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Pan, Qi, Yue-Juan Liu, Xue-Feng Bai, Xiao-Le Han, Yong Jiang, Bo Ai, Shan-Shan Shi i in. "VARAdb: a comprehensive variation annotation database for human". Nucleic Acids Research 49, nr D1 (23.10.2020): D1431—D1444. http://dx.doi.org/10.1093/nar/gkaa922.
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Abstract With the study of human diseases and biological processes increasing, a large number of non-coding variants have been identified and facilitated. The rapid accumulation of genetic and epigenomic information has resulted in an urgent need to collect and process data to explore the regulation of non-coding variants. Here, we developed a comprehensive variation annotation database for human (VARAdb, http://www.licpathway.net/VARAdb/), which specifically considers non-coding variants. VARAdb provides annotation information for 577,283,813 variations and novel variants, prioritizes variations based on scores using nine annotation categories, and supports pathway downstream analysis. Importantly, VARAdb integrates a large amount of genetic and epigenomic data into five annotation sections, which include ‘Variation information’, ‘Regulatory information’, ‘Related genes’, ‘Chromatin accessibility’ and ‘Chromatin interaction’. The detailed annotation information consists of motif changes, risk SNPs, LD SNPs, eQTLs, clinical variant-drug-gene pairs, sequence conservation, somatic mutations, enhancers, super enhancers, promoters, transcription factors, chromatin states, histone modifications, chromatin accessibility regions and chromatin interactions. This database is a user-friendly interface to query, browse and visualize variations and related annotation information. VARAdb is a useful resource for selecting potential functional variations and interpreting their effects on human diseases and biological processes.
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Laurent, Jon M., Sudarshan Pinglay, Leslie Mitchell i Ran Brosh. "Probing the dark matter of the human genome with big DNA". Biochemist 41, nr 3 (1.06.2019): 46–48. http://dx.doi.org/10.1042/bio04103046.
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Less than 2% of our genome is protein-coding DNA. The vast expanses of non-coding DNA make up the genome's “dark matter”, where introns, repetitive and regulatory elements reside. Variation between individuals in non-coding regulatory DNA is emerging as a major factor in the genetics of numerous diseases and traits, yet very little is known about how such variations contribute to disease risk. Studying the genetics of regulatory variation is technically challenging as regulatory elements can affect genes located tens of thousands of base pairs away, and often, multiple distal regulatory variations, each with a very small effect, combine in an unknown way to significantly modulate the expression of genes. At the Center for Synthetic Regulatory Genomics (SyRGe) we directly tackle these problems in order to systematically elucidate the mechanisms of regulatory variation underlying human disease.
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Sedláková, V., P. Sedlák, D. Zeka, J. Domkářová, P. Doležal i P. Vejl. "Evaluation of variations in plastid DNA non-coding regions in selected species of the genus Solanum". Czech Journal of Genetics and Plant Breeding 53, No. 3 (13.09.2017): 127–31. http://dx.doi.org/10.17221/76/2015-cjgpb.
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The diversity of three non-coding plastid DNA loci (trnL/trnF spacer, trnV/16SrRNA spacer, trnL/trnL intron) was assessed in 16 Solanum L. species (135 individuals). Polymorphisms were detected by denaturing gradient gel electrophoresis (DGGE) and verified by direct sequencing. No intraspecific diversity and only poor interspecific diversity was detected. Unique S. mochiquense Ochoa specific length polymorphism at the trnL/trnL locus represented by duplication of an 18 bp segment was discovered. The detected DGGE interspecific trnL/trnF locus polymorphism did not specifically associate with single point mutations in the sequence confirmed by sequencing. The DGGE method was found to be a simple and cheap pre-exploring tool for mutation detection in compared DNA regions. Some identified polymorphisms can be used in the management of genetic resources.
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Meerschaut, Ilse, Sarah Vergult, Annelies Dheedene, Björn Menten, Katya De Groote, Hans De Wilde, Laura Muiño Mosquera i in. "A Reassessment of Copy Number Variations in Congenital Heart Defects: Picturing the Whole Genome". Genes 12, nr 7 (8.07.2021): 1048. http://dx.doi.org/10.3390/genes12071048.
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Copy number variations (CNVs) can modulate phenotypes by affecting protein-coding sequences directly or through interference of gene expression. Recent studies in cancer and limb defects pinpointed the relevance of non-coding gene regulatory elements such as long non-coding RNAs (lncRNAs) and topologically associated domain (TAD)-related gene-enhancer interactions. The contribution of such non-coding elements is largely unexplored in congenital heart defects (CHD). We performed a retrospective analysis of CNVs reported in a cohort of 270 CHD patients. We reviewed the diagnostic yield of pathogenic CNVs, and performed a comprehensive reassessment of 138 CNVs of unknown significance (CNV-US), evaluating protein-coding genes, lncRNA genes, and potential interferences with TAD-related gene-enhancer interactions. Fifty-two of the 138 CNV-US may relate to CHD, revealing three candidate CHD regions, 19 candidate CHD genes, 80 lncRNA genes of interest, and six potentially CHD-related TAD interferences. Our study thus indicates a potential relevance of non-coding gene regulatory elements in CNV-related CHD pathogenesis. Shortcomings in our current knowledge on genomic variation call for continuous reporting of CNV-US in international databases, careful patient counseling, and additional functional studies to confirm these preliminary findings.
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Bhartiya, Deeksha, i Vinod Scaria. "Genomic variations in non-coding RNAs: Structure, function and regulation". Genomics 107, nr 2-3 (marzec 2016): 59–68. http://dx.doi.org/10.1016/j.ygeno.2016.01.005.
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Bozgeyik, Esra, i Ibrahim Bozgeyik. "Non-coding RNA variations in oral cancers: A comprehensive review". Gene 851 (styczeń 2023): 147012. http://dx.doi.org/10.1016/j.gene.2022.147012.
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Scarpa, Aldo, i Andrea Mafficini. "Non-coding regulatory variations: the dark matter of pancreatic cancer genomics". Gut 67, nr 3 (28.06.2017): 399–400. http://dx.doi.org/10.1136/gutjnl-2017-314310.
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Haas, Jan, Stefan Mester, Alan Lai, Karen S. Frese, Farbod Sedaghat‐Hamedani, Elham Kayvanpour, Tobias Rausch i in. "Genomic structural variations lead to dysregulation of important coding and non‐coding RNA species in dilated cardiomyopathy". EMBO Molecular Medicine 10, nr 1 (14.11.2017): 107–20. http://dx.doi.org/10.15252/emmm.201707838.
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Sedano, Melina J., Alana L. Harrison, Mina Zilaie, Chandrima Das, Ramesh Choudhari, Enrique Ramos i Shrikanth S. Gadad. "Emerging Roles of Estrogen-Regulated Enhancer and Long Non-Coding RNAs". International Journal of Molecular Sciences 21, nr 10 (25.05.2020): 3711. http://dx.doi.org/10.3390/ijms21103711.
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Genome-wide RNA sequencing has shown that only a small fraction of the human genome is transcribed into protein-coding mRNAs. While once thought to be “junk” DNA, recent findings indicate that the rest of the genome encodes many types of non-coding RNA molecules with a myriad of functions still being determined. Among the non-coding RNAs, long non-coding RNAs (lncRNA) and enhancer RNAs (eRNA) are found to be most copious. While their exact biological functions and mechanisms of action are currently unknown, technologies such as next-generation RNA sequencing (RNA-seq) and global nuclear run-on sequencing (GRO-seq) have begun deciphering their expression patterns and biological significance. In addition to their identification, it has been shown that the expression of long non-coding RNAs and enhancer RNAs can vary due to spatial, temporal, developmental, or hormonal variations. In this review, we explore newly reported information on estrogen-regulated eRNAs and lncRNAs and their associated biological functions to help outline their markedly prominent roles in estrogen-dependent signaling.
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Mattick, John S. "The central role of RNA in the genetic programming of complex organisms". Anais da Academia Brasileira de Ciências 82, nr 4 (grudzień 2010): 933–39. http://dx.doi.org/10.1590/s0001-37652010000400016.
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Notwithstanding lineage-specific variations, the number and type of protein-coding genes remain relatively static across the animal kingdom. By contrast there has been a massive expansion in the extent of genomic non-proteincoding sequences with increasing developmental complexity. These non-coding sequences are, in fact, transcribed in a regulated manner to produce large numbers of large and small non-protein-coding RNAs that control gene expression at many levels including chromatin architecture, post-transcriptional processing and translation. Moreover, many RNAs are edited, especially in the nervous system, which may be the basis of epigenome-environment interactions and the function of the brain.
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Kim, Eun Jin, Hyun Jin Yu i Dong Wook Kim. "Sequence Variations in the Non-Coding Sequence of CTX Phages in Vibrio cholerae". Journal of Microbiology and Biotechnology 26, nr 8 (28.08.2016): 1473–80. http://dx.doi.org/10.4014/jmb.1604.04022.
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Labani, Mahdieh, Amin Beheshti, Ahmadreza Argha i Hamid Alinejad-Rokny. "A Comprehensive Investigation of Genomic Variants in Prostate Cancer Reveals 30 Putative Regulatory Variants". International Journal of Molecular Sciences 24, nr 3 (27.01.2023): 2472. http://dx.doi.org/10.3390/ijms24032472.
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Prostate cancer (PC) is the most frequently diagnosed non-skin cancer in the world. Previous studies have shown that genomic alterations represent the most common mechanism for molecular alterations responsible for the development and progression of PC. This highlights the importance of identifying functional genomic variants for early detection in high-risk PC individuals. Great efforts have been made to identify common protein-coding genetic variations; however, the impact of non-coding variations, including regulatory genetic variants, is not well understood. Identification of these variants and the underlying target genes will be a key step in improving the detection and treatment of PC. To gain an understanding of the functional impact of genetic variants, and in particular, regulatory variants in PC, we developed an integrative pipeline (AGV) that uses whole genome/exome sequences, GWAS SNPs, chromosome conformation capture data, and ChIP-Seq signals to investigate the potential impact of genomic variants on the underlying target genes in PC. We identified 646 putative regulatory variants, of which 30 significantly altered the expression of at least one protein-coding gene. Our analysis of chromatin interactions data (Hi-C) revealed that the 30 putative regulatory variants could affect 131 coding and non-coding genes. Interestingly, our study identified the 131 protein-coding genes that are involved in disease-related pathways, including Reactome and MSigDB, for most of which targeted treatment options are currently available. Notably, our analysis revealed several non-coding RNAs, including RP11-136K7.2 and RAMP2-AS1, as potential enhancer elements of the protein-coding genes CDH12 and EZH1, respectively. Our results provide a comprehensive map of genomic variants in PC and reveal their potential contribution to prostate cancer progression and development.
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Tsilimigras, Diamantis I., Sofia-Iris Bibli, Gerasimos Siasos, Evangelos Oikonomou, Despina N. Perrea, Konstantinos Filis, Dimitrios Tousoulis i Fragiska Sigala. "Regulation of Long Non-Coding RNAs by Statins in Atherosclerosis". Biomolecules 11, nr 5 (22.04.2021): 623. http://dx.doi.org/10.3390/biom11050623.
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Despite increased public health awareness, atherosclerosis remains a leading cause of mortality worldwide. Significant variations in response to statin treatment have been noted among different populations suggesting that the efficacy of statins may be altered by both genetic and environmental factors. The existing literature suggests that certain long noncoding RNAs (lncRNAs) might be up- or downregulated among patients with atherosclerosis. LncRNA may act on multiple levels (cholesterol homeostasis, vascular inflammation, and plaque destabilization) and exert atheroprotective or atherogenic effects. To date, only a few studies have investigated the interplay between statins and lncRNAs known to be implicated in atherosclerosis. The current review characterizes the role of lncRNAs in atherosclerosis and summarizes the available evidence related to the effect of statins in regulating lncRNAs.
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Yasmin, Tahirah. "In silico comprehensive analysis of coding and non-coding SNPs in human mTOR protein". PLOS ONE 17, nr 7 (5.07.2022): e0270919. http://dx.doi.org/10.1371/journal.pone.0270919.
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The mammalian/mechanistic target of rapamycin (mTOR) protein is an important growth regulator and has been linked with multiple diseases including cancer and diabetes. Non-synonymous mutations of this gene have already been found in patients with renal clear cell carcinoma, melanoma, and acute lymphoid leukemia among many others. Such mutations can potentially affect a protein’s structure and hence its functions. In this study, therefore, the most deleterious SNPs of mTOR protein have been determined to identify potential biomarkers for various disease treatments. The aim is to generate a structured dataset of the mTOR gene’s SNPs that may prove to be an asset for the identification and treatment of multiple diseases associated with the target gene. Both sequence and structure-based approaches were adopted and a wide variety of bioinformatics tools were applied to analyze the SNPs of mTOR protein. In total 11 nsSNPs have been filtered out of 2178 nsSNPs along with two non-coding variations. All of the nsSNPs were found to destabilize the protein structure and disrupt its function. While R619C, A1513D, and T1977R mutations were shown to alter C alpha distances and bond angles of the mTOR protein, L509Q, R619C and N2043S were predicted to disrupt the mTOR protein’s interaction with NBS1 protein and FKBP1A/rapamycin complex. In addition, one of the non-coding SNPs was shown to alter miRNA binding sites. Characterizing nsSNPs and non-coding SNPs and their harmful effects on a protein’s structure and functions will enable researchers to understand the critical impact of mutations on the molecular mechanisms of various diseases. This will ultimately lead to the identification of potential targets for disease diagnosis and therapeutic interventions.
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Lange, Marios, Rodiola Begolli i Antonis Giakountis. "Non-Coding Variants in Cancer: Mechanistic Insights and Clinical Potential for Personalized Medicine". Non-Coding RNA 7, nr 3 (2.08.2021): 47. http://dx.doi.org/10.3390/ncrna7030047.
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The cancer genome is characterized by extensive variability, in the form of Single Nucleotide Polymorphisms (SNPs) or structural variations such as Copy Number Alterations (CNAs) across wider genomic areas. At the molecular level, most SNPs and/or CNAs reside in non-coding sequences, ultimately affecting the regulation of oncogenes and/or tumor-suppressors in a cancer-specific manner. Notably, inherited non-coding variants can predispose for cancer decades prior to disease onset. Furthermore, accumulation of additional non-coding driver mutations during progression of the disease, gives rise to genomic instability, acting as the driving force of neoplastic development and malignant evolution. Therefore, detection and characterization of such mutations can improve risk assessment for healthy carriers and expand the diagnostic and therapeutic toolbox for the patient. This review focuses on functional variants that reside in transcribed or not transcribed non-coding regions of the cancer genome and presents a collection of appropriate state-of-the-art methodologies to study them.
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Yarahmadi, Elham, Parnaz Borjian Boroujeni, Mehdi Totonchi i Hamid Gourabi. "Genotyping of the EIF1AY Gene in Iranian Patients with Non-Obstructive Azoospermia". Current Urology 13, nr 1 (2019): 46–50. http://dx.doi.org/10.1159/000499295.
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Background: EIF1AY is one of the genes essential for normal spermatogenesis and is located in azoospermic factors region. Objective: The present study was designed to investigate the EIF1AY gene nucleotide variations, and correlate it with spermatogenic maturation arrest and azoospermia in Iranian population. Methods: A total number of 30 Iranian idiopathic non-obstructive azoospermic patients were selected as case group and 30 fertile men served as a control group who had at least 1 child. Nucleotide variation was analyzed in exon 3 and exon 5 in EIF1AY gene of both groups. DNA extraction from peripheral blood samples of selected individuals was done followed by amplification by PCR and sequencing with Sangar method. Results: Totally 3 single nucleotide variations were identified: one in the intronic region of exon 3, next one in non-coding transcript exon variant (rs13447352) and the third one in the exonic region of exon 5, all were registered in NCBI-Gene database. Conclusion: There was no statistically significant difference in the incidence of nucleotide variation between 2 study populations (p > 0.05). Further studies are required to specify the effects of Y: T20588295G variation on modification of protein structure, as well as the expression pattern of the gene and its association with azoospermia.
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Wilson, Claire, i Aditi Kanhere. "8q24.21 Locus: A Paradigm to Link Non-Coding RNAs, Genome Polymorphisms and Cancer". International Journal of Molecular Sciences 22, nr 3 (22.01.2021): 1094. http://dx.doi.org/10.3390/ijms22031094.
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The majority of the human genome is comprised of non-protein-coding genes, but the relevance of non-coding RNAs in complex diseases has yet to be fully elucidated. One class of non-coding RNAs is long non-coding RNAs or lncRNAs, many of which have been identified to play a range of roles in transcription and translation. While the clinical importance of the majority of lncRNAs have yet to be identified, it is puzzling that a large number of disease-associated genetic variations are seen in lncRNA genes. The 8q24.21 locus is rich in lncRNAs and very few protein-coding genes are located in this region. Interestingly, the 8q24.21 region is also a hot spot for genetic variants associated with an increased risk of cancer. Research focusing on the lncRNAs in this area of the genome has indicated clinical relevance of lncRNAs in different cancers. In this review, we summarise the lncRNAs in the 8q24.21 region with respect to their role in cancer and discuss the potential impact of cancer-associated genetic polymorphisms on the function of lncRNAs in initiation and progression of cancer.
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Allen, Ethan J., i Roberta K. Weber. "An Exploration of Indexed and Non-Indexed Open Access Journals: Identifying Metadata Coding Variations". Journal of Web Librarianship 9, nr 2-3 (3.07.2015): 65–84. http://dx.doi.org/10.1080/19322909.2015.1020185.
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Torgersen, H., T. Skern i D. Blaas. "Typing of Human Rhinoviruses Based on Sequence Variations in the 5' Non-coding Region". Journal of General Virology 70, nr 11 (1.11.1989): 3111–16. http://dx.doi.org/10.1099/0022-1317-70-11-3111.
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Williams, Sarah M., Joon Yong An, Janette Edson, Michelle Watts, Valentine Murigneux, Andrew J. O. Whitehouse, Colin J. Jackson, Mark A. Bellgrove, Alexandre S. Cristino i Charles Claudianos. "An integrative analysis of non-coding regulatory DNA variations associated with autism spectrum disorder". Molecular Psychiatry 24, nr 11 (27.04.2018): 1707–19. http://dx.doi.org/10.1038/s41380-018-0049-x.
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Uvarova, Aksinya N., Elena A. Tkachenko, Ekaterina M. Stasevich, Elina A. Zheremyan, Kirill V. Korneev i Dmitry V. Kuprash. "Methods for Functional Characterization of Genetic Polymorphisms of Non-Coding Regulatory Regions of the Human Genome". Biochemistry (Moscow) 89, nr 6 (czerwiec 2024): 1002–13. http://dx.doi.org/10.1134/s0006297924060026.
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Abstract Currently, numerous associations between genetic polymorphisms and various diseases have been characterized through the Genome-Wide Association Studies. Majority of the clinically significant polymorphisms are localized in non-coding regions of the genome. While modern bioinformatic resources make it possible to predict molecular mechanisms that explain influence of the non-coding polymorphisms on gene expression, such hypotheses require experimental verification. This review discusses the methods for elucidating molecular mechanisms underlying dependence of the disease pathogenesis on specific genetic variants within the non-coding sequences. A particular focus is on the methods for identification of transcription factors with binding efficiency dependent on polymorphic variations. Despite remarkable progress in bioinformatic resources enabling prediction of the impact of polymorphisms on the disease pathogenesis, there is still the need for experimental approaches to investigate this issue.
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Begum, Ghausia, Ammar Albanna, Asma Bankapur, Nasna Nassir, Richa Tambi, Bakhrom K. Berdiev, Hosneara Akter i in. "Long-Read Sequencing Improves the Detection of Structural Variations Impacting Complex Non-Coding Elements of the Genome". International Journal of Molecular Sciences 22, nr 4 (19.02.2021): 2060. http://dx.doi.org/10.3390/ijms22042060.
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The advent of long-read sequencing offers a new assessment method of detecting genomic structural variation (SV) in numerous rare genetic diseases. For autism spectrum disorders (ASD) cases where pathogenic variants fail to be found in the protein-coding genic regions along chromosomes, we proposed a scalable workflow to characterize the risk factor of SVs impacting non-coding elements of the genome. We applied whole-genome sequencing on an Emirati family having three children with ASD using long and short-read sequencing technology. A series of analytical pipelines were established to identify a set of SVs with high sensitivity and specificity. At 15-fold coverage, we observed that long-read sequencing technology (987 variants) detected a significantly higher number of SVs when compared to variants detected using short-read technology (509 variants) (p-value < 1.1020 × 10−57). Further comparison showed 97.9% of long-read sequencing variants were spanning within the 1–100 kb size range (p-value < 9.080 × 10−67) and impacting over 5000 genes. Moreover, long-read variants detected 604 non-coding RNAs (p-value < 9.02 × 10−9), comprising 58% microRNA, 31.9% lncRNA, and 9.1% snoRNA. Even at low coverage, long-read sequencing has shown to be a reliable technology in detecting SVs impacting complex elements of the genome.
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Prodan-Bărbulescu, Cătălin, Edward Paul Şeclăman, Virgil Enătescu, Ionuţ Flaviu Faur, Laura Andreea Ghenciu, Paul Tuţac, Paul Paşca i Laura Octavia Grigoriţă. "Evaluating the Connection between MicroRNAs and Long Non-Coding RNAs for the Establishment of the Major Depressive Disorder Diagnosis". Biomedicines 12, nr 3 (25.02.2024): 516. http://dx.doi.org/10.3390/biomedicines12030516.
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The most prevalent mental illness worldwide and the main contributor to suicide and disability is major depressive disorder. Major depressive disorder is now diagnosed and treated based on the patient’s statement of symptoms, mental status tests, and clinical behavioral observations. The central element of this review is the increased need for an accurate diagnostic method. In this context, the present research aims to investigate the potential role of two non-coding RNA species (microRNA and long non-coding RNA) in peripheral blood samples and brain tissue biopsy from patients with major depressive disorder. This study reviewed the literature on microRNA and long non-coding RNA expression in blood and brain tissue samples in human and animal depression models by retrieving relevant papers using the PubMed database. The results reveal significant variations in microRNA and long non-coding RNA levels in depressed patients, making it a crucial diagnostic tool that predicts treatment outcomes. It can help track severe cases and adjust therapy dosages based on treatment responses. In conclusion, microRNAs and long non-coding RNAs are pertinent biomarkers that can be added to the diagnostic test panel for major depressive disorder. Both microRNAs and non-coding RNAs can also be used as a tool to track patient progress during therapy and to assist the attending physician in tracking the molecular development of the disease.
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Olufunmilayo, Edward O., i R. M. Damian Holsinger. "Roles of Non-Coding RNA in Alzheimer’s Disease Pathophysiology". International Journal of Molecular Sciences 24, nr 15 (6.08.2023): 12498. http://dx.doi.org/10.3390/ijms241512498.
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Alzheimer’s disease (AD) is a chronic neurodegenerative disorder that is accompanied by deficits in memory and cognitive functions. The disease is pathologically characterised by the accumulation and aggregation of an extracellular peptide referred to as amyloid-β (Aβ) in the form of amyloid plaques and the intracellular aggregation of a hyperphosphorelated protein tau in the form of neurofibrillary tangles (NFTs) that cause neuroinflammation, synaptic dysfunction, and oxidative stress. The search for pathomechanisms leading to disease onset and progression has identified many key players that include genetic, epigenetic, behavioural, and environmental factors, which lend support to the fact that this is a multi-faceted disease where failure in various systems contributes to disease onset and progression. Although the vast majority of individuals present with the sporadic (non-genetic) form of the disease, dysfunctions in numerous protein-coding and non-coding genes have been implicated in mechanisms contributing to the disease. Recent studies have provided strong evidence for the association of non-coding RNAs (ncRNAs) with AD. In this review, we highlight the current findings on changes observed in circular RNA (circRNA), microRNA (miRNA), short interfering RNA (siRNA), piwi-interacting RNA (piRNA), and long non-coding RNA (lncRNA) in AD. Variations in these ncRNAs could potentially serve as biomarkers or therapeutic targets for the diagnosis and treatment of Alzheimer’s disease. We also discuss the results of studies that have targeted these ncRNAs in cellular and animal models of AD with a view for translating these findings into therapies for Alzheimer’s disease.
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Tan, Fengxiao, Weixi Li, Hui Feng, Yelin Huang i Achyut Kumar Banerjee. "Interspecific variation and phylogenetic relationship between mangrove and non-mangrove species of a same family (Meliaceae)—insights from comparative analysis of complete chloroplast genome". PeerJ 11 (26.06.2023): e15527. http://dx.doi.org/10.7717/peerj.15527.
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The mahogany family, Meliaceae, contains 58 genera with only one mangrove genus: Xylocarpus. Two of the three species of the genus Xylocarpus are true mangroves (X. granatum and X. moluccensis), and one is a non-mangrove (X. rumphii). In order to resolve the phylogenetic relationship between the mangrove and non-mangrove species, we sequenced chloroplast genomes of these Xylocarpus species along with two non-mangrove species of the Meliaceae family (Carapa guianensis and Swietenia macrophylla) and compared the genome features and variations across the five species. The five Meliaceae species shared 130 genes (85 protein-coding genes, 37 tRNA, and eight rRNA) with identical direction and order, with a few variations in genes and intergenic spacers. The repetitive sequences identified in the rpl22 gene region only occurred in Xylocarpus, while the repetitive sequences in accD were found in X. moluccensis and X. rumphii. The TrnH-GUG and rpl32 gene regions and four non-coding gene regions showed high variabilities between X. granatum and the two non-mangrove species (S. macrophylla and C. guianensis). In addition, among the Xylocarpus species, only two genes (accD and clpP) showed positive selection. Carapa guianensis and S. macrophylla owned unique RNA editing sites. The above genes played an important role in acclimation to different stress factors like heat, low temperature, high UV light, and high salinity. Phylogenetic analysis with 22 species in the order Sapindales supported previous studies, which revealed that the non-mangrove species X. rumphii is closer to X. moluccensis than X. granatum. Overall, our results provided important insights into the variation of genetic structure and adaptation mechanism at interspecific (three Xylocarpus species) and intergeneric (mangrove and non-mangrove genera) levels.
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Chawla, Anjali, Corina Nagy i Gustavo Turecki. "Chromatin Profiling Techniques: Exploring the Chromatin Environment and Its Contributions to Complex Traits". International Journal of Molecular Sciences 22, nr 14 (16.07.2021): 7612. http://dx.doi.org/10.3390/ijms22147612.
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The genetic architecture of complex traits is multifactorial. Genome-wide association studies (GWASs) have identified risk loci for complex traits and diseases that are disproportionately located at the non-coding regions of the genome. On the other hand, we have just begun to understand the regulatory roles of the non-coding genome, making it challenging to precisely interpret the functions of non-coding variants associated with complex diseases. Additionally, the epigenome plays an active role in mediating cellular responses to fluctuations of sensory or environmental stimuli. However, it remains unclear how exactly non-coding elements associate with epigenetic modifications to regulate gene expression changes and mediate phenotypic outcomes. Therefore, finer interrogations of the human epigenomic landscape in associating with non-coding variants are warranted. Recently, chromatin-profiling techniques have vastly improved our understanding of the numerous functions mediated by the epigenome and DNA structure. Here, we review various chromatin-profiling techniques, such as assays of chromatin accessibility, nucleosome distribution, histone modifications, and chromatin topology, and discuss their applications in unraveling the brain epigenome and etiology of complex traits at tissue homogenate and single-cell resolution. These techniques have elucidated compositional and structural organizing principles of the chromatin environment. Taken together, we believe that high-resolution epigenomic and DNA structure profiling will be one of the best ways to elucidate how non-coding genetic variations impact complex diseases, ultimately allowing us to pinpoint cell-type targets with therapeutic potential.
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Shapiro, James A. "Biological action in Read–Write genome evolution". Interface Focus 7, nr 5 (18.08.2017): 20160115. http://dx.doi.org/10.1098/rsfs.2016.0115.
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Many of the most important evolutionary variations that generated phenotypic adaptations and originated novel taxa resulted from complex cellular activities affecting genome content and expression. These activities included (i) the symbiogenetic cell merger that produced the mitochondrion-bearing ancestor of all extant eukaryotes, (ii) symbiogenetic cell mergers that produced chloroplast-bearing ancestors of photosynthetic eukaryotes, and (iii) interspecific hybridizations and genome doublings that generated new species and adaptive radiations of higher plants and animals. Adaptive variations also involved horizontal DNA transfers and natural genetic engineering by mobile DNA elements to rewire regulatory networks, such as those essential to viviparous reproduction in mammals. In the most highly evolved multicellular organisms, biological complexity scales with ‘non-coding’ DNA content rather than with protein-coding capacity in the genome. Coincidentally, ‘non-coding’ RNAs rich in repetitive mobile DNA sequences function as key regulators of complex adaptive phenotypes, such as stem cell pluripotency. The intersections of cell fusion activities, horizontal DNA transfers and natural genetic engineering of Read–Write genomes provide a rich molecular and biological foundation for understanding how ecological disruptions can stimulate productive, often abrupt, evolutionary transformations.
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Cao, Ting, ShuangYang Zhang, Qian Chen, CuiRong Zeng, LiWei Wang, ShiMeng Jiao, Hui Chen, BiKui Zhang i HuaLin Cai. "Long non-coding RNAs in schizophrenia: Genetic variations, treatment markers and potential targeted signaling pathways". Schizophrenia Research 260 (październik 2023): 12–22. http://dx.doi.org/10.1016/j.schres.2023.07.027.
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Pinjou Tsai, Becky, Liang Li, Min Li, Patrick Halliday, Anastasia Rosales, Stephen J. Forman, Smita Bhatia i Ravi Bhatia. "Development Of t-MDS In Patients Undergoing Autologous Transplantation For Lymphoma Is Not Associated With Increased Frequency Of Mitochondrial DNA Mutations". Blood 122, nr 21 (15.11.2013): 1535. http://dx.doi.org/10.1182/blood.v122.21.1535.1535.
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Abstract Therapy-related myelodysplasia/acute myeloid leukemia (t-MDS) is a lethal complication of cytotoxic cancer treatment. The incidence of t-MDS is particularly high in patients undergoing autologous hematopoietic cell transplantation (aHCT) for Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL). To better understand pathogenetic mechanisms underlying development of t-MDS we are prospectively following a cohort of patients undergoing aHCT for lymphoma at our center. In previous studies using samples from this cohort we identified altered expression of genes related to mitochondrial function in pre-aHCT samples from lymphoma patients who later developed t-MDS (cases) compared to patients from the cohort who did not develop t-MDS (controls) (Cancer Cell 2011 20:591). Altered mitochondrial gene expression was associated with increased levels of mitochondrial reactive oxygen species (ROS) in samples from patients who subsequently developed t-MDS. These results suggest a possible role for mitochondrial dysfunction and increased ROS in pathogenesis of t-MDS. Somatic mutations of mitochondria DNA (mtDNA) are observed at increased frequency in many malignant conditions. Somatic mtDNA mutations may reflect increased susceptibility to mutagenesis, and could contribute to altered mitochondrial function in patients with t-MDS. Here we sought to investigate the role of mitochondrial genomic instability in t-MDS development by analyzing the mutation profile of mtDNA in hematopoietic cells from pre-HCT samples obtained from cases that developed t-MDS and controls that did not develop t-MDS after aHCT for lymphoma. We isolated myeloid and lymphoid cell populations from t-MDS cases (n=13) and controls (n=18) using flow cytometry, amplified mtDNA by PCR using specific primers, and sequenced pooled, barcoded amplicons using next generation sequencing on a Illumina Hi-Seq instrument. Sequences were alighted to the revised Cambridge Reference Sequence (rCRS) in the MITOMAP database. We did not identify significant differences in abundance of variations between controls and cases in protein coding genes (control 13.9, case 14.9), hypervariable region (control 7.7, case 6.6) and rRNA/tRNA genes (control 5.7, case 5.6). In addition we did not observe differences in the abundance of variation between cases and controls in individual genes. We also did not detect significant differences in the abundance of SNPs resulting in non-synonymous amino acid changes in lymphoid compared to myeloid populations from both cases (lymphoid 5.0, myeloid 4.7) and controls (lymphoid 5.3, myeloid 4.3). Several new variations in both coding and noncoding regions were identified that were not previously reported in the rCRS database, which were present in greater abundance in myeloid (control 5.3, case 5.3) compared to lymphoid cells (control 1.7, case 2.2). Amongst new variations, the top 5 protein coding genes with the highest number of mutations were found in myeloid cells and included NADH dehydrogenase subunit 2, 4, and 5, and cytochrome c oxidase subunit 1 and 2. We also analyzed the specific mutations that displayed a variation frequency greater than 25% in myeloid control and case samples. Interestingly, the A10398G mutation, in the NADH dehydrogenase subunit 3 (ND3) coding region, associated with metabolic syndrome and increased risk for breast cancer, was found in ∼30% of t-MDS myeloid case samples. In summary our data suggests that there is increased abundance of novel variations in mtDNA in myeloid compared to lymphoid populations. Although several new, previously unreported variations were identified, we did not observe any significant differences in type of lesions, abundance of lesions in coding and non-coding regions, or in individual genes between cases and controls. We conclude that changes in mtDNA sequence are not significantly different between patients that later develop t-MDS after aHCT (cases) compared to controls that do not develop t-MDS. These observations suggest that differences in mtDNA sequence cannot by itself explain the alterations in altered mitochondrial function seen early during the course of development of t-MDS. Disclosures: No relevant conflicts of interest to declare.
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Policarpo, Rafaela, i Constantin d’Ydewalle. "Missing lnc(RNAs) in Alzheimer’s Disease?" Genes 13, nr 1 (23.12.2021): 39. http://dx.doi.org/10.3390/genes13010039.
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With the ongoing demographic shift towards increasingly elderly populations, it is estimated that approximately 150 million people will live with Alzheimer’s disease (AD) by 2050. By then, AD will be one of the most burdensome diseases of this and potentially next centuries. Although its exact etiology remains elusive, both environmental and genetic factors play crucial roles in the mechanisms underlying AD neuropathology. Genome-wide association studies (GWAS) identified genetic variants associated with AD susceptibility in more than 40 different genomic loci. Most of these disease-associated variants reside in non-coding regions of the genome. In recent years, it has become clear that functionally active transcripts arise from these non-coding loci. One type of non-coding transcript, referred to as long non-coding RNAs (lncRNAs), gained significant attention due to their multiple roles in neurodevelopment, brain homeostasis, aging, and their dysregulation or dysfunction in neurological diseases including in AD. Here, we will summarize the current knowledge regarding genetic variations, expression profiles, as well as potential functions, diagnostic or therapeutic roles of lncRNAs in AD. We postulate that lncRNAs may represent the missing link in AD pathology and that unraveling their role may open avenues to better AD treatments.
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Calin, George A. "Abstract IA025: About motifs, non-codingRNAs and metastases". Cancer Research 83, nr 2_Supplement_2 (15.01.2023): IA025. http://dx.doi.org/10.1158/1538-7445.metastasis22-ia025.
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Abstract MicroRNA and other short or long non-codingRNAs alterations are involved in the initiation, progression and metastases of human cancer. The main molecular alterations are represented by variations in gene expression, usually mild and with consequences for a vast number of target protein coding genes. The causes of the widespread differential expression of non-codingRNAs in malignant compared with normal cells can be explained by the location of these genes in cancer-associated genomic regions, by epigenetic mechanisms and by alterations in the processing machinery. MicroRNA and other short or long non-codingRNAs expression profiling of human tumors has identified signatures associated with diagnosis, staging, progression, prognosis and response to treatment. In addition, profiling has been exploited to identify non-codingRNAs that may represent downstream targets of activated oncogenic pathways or that are targeting protein coding genes involved in cancer. Recent studies proved that miRNAs and non-coding ultraconserved genes are main candidates for the elusive class of cancer predisposing genes and that other types of non-codingRNAs participate in the genetic puzzle giving rise to the malignant phenotype. These discoveries could be exploited for the development of useful markers for diagnosis and prognosis, as well as for the development of new RNA-based cancer therapies. Citation Format: George A. Calin. About motifs, non-codingRNAs and metastases [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr IA025.
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Huo, Yan, Han Yang, Wenjie Ding, Zhaohe Yuan i Zunling Zhu. "Exploring the Relationship between Genomic Variation and Phenotype in Ornamental Pomegranate: A Study of Single and Double-Petal Varieties". Horticulturae 9, nr 3 (9.03.2023): 361. http://dx.doi.org/10.3390/horticulturae9030361.
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The double-petal varieties of ornamental pomegranate have higher ornamental value and garden development potential than the single-petal varieties but there has been no study on the genomic variation between them. This study aimed to determine the genomic variation between the two kinds of varieties and the relationship between the variation and phenotype by identifying the DNA variation of three single-petal varieties and three double-petal varieties using re-sequencing technology. The results showed that the variation number of each variety was in the order of single nucleotide polymorphisms (SNPs) > insertions and deletions (InDels) > structural variations (SVs) > copy number variations (CNVs). The number of SNPs and InDels in the double-petal varieties was significantly higher than that in the single-petal varieties, and there was no significant difference in the number of SVs and CNVs. The number of non-synonymous SNPs in the coding region (Nonsyn_CDS_SNPs) and InDels with a 3X length in the coding region (3X_shiftMutation_CDS_InDel) was significantly higher in the double-petal varieties than that in the single-petal varieties. The number of the two variants was strongly positively correlated with each morphological index that was related to the phenotypic difference between the two varieties. Nonsyn_CDS_SNPs and 3X_shiftMutation_CDS_InDel were enriched in the cell membrane system, cell periphery, and signal transduction, from which 15 candidate genes were screened. Our results provide genomic data for the study of the formation mechanism of the double-petal flower and lay a theoretical foundation for new variety breeding of ornamental pomegranate.
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El-Hageen, Hazem M., Aadel M. Alatwi i Ahmed Nabih Zaki Rashed. "Advanced modulation coding schemes for an optical transceiver systems–based OWC communication channel model". Bulletin of Electrical Engineering and Informatics 10, nr 2 (1.04.2021): 767–75. http://dx.doi.org/10.11591/eei.v10i2.2433.
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This paper examines advanced modulation coding schemes for an optical transceiver systems–based optical wireless communication (OWC) channel model. These modulation techniquesinclude On-Off keying and return to zero (RZ)/non–return to zero (NRZ) coding. The signal power level against time and frequency spectral variations are measured. The max. Q factor and min. bit error rate (BER) are estimated and clarified for each modulation code scheme by using an optisystem simulation model. Transmission bit rates of up to 40 Gb/s can be achieved for possible distances up to 500 km with acceptable Q factor. The received power and max. Q factor are measured and clarified with OWC distance variations. The On-Off keying modulation code scheme resulted in better performance than the other modulation code schemes did.
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Bui, Linh T., Heini M. Natri, Lance M. Peter, Bianca Argente, Austin J. Gutierrez, Arnold Federico, Mei-I. Chung, Jonathan Keats i Nicholas E. Banovich. "Abstract 5780: Functions of genetic variation on gene expression and survival in multiple myeloma". Cancer Research 82, nr 12_Supplement (15.06.2022): 5780. http://dx.doi.org/10.1158/1538-7445.am2022-5780.
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Abstract Multiple myeloma (MM) is a malignancy of plasma cells in the bone marrow and the second most common hematological malignancy. MM is characterized by a high degree of heterogeneity and has a hereditary genetic component with relatives of MM patients having a higher risk of disease development. Additionally, MM displays a disparity in occurrence and mortality among sexes with males having a higher risk than females. Although new therapies have significantly improved survival rates, MM remains incurable as most patients experience relapses. Therefore, understanding the genetic control underlying complex outcomes is important for the development of better treatments for MM patients. While the majority of research has been focusing on protein-coding regions of the genome, recent studies have started to illuminate the role of non-coding variations on MM. For example, many of the 176 GWAS risk loci associated with MM susceptibility are located within or adjacent to regulatory regions, indicating a role in transcriptional regulation. However, how the non-coding genetic variations affect gene expression, tumor etiology and outcome is poorly understood. To better understand the genetic and biological underpinnings of MM, we utilize genomic approaches to examine non-coding germline and somatic effects on gene expression and cancer outcome. First, we analyzed whole-genome sequencing (WGS) from peripheral blood and WGS and RNA-seq from baseline tumor specimens of 607 participants from the CoMMpass longitudinal study of the Multiple Myeloma Research Foundation. Using both joint and sex-stratified analyses, we detected 6,504 unique germline variants associated with changes in gene expression, i.e. expression quantitative trait loci (eQTLs), corresponding to 4,598 unique eGenes. Among the identified eQTLs, 33.76% exhibit sex-specific effects and 654 variants are associated with genes that influence survival in the CoMMpass cohort. In addition to the germline eQTLs, we identified 266 somatic eQTLs, corresponding to 208 eGenes. Among the identified eQTLs, 566 germline and 88 somatic eQTLs overlap with an ATACseq peak in MM cell lines. Second, we selected a set of eQTLs to validate their functions in transcriptional activity in MM cell lines (2 females, 2 males) using CRISPR interference screens (CRISPRi) with a scRNA-seq readout. By analyzing global transcriptional changes, we identify potential downstream targets that may play essential roles in MM genesis and progression. In conclusion, using computational and functional genomics approaches, we have identified germline and somatic eQTLs that are associated with gene expression and survival in MM, thus providing insights into how these non-coding variations contribute to tumor etiology and outcome. Citation Format: Linh T. Bui, Heini M. Natri, Lance M. Peter, Bianca Argente, Austin J. Gutierrez, Arnold Federico, Mei-I Chung, Jonathan Keats, Nicholas E. Banovich. Functions of genetic variation on gene expression and survival in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5780.
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Su, Yi, Xi Yang, Hai Yi, Fangyi Fan, Haoping Sun, Sihan Lai i Ting Niu. "Identification and Characterization of EBV Genome in NKT Cell Lymphoma". Blood 132, Supplement 1 (29.11.2018): 5304. http://dx.doi.org/10.1182/blood-2018-99-118710.
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Abstract Background: Epstein-Barr virus (EBV) is closely related to (Natural Killer/T) NKT cell lymphoma. However, the genomic characteristics of EBV genome in NKT cell lymphoma are poorly understood. Methods: We targeted the EBV gene sequence of 5 samples of NKT cell lymphoma tissue and identified the genomic variation of EBV in NKT cell lymphoma, and compared with other EBV strains by bioinformatics. Results: The EBV genome was successfully retrieved from 5 samples and the variation was detected. We found a total of 3220 mutations in 5 cases of NKT cell lymphoma, including 2996 substitutions, 105 insertion and 119 deletion, of which 2103 of the mutations in the gene coding region, others were in the non-coding region. The non-synonymous mutations in 5 samples were 563, 586, 596, 667 and 578, respectively. Most of them were located in the exons of tegument, membrane glycoprotein, transcription factor and replication. Phylogenetic analysis of LMP1, EBNA1, EBNA2, EBNA3A, BZLF1, BLLF1 were performed with other EBV strains. The results showed that the LMP1 and BZLF1 genes of EBV in NKT cell lymphoma were different from those of other EBV strains, suggesting that LMP1 and BZLF1 were specific in NKT cell lymphoma. The comparison of EBNA2 and EBNA3A between EBV in NKT cell lymphoma and other strains suggested that the EBV in NKT cell lymphoma was type I EBV. The characteristics of EBNA1 in different strains have no correlation and need further investigation. Conclusion: By targeting sequencing technology, we had shown that there were many variations of EBV in NKT cell lymphoma, including substitutions, insertions and deletions, and most of the variations were located in the gene coding region. The EBV in NKT cell lymphoma was type I EBV. LMP1 and BZLF1 in the EBV genome of NKT cell lymphoma were tumor specific and might serve as potential biomarkers for EBV genotyping. Disclosures No relevant conflicts of interest to declare.
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Hong, Thanh Phuoc, i Ling Guan. "A Scale and Rotational Invariant Key-point Detector based on Sparse Coding". ACM Transactions on Intelligent Systems and Technology 12, nr 3 (11.06.2021): 1–19. http://dx.doi.org/10.1145/3452009.
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Most popular hand-crafted key-point detectors such as Harris corner, SIFT, SURF aim to detect corners, blobs, junctions, or other human-defined structures in images. Though being robust with some geometric transformations, unintended scenarios or non-uniform lighting variations could significantly degrade their performance. Hence, a new detector that is flexible with context change and simultaneously robust with both geometric and non-uniform illumination variations is very desirable. In this article, we propose a solution to this challenging problem by incorporating Scale and Rotation Invariant design (named SRI-SCK) into a recently developed Sparse Coding based Key-point detector (SCK). The SCK detector is flexible in different scenarios and fully invariant to affine intensity change, yet it is not designed to handle images with drastic scale and rotation changes. In SRI-SCK, the scale invariance is implemented with an image pyramid technique, while the rotation invariance is realized by combining multiple rotated versions of the dictionary used in the sparse coding step of SCK. Techniques for calculation of key-points’ characteristic scales and their sub-pixel accuracy positions are also proposed. Experimental results on three public datasets demonstrate that significantly high repeatability and matching score are achieved.
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ALKANLI, Nevra, i Arzu AY. "Kanser Gelişimi ve Progresyonunda miRNA’LAR VE miRNA Gen Varyasyonları". Gevher Nesibe Journal IESDR 6, nr 13 (25.07.2021): 38–45. http://dx.doi.org/10.46648/gnj.226.
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MicroRNAs (miRNAs) are short non-coding RNA class and perform regulatory functions at the post transcriptional level as tumor suppressors or oncogenes. miRNAs are effective in cell differentiation, cell proliferation and apoptosis regulation in normal development processes. miRNA gene variations associated with gene silencing mechanisms, , pri-miRNA, pre-miRNA, mat-miRNA gene variations, genetic cariations in target sites of miRNAs have been identified. Significant changes may occur in miRNA expression levels as a result of genetic variations defined in miRNA genes. Therefore, it is thought that genetic variations in miRNA genes may be biomarkers that can play an important role in cancer formation, prognosis and progression. MiRNA function disorder due to miRNA-mediated dysregulation in target genes that may occur as a result of miRNA gene variations in the diagnosis and progression of various types of cancer should be evaluated. In addition, determining miRNAs and miRNA gene variations in target genes that affect drug behavior in increasing the effectiveness of drugs is very important in terms of developing new treatment methods and different therapeutic strategies for various cancer types. In this review, it is aimed to examine the potential roles of miRNAs and miRNA gene variations in cancer development, progression and treatment.
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Tang, Jianmin, Rong Zou, Taiguo Chen, Lipo Pan, Shujing Zhu, Tao Ding, Shengfeng Chai i Xiao Wei. "Comparative Analysis of the Complete Chloroplast Genomes of Six Endangered Cycas Species: Genomic Features, Comparative Analysis, and Phylogenetic Implications". Forests 14, nr 10 (16.10.2023): 2069. http://dx.doi.org/10.3390/f14102069.
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Cycas (family Cycadaceae), which spread throughout tropical and subtropical regions, is crucial in conservation biology. Due to subtle morphological variations between species, a solid species-level phylogeny for Cycas is lacking. In the present study, we assembled and analyzed the chloroplast genomes of six Cycas plants, including their genome structure, GC content, and nucleotide diversity. The Cycas chloroplast genome spans from 162,038 to 162,159 bp and contains 131 genes, including 86 protein-coding genes, 37 transfer RNA (tRNA) genes, and 8 ribosomal RNA (rRNA) genes. Through a comparative analysis, we found that the chloroplast genome of Cycas was highly conserved, as indicated by the contraction and expansion of the inverted repeat (IR) regions and sequence polymorphisms. In addition, several non-coding sites (psbK-psbI, petN-psbM, trnE-UUC-psbD, ndhC-trnM-CAU, and rpl32-trnP-GGG) showed significant variation. The utilization of phylogenetic analysis relying on protein-coding genes has substantiated the division of Cycas primarily into four groups. The application of these findings will prove valuable in evaluating genetic diversity and the phylogenetic connections among closely related species. Moreover, it will provide essential support for the advancement of wild germplasm resources.
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Moutsopoulos, Ilias, Lukas Maischak, Elze Lauzikaite, Sergio A. Vasquez Urbina, Eleanor C. Williams, Hajk-Georg Drost i Irina I. Mohorianu. "noisyR: enhancing biological signal in sequencing datasets by characterizing random technical noise". Nucleic Acids Research 49, nr 14 (2.06.2021): e83-e83. http://dx.doi.org/10.1093/nar/gkab433.
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Abstract High-throughput sequencing enables an unprecedented resolution in transcript quantification, at the cost of magnifying the impact of technical noise. The consistent reduction of random background noise to capture functionally meaningful biological signals is still challenging. Intrinsic sequencing variability introducing low-level expression variations can obscure patterns in downstream analyses. We introduce noisyR, a comprehensive noise filter to assess the variation in signal distribution and achieve an optimal information-consistency across replicates and samples; this selection also facilitates meaningful pattern recognition outside the background-noise range. noisyR is applicable to count matrices and sequencing data; it outputs sample-specific signal/noise thresholds and filtered expression matrices. We exemplify the effects of minimizing technical noise on several datasets, across various sequencing assays: coding, non-coding RNAs and interactions, at bulk and single-cell level. An immediate consequence of filtering out noise is the convergence of predictions (differential-expression calls, enrichment analyses and inference of gene regulatory networks) across different approaches.
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Baumgart, Simon J., Ekaterina Nevedomskaya i Bernard Haendler. "Dysregulated Transcriptional Control in Prostate Cancer". International Journal of Molecular Sciences 20, nr 12 (13.06.2019): 2883. http://dx.doi.org/10.3390/ijms20122883.
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Recent advances in whole-genome and transcriptome sequencing of prostate cancer at different stages indicate that a large number of mutations found in tumors are present in non-protein coding regions of the genome and lead to dysregulated gene expression. Single nucleotide variations and small mutations affecting the recruitment of transcription factor complexes to DNA regulatory elements are observed in an increasing number of cases. Genomic rearrangements may position coding regions under the novel control of regulatory elements, as exemplified by the TMPRSS2-ERG fusion and the amplified enhancer identified upstream of the androgen receptor (AR) gene. Super-enhancers are increasingly found to play important roles in aberrant oncogenic transcription. Several players involved in these processes are currently being evaluated as drug targets and may represent new vulnerabilities that can be exploited for prostate cancer treatment. They include factors involved in enhancer and super-enhancer function such as bromodomain proteins and cyclin-dependent kinases. In addition, non-coding RNAs with an important gene regulatory role are being explored. The rapid progress made in understanding the influence of the non-coding part of the genome and of transcription dysregulation in prostate cancer could pave the way for the identification of novel treatment paradigms for the benefit of patients.
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Hawkins, Gregory A., David J. Friedman, Lingyi Lu, David R. McWilliams, Jeff W. Chou, Satria Sajuthi, Jasmin Divers i in. "Re-Sequencing of the APOL1-APOL4 and MYH9 Gene Regions in African Americans Does Not Identify Additional Risks for CKD Progression". American Journal of Nephrology 42, nr 2 (2015): 99–106. http://dx.doi.org/10.1159/000439448.
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Background: In African Americans (AAs), APOL1 G1 and G2 nephropathy risk variants are associated with non-diabetic end-stage kidney disease (ESKD) in an autosomal recessive pattern. Additional risk and protective genetic variants may be present near the APOL1 loci, since earlier age ESKD is observed in some AAs with one APOL1 renal-risk variant, and because the adjacent gene MYH9 is associated with nephropathy in populations lacking G1 and G2 variants. Methods: Re-sequencing was performed across a ∼275 kb region encompassing the APOL1-APOL4 and MYH9 genes in 154 AA cases with non-diabetic ESKD and 38 controls without nephropathy who were heterozygous for a single APOL1 G1 or G2 risk variant. Results: Sequencing identified 3,246 non-coding single nucleotide polymorphisms (SNPs), 55 coding SNPs, and 246 insertion/deletions. No new coding variations were identified. Eleven variants, including a rare APOL3 Gln58Ter null variant (rs11089781), were genotyped in a replication panel of 1,571 AA ESKD cases and 1,334 controls. After adjusting for APOL1 G1 and G2 risk effects, these variations were not significantly associated with ESKD. In subjects with <2 APOL1 G1 and/or G2 alleles (849 cases; 1,139 controls), the APOL3 null variant was nominally associated with ESKD (recessive model, OR 1.81; p = 0.026); however, analysis in 807 AA cases and 634 controls from the Family Investigation of Nephropathy and Diabetes did not replicate this association. Conclusion: Additional common variants in the APOL1-APOL4-MYH9 region do not contribute significantly to ESKD risk beyond the APOL1 G1 and G2 alleles.
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Ouedraogo, Zangbéwendé Guy, Caroline Janel, Alexandre Janin, Gilles Millat, Sarah Langlais, Bénédicte Pontier, Marie Biard i in. "Relevance of Extending FGFR3 Gene Analysis in Osteochondrodysplasia to Non-Coding Sequences: A Case Report". Genes 15, nr 2 (10.02.2024): 225. http://dx.doi.org/10.3390/genes15020225.
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Skeletal dysplasia, also called osteochondrodysplasia, is a category of disorders affecting bone development and children’s growth. Up to 552 genes, including fibroblast growth factor receptor 3 (FGFR3), have been implicated by pathogenic variations in its genesis. Frequently identified causal mutations in osteochondrodysplasia arise in the coding sequences of the FGFR3 gene: c.1138G>A and c.1138G>C in achondroplasia and c.1620C>A and c.1620C>G in hypochondroplasia. However, in some cases, the diagnostic investigations undertaken thus far have failed to identify the causal anomaly, which strengthens the relevance of the diagnostic strategies being further refined. We observed a Caucasian adult with clinical and radiographic features of achondroplasia, with no common pathogenic variant. Exome sequencing detected an FGFR3(NM_000142.4):c.1075+95C>G heterozygous intronic variation. In vitro studies showed that this variant results in the aberrant exonization of a 90-nucleotide 5′ segment of intron 8, resulting in the substitution of the alanine (Ala359) for a glycine (Gly) and the in-frame insertion of 30 amino acids. This change may alter FGFR3’s function. Our report provides the first clinical description of an adult carrying this variant, which completes the phenotype description previously provided in children and confirms the recurrence, the autosomal-dominant pathogenicity, and the diagnostic relevance of this FGFR3 intronic variant. We support its inclusion in routinely used diagnostic tests for osteochondrodysplasia. This may increase the detection rate of causal variants and therefore could have a positive impact on patient management. Finally, FGFR3 alteration via non-coding sequence exonization should be considered a recurrent disease mechanism to be taken into account for new drug design and clinical trial strategies.
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Norman, Jane E., Matthew L. Jones, Neil V. Morgan, Jacqui Stockley, Martina E. Daly, Stuart J. Mundell, Steve P. Watson i Andrew D. Mumford. "Functional Variations In Genes Encoding Platelet G-Protein Coupled Receptors In Unselected and Platelet Function Disorder Populations". Blood 122, nr 21 (15.11.2013): 3511. http://dx.doi.org/10.1182/blood.v122.21.3511.3511.
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Abstract Introduction G-protein coupled receptors (GPCRs) are critical mediators of platelet responses to stimulatory and inhibitory agonists. In rare families with mild bleeding, it is recognised that heterozygous loss of function variations in platelet GPCR genes may diminish platelet agonist responses. However, the population prevalence of loss of function variations in these genes is unknown. We have utilised population databases and next generation sequencing from patients with inherited platelet function disorders (IPFD) to describe the extent of genetic variation in the major platelet GPCRs. We have also used predictive computation and a new consensus structure of GPCRs (Venkatakrishnan AJ et al.Nature 2013; 494) to estimate which variations confer loss of function. Methods We interrogated the ESP and 1000 genomes population datasets for single nucleotide (SNV) and insertion-deletion (indel) variations in the genes encoding 6 stimulatory (ADRA2A, F2R, F2RL3, P2RY1, P2RY12, TBXA2R) and 2 inhibitory (PTGER4, PTGIR) platelet GPCRs. Coding and splice region variations within the relevant Refseq transcripts were functionally annotated using the Polyphen-2, SIFT and FATHMM algorithms. Missense variations within GPCR transmembrane (TM) domains, were annotated manually by expressing the substitutions in Ballesteros-Weinstein nomenclature before comparison with the consensus GPCR structure. Missense variations in the N- and C-terminal regions (NR and CR) and the intra- and extra- cellular loops (ICL and ECL) were annotated by identifying the position of the substituted residue relative to experimentally confirmed or putative functional motifs. An identical analysis was performed using exome data from 31 unrelated patients with IPFD recruited through the UK GAPP study with clinical bleeding and abnormal platelet function by light transmission aggregation. Results In 7745 individuals from the ESP and 1000 genomes cohorts, we identified 332 SNV in the target regions of the 8 GPCR genes (40.5 variations/kb) comprising 183 non-synonymous and 148 synonymous coding variants and 4 variations within intronic splice regions. There were no indel variations. Functional annotation of the non-synonymous SNVs identified 41 that potentially conferred loss of function, distributed in all the target GPCRs but with low population frequency (minor allele frequency range 1-0.008%). Five SNVs affected the NT, including Gly48Asp and Arg47His substitutions at the PAR4 receptor thrombin/trypsin cleavage site. There were 12 SNVs affecting the TM domains, of which 4 were predicted to disrupt GPCR folding, including a TPα receptor Pro305Leu substitution within the structural N/DPXXY motif and the P2Y12 receptor Met108Leu and Thr283Ile substitutions predicted to disrupt non-covalent TM network contacts. There were 14 SNVs affecting the ICL including the P2Y12 receptor Asp121Asn substitution in the E/DRY motif and prostacyclin (IP1) receptor Arg212Cys and Arg215Cys substitutions predicted to disrupt Gs coupling. Ten functional SNVs affected the CT. In 31 IPFD patients with complex laboratory phenotypes that could not be explained by loss of a single GPCR, there were 8 non-synonymous SNVs, of which 5 were predicted to confer loss of function (table). Discussion In unselected populations, heterozygous loss of function GPCR gene variations which potentially affect platelet agonist responses are individually rare, but collectively numerous. Loss of function GPCR variations were also present in patients with underlying IPFD. These data illustrate that variations in platelet regulatory genes may act as modifiers of laboratory phenotype in patients with underlying IPFD and that the net phenotype may be the product of multiple gene defects. Disclosures: No relevant conflicts of interest to declare.
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Zorc, Minja, i Tanja Kunej. "In silico screening of the chicken genome for overlaps between genomic regions: microRNA genes, coding and non-coding transcriptional units, QTL, and genetic variations". Chromosome Research 24, nr 2 (22.01.2016): 225–30. http://dx.doi.org/10.1007/s10577-016-9517-9.
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Amirkhah, Raheleh, Hojjat Naderi-Meshkin, Jaynish Shah, Philip Dunne i Ulf Schmitz. "The Intricate Interplay between Epigenetic Events, Alternative Splicing and Noncoding RNA Deregulation in Colorectal Cancer". Cells 8, nr 8 (19.08.2019): 929. http://dx.doi.org/10.3390/cells8080929.
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Colorectal cancer (CRC) results from a transformation of colonic epithelial cells into adenocarcinoma cells due to genetic and epigenetic instabilities, alongside remodelling of the surrounding stromal tumour microenvironment. Epithelial-specific epigenetic variations escorting this process include chromatin remodelling, histone modifications and aberrant DNA methylation, which influence gene expression, alternative splicing and function of non-coding RNA. In this review, we first highlight epigenetic modulators, modifiers and mediators in CRC, then we elaborate on causes and consequences of epigenetic alterations in CRC pathogenesis alongside an appraisal of the complex feedback mechanisms realized through alternative splicing and non-coding RNA regulation. An emphasis in our review is put on how this intricate network of epigenetic and post-transcriptional gene regulation evolves during the initiation, progression and metastasis formation in CRC.
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Adriaanse, Fabienne R. S., Sadie M. Sakurada, Shondra M. Pruett-Miller, Ronald W. Stam, Michel C. Zwaan i Tanja A. Gruber. "Non-Coding HOX Fusions in Pediatric Non-Down Syndrome Acute Megakaryoblastic Leukemia". Blood 134, Supplement_1 (13.11.2019): 533. http://dx.doi.org/10.1182/blood-2019-127014.
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The homeobox (HOX) genes are a highly conserved family of transcription factors involved in embryonic patterning as well as adult hematopoiesis. Dysregulation of HOX genes, in particular upregulation of HOXA cluster genes, is a frequent event in Acute Myelogenous Leukemia (AML). Recently, we performed a detailed genomic analysis on pediatric non-Down Syndrome Acute Megakaryoblastic Leukemia (non-DS-AMKL) and identified novel fusions involving a HOX cluster gene in 14.9% of the cases. While most fusions were predicted to lead to an in-frame functional protein, several fusions included a non-coding HOX antisense gene (PLEK-HOXA11-AS, C8orf76-HOXA11-AS, HOXA10-AS-CD164) that were predicted to result in a loss of function of these regulatory transcripts. The functional consequence of these events, however, remain unknown. HOXA11-AS (human) and Hoxa11os (mouse) have been previously shown to have mutually exclusive expression with the Hoxa11 transcript throughout development. We therefore hypothesized that loss of function of non-coding HOX antisense genes as a result of these structural variations would cause upregulation of nearby coding HOXA genes that in turn promote leukemogenesis. To test this hypothesis, using CRISPR-Cas9 technology, we genome edited the human AMKL cell line CMK to carry the PLEK-HOXA11-AS translocation. qRT-PCR of HOXA11-AS and HOXA9-11 transcripts in this cell line recapitulated the pattern seen in patient specimens. Specifically, HOXA11-AS expression was significantly diminished while HOXA10 and HOXA11 transcripts were upregulated 1.8-2.5-fold when compared to parental CMK cells (p=0.0385 and p=0.006 respectively). To further investigate the loss of HOXA11-ASin vivo a CRISPR-Cas9 Hoxa11os knockout mouse model was established. qRT-PCR on bone marrow confirmed the loss of Hoxa11os transcripts in heterozygous (Hoxa11os1+/-) and homozygous (Hoxa11os-/-) mice of both genders (p=<0.0001-0.0012). Consistent with Hoxa11os knockdown, Hoxa11 transcripts were upregulated in male (1.8-fold p=0.0023 Hoxa11os+/-, and 2-fold p=0.0052 Hoxa11os-/-)and female (1.3-fold p=0.0074 Hoxa11os+/- and 2.2-fold p=0.0226 Hoxa11os-/-) bone marrow compared to wild type gender matched littermates. Interestingly, flow cytometry analysis of progenitor subsets revealed gender specific findings. We found a significant increase in the frequency of the lineage negative, Sca-1 and c-Kit positive (LSK) population in males (0.13% of total bone marrow Hoxa11os+/+, 0.19% p=0.0214 Hoxa11os+/-, and 0.25% p=0.0001 Hoxa11os-/-) compared to wild type male littermates but not in female mice at 8 weeks of age. In contrast an increase in the megakaryocyte-erythroid (MEP) population was seen only in the female setting (0.07% Hoxa11os+/+, 0.15% p=0.0055 Hoxa11os+/-, and 0.165% p<0.0001 Hoxa11os-/-). Limiting dilution colony forming assay confirmed the higher LSK frequency with a 2-fold increase in the number of colonies for male knockout marrow compared to wild type marrow in contrast to the female setting where no significant differences were seen. As hormonal signals have been shown to regulate expression of HOX genes and differences in clonogenicity of male and female stem cells has been previously demonstrated, we reasoned this phenomenon could be secondary to extrinsic stimuli in vivo. The relatively uniform Hoxa11 levels in male and female knockout mice, however, suggested that cell intrinsic factors may also play a role. We therefore overexpressed HOXA11 into male and female wild type bone marrow ex vivo for colony forming assays to determine if elevated levels of the HOXA11 protein led to functional differences. This assay demonstrated a clear enhancement of self-renewal in male but not female bone marrow in contrast to HOXA9 overexpression which serially replated in both genders. Combined these data demonstrate that loss of function alterations in Hoxa11os transcripts lead to upregulation of Hoxa11 and gender specific hematopoietic progenitor cell perturbations. Ongoing efforts include competitive transplant studies as well as RNA and ChIP sequencing to identify gender specific downstream targets of Hoxa11 in the hematopoietic compartment in order to understand the selective expansion of progenitor subsets and male specific self-renewal capacity of this protein. These data will contribute to our understanding on how HOXA11-AS translocations promote oncogenesis. Disclosures Zwaan: Daiichi Sankyo: Consultancy; Sanofi: Consultancy; Roche: Consultancy; Pfizer: Research Funding; BMS: Research Funding; Incyte: Consultancy; Celgene: Consultancy, Research Funding; Servier: Consultancy; Jazz Pharmaceuticals: Other: Travel support; Janssen: Consultancy. Gruber:Bristol-Myers Squibb: Consultancy.
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Umlauf, David, Peter Fraser i Takashi Nagano. "The role of long non-coding RNAs in chromatin structure and gene regulation: variations on a theme". Biological Chemistry 389, nr 4 (1.04.2008): 323–31. http://dx.doi.org/10.1515/bc.2008.047.
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Abstract Transcriptome studies have uncovered a plethora of non-coding RNAs (ncRNA) in mammals. Most originate within intergenic regions of the genome and recent evidence indicates that some are involved in many different pathways that ultimately act on genome architecture and gene expression. In this review, we discuss the role of well-characterized long ncRNAs in gene regulation pointing to their similarities, but also their differences. We will attempt to highlight a paradoxical situation in which transcription is needed to repress entire chromosomal domains possibly through the action of ncRNAs that create nuclear environments refractory to transcription.
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Kin, Katherine, Xi Chen, Manuel Gonzalez-Garay i Walid D. Fakhouri. "The effect of non-coding DNA variations on P53 and cMYC competitive inhibition at cis-overlapping motifs". Human Molecular Genetics 25, nr 8 (7.02.2016): 1517–27. http://dx.doi.org/10.1093/hmg/ddw030.
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Lezirovitz, Karina, Gleiciele A. Vieira-Silva, Ana C. Batissoco, Débora Levy, Joao P. Kitajima, Alix Trouillet, Ellen Ouyang i in. "A rare genomic duplication in 2p14 underlies autosomal dominant hearing loss DFNA58". Human Molecular Genetics 29, nr 9 (27.04.2020): 1520–36. http://dx.doi.org/10.1093/hmg/ddaa075.
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Abstract Here we define a ~200 Kb genomic duplication in 2p14 as the genetic signature that segregates with postlingual progressive sensorineural autosomal dominant hearing loss (HL) in 20 affected individuals from the DFNA58 family, first reported in 2009. The duplication includes two entire genes, PLEK and CNRIP1, and the first exon of PPP3R1 (protein coding), in addition to four uncharacterized long non-coding (lnc) RNA genes and part of a novel protein-coding gene. Quantitative analysis of mRNA expression in blood samples revealed selective overexpression of CNRIP1 and of two lncRNA genes (LOC107985892 and LOC102724389) in all affected members tested, but not in unaffected ones. Qualitative analysis of mRNA expression identified also fusion transcripts involving parts of PPP3R1, CNRIP1 and an intergenic region between PLEK and CNRIP1, in the blood of all carriers of the duplication, but were heterogeneous in nature. By in situ hybridization and immunofluorescence, we showed that Cnrip1, Plek and Ppp3r1 genes are all expressed in the adult mouse cochlea including the spiral ganglion neurons, suggesting changes in expression levels of these genes in the hearing organ could underlie the DFNA58 form of deafness. Our study highlights the value of studying rare genomic events leading to HL, such as copy number variations. Further studies will be required to determine which of these genes, either coding proteins or non-coding RNAs, is or are responsible for DFNA58 HL.
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Rischewski, Johannes R., Johanna Wyss, Sylvie Stocker, Martin Hergersberg, Andreas R. Huber i Thomas Kühne. "Rare SOX13 Sequence Variations in Pediatric Idiopathic Thrombocytopenic Purpura Patients." Blood 112, nr 11 (16.11.2008): 3420. http://dx.doi.org/10.1182/blood.v112.11.3420.3420.
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Abstract Introduction: Idiopathic or immune-thrombocytopenic purpura (ITP) is defined as a bleeding disorder with the hallmark of autoimmune mediated thrombocytopenia. ITP is a diagnosis of exclusion. Primary biliary cirrhosis (PBC) is a presumed autoimmune disease of the liver. Many nonhepatic autoimmune diseases are found in association with PBC, and may prompt initial presentation. Several case reports described the co-occurrence of ITP and PBC. In some PBC patients, autoantibodies against SOX13 can be detected. SOX13 has been identified as a transcription factor promoting gamma-delta T-cell development while opposing alpha-beta T cell differentiation. As ITP has been linked to the autoimmune bicytopenic Evans syndrome, which may present as autoimmune lymphoproliferative syndrome (ALPS) with the hallmark of increased alpha-beta double negative T-cells, we are interested in a potentially etiological role of molecular SOX13 sequence variations in ITP patients. Material and methods: After obtaining informed consent from ITP patients (n=34) and their legal guardians to participate in the IRB approved study genomic DNA was extracted from peripheral blood samples. The complete coding region of SOX13 including the classical non-coding splice sites was amplified by PCR. The amplicons were screened for sequence variations by Denaturing High Performance Liquid Chromatography (DHPLC) after heteroduplex induction. All samples with aberrant DHPLC retention patterns were directly sequenced. Results: Two rare heterozygous sequence variations in the coding region of SOX13 were detected in a total of 4 patients (12%): c.1603C>T (Pro534Ser) and c.1836 C>T (synonymous). Discussion: In a healthy cohort with European ancestry the heterozygous c.1603C>T (Pro534Ser) genotype was detected in 1.7% of individuals. In our cohort 6% of the ITP patients were heterozygous. 2.6% of individuals in a cohort of African-Americans and Caucasians carried the heterozygous genotype c.1836C>T (synonymous). 6% of the investigated ITP patients were heterozygous. A surprising high proportion (12%) of pediatric ITP patients carries one of two rare SOX13 sequence variations. The rare heterozygous genotypes are 3.5 (c.1603C>T) respectively 2.3 times (c.1836C>T) more common than in published non-ITP cohorts. Conclusion: It seems possible, that rare alleles of SOX13 accumulate in pediatric ITP cohorts. Larger case-control sample studies are needed to verify the results. The rare genotypes could influence the alpha-beta versus gamma-delta T-cell balance in the studied pediatric ITP patients. Immunological studies of our cohort are necessary to evaluate this suggested association.