porto Portugal Univ Porto CMUP Ctr Matemat P-4169007 Porto Portugal

Migraine is a common and complex neurological disease potentially caused by a polygenic interaction of multiple gene variants. Many genes associated with migraine are involved in pathways controlling the synaptic function and neurotransmitters release. However, the molecular mechanisms underpinning migraine need to be further *** studies raised the possibility that migraine may arise from the effect of regulatory non-coding variants. In this study, we explored the effect of candidate non-coding variants potentially associated with migraine and predicted to lie within regulatory elements: VAMP2_rs1150, SNAP25_rs2327264, and STX1A_rs6951030. The involvement of these genes, which are constituents of the SNARE complex involved in membrane fusion and neurotransmitter release, underscores their significance in migraine pathogenesis. Our reporter gene assays confirmed the impact of at least two of these non-coding variants. VAMP2 and SNAP25 risk alleles were associated with a decrease and increase in gene expression, respectively, while STX1A risk allele showed a tendency to reduce luciferase activity in neuronal-like cells. Therefore, the VAMP2_rs1150 and SNAP25_rs2327264 non-coding variants affect gene expression, which may have implications in migraine susceptibility. Based on previous in silico analysis, it is plausible that these variants influence the binding of regulators, such as transcription factors and micro-RNAs. Still, further studies exploring these mechanisms would be important to shed light on the association between SNAREs dysregulation and migraine susceptibility.

关键词： Migraine Reporter gene assays SNARE complex non-coding variants VAMP2 SNAP25 STX1A Gene expression

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Disease-associated non-coding variants alter NKX2-5 DNA-binding affinity

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BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2023年第1期1866卷 194906页

作者： Pena-Martinez, Edwin G. Rivera-Madera, Alejandro Pomales-Matos, Diego A. Sanabria-Alberto, Leandro Rosario-Canuelas, Brittany M. Rodriguez-Rios, Jessica M. Carrasquillo-Dones, Emanuel A. Rodriguez-Martinez, Jose A. Univ Puerto Rico Rio Piedras San Juan PR 00925 USA Univ Puerto Rico Cayey PR USA

Genome-wide association studies (GWAS) have mapped over 90 % of disease- or trait-associated variants within the non-coding genome, like cis-regulatory elements (CREs). non-coding single nucleotide polymorphisms (SNPs) are genomic variants that can change how DNA-binding regulatory proteins, like transcription factors (TFs), interact with the genome and regulate gene expression. NKX2-5 is a TF essential for proper heart development, and mutations affecting its function have been associated with congenital heart diseases (CHDs). However, establishing a causal mechanism between non-coding genomic variants and human disease remains challenging. To address this challenge, we identified 8475 SNPs predicted to alter NKX2-5 DNA-binding using a position weight matrix (PWM)-based predictive model. Five variants were prioritized for in vitro validation;four of them are associated with traits and diseases that impact cardiovascular health. The impact of these variants on NKX2-5 binding was evaluated with electrophoretic mobility shift assay (EMSA) using purified recombinant NKX2-5 homeodomain. Binding curves were constructed to determine changes in binding between variant and reference alleles. variants rs7350789, rs7719885, rs747334, and rs3892630 increased binding affinity, whereas rs61216514 decreased binding by NKX2-5 when compared to the reference genome. Our findings suggest that differential TF-DNA binding affinity can be key in establishing a causal mechanism of pathogenic variants.

关键词： Transcription factors non-coding variants Binding affinity Gene regulation

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non-coding DNA variants for risk in lupus☆

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BEST PRACTICE & RESEARCH IN CLINICAL RHEUMATOLOGY 2024年第2期38卷 101937-101937页

作者： Zhang, Yutong Hou, Guojun Shen, Nan Shanghai Jiao Tong Univ Renji Hosp Shanghai Inst Rheumatol Sch Med SJTUSM Shanghai 200001 Peoples R China

Systemic Lupus Erythematosus (SLE) is a multifactorial autoimmune disease that arises from a dynamic interplay between genetics and environmental triggers. The advent of sophisticated genomics technology has catalyzed a shift in our understanding of disease etiology, spotlighting the pivotal role of non-coding DNA variants in SLE pathogenesis. In this review, we present a comprehensive examination of the non-coding variants associated with SLE, shedding light on their role in influencing disease risk and progression. We discuss the latest methodological advancements that have been instrumental in the identification and functional characterization of these genomic elements, with a special focus on the transformative power of CRISPR-based geneediting technologies. Additionally, the review probes into the therapeutic opportunities that arise from modulating non-coding regions associated with SLE. Through an exploration of the complex network of non-coding DNA, this review aspires to decode the genetic puzzle of SLE and set the stage for groundbreaking gene-based therapeutic interventions and the advancement of precision medicine strategies tailored to SLE management.

关键词： Systemic lupus erythematosus Genetics non-coding variants CRISPR

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DNA-binding factor footprints and enhancer RNAs identify functional non-coding genetic variants

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GENOME BIOLOGY 2024年第1期25卷 1页

作者： Biddie, Simon C. Weykopf, Giovanna Hird, Elizabeth F. Friman, Elias T. Bickmore, Wendy A. Univ Edinburgh Inst Genet & Canc MRC Human Genet Unit Edinburgh Scotland NHS Lothian Edinburgh Scotland

BackgroundGenome-wide association studies (GWAS) have revealed a multitude of candidate genetic variants affecting the risk of developing complex traits and diseases. However, the highlighted regions are typically in the non-coding genome, and uncovering the functional causative single nucleotide variants (SNVs) is challenging. Prioritization of variants is commonly based on genomic annotation with markers of active regulatory elements, but current approaches still poorly predict functional variants. To address this, we systematically analyze six markers of active regulatory elements for their ability to identify functional *** benchmark against molecular quantitative trait loci (molQTL) from assays of regulatory element activity that identify allelic effects on DNA-binding factor occupancy, reporter assay expression, and chromatin accessibility. We identify the combination of DNase footprints and divergent enhancer RNA (eRNA) as markers for functional variants. This signature provides high precision, but with a trade-off of low recall, thus substantially reducing candidate variant sets to prioritize variants for functional validation. We present this as a framework called FINDER-Functional SNV IdeNtification using DNase footprints and *** demonstrate the utility to prioritize variants using leukocyte count trait and analyze variants in linkage disequilibrium with a lead variant to predict a functional variant in asthma. Our findings have implications for prioritizing variants from GWAS, in development of predictive scoring algorithms, and for functionally informed fine mapping approaches.

关键词： Functional genetics Functional genomics Single nucleotide variants Single nucleotide polymorphism non-coding genome non-coding variants Genome-wide association study

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Challenges and progress in interpretation of non-coding genetic variants associated with human disease

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EXPERIMENTAL BIOLOGY AND MEDICINE 2017年第13期242卷 1325-1334页

作者： Zhu, Yizhou Tazearslan, Cagdas Suh, Yousin Albert Einstein Coll Med Dept Genet Bronx NY 10461 USA Albert Einstein Coll Med Dept Ophthalmol & Visual Sci Bronx NY 10461 USA Albert Einstein Coll Med Dept Med Bronx NY 10461 USA

Genome-wide association studies have shown that the far majority of disease-associated variants reside in the non-coding regions of the genome, suggesting that gene regulatory changes contribute to disease risk. To identify truly causal non-coding variants and their affected target genes remains challenging but is a critical step to translate the genetic associations to molecular mechanisms and ultimately clinical applications. Here we review genomic/epigenomic resources and in silico tools that can be used to identify causal non-coding variants and experimental strategies to validate their functionalities.

关键词： Causal variants enhancers functional genomics genome-wide association studies non-coding variants variant annotation

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