29,457 results on '"Bioinformatics"'
Search Results
2. Statistics or biology: the zero-inflation controversy about scRNA-seq data
- Author
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Jiang, Ruochen, Sun, Tianyi, Song, Dongyuan, and Li, Jingyi Jessica
- Subjects
Biological Sciences ,Bioinformatics and Computational Biology ,Genetics ,Benchmarking ,Biology ,Sequence Analysis ,RNA ,Single-Cell Analysis ,Exome Sequencing ,Environmental Sciences ,Information and Computing Sciences ,Bioinformatics - Abstract
Researchers view vast zeros in single-cell RNA-seq data differently: some regard zeros as biological signals representing no or low gene expression, while others regard zeros as missing data to be corrected. To help address the controversy, here we discuss the sources of biological and non-biological zeros; introduce five mechanisms of adding non-biological zeros in computational benchmarking; evaluate the impacts of non-biological zeros on data analysis; benchmark three input data types: observed counts, imputed counts, and binarized counts; discuss the open questions regarding non-biological zeros; and advocate the importance of transparent analysis.
- Published
- 2022
3. Genomic and Transcriptomic Examination of Functional Elements and Absent Sequences
- Author
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Chan, Candace S.Y
- Subjects
Genetics ,Bioinformatics ,Biology ,Gene regulation ,Genomics ,Hypothalamus ,Nullomer ,Transcriptional regulatory elements - Abstract
Background: Genome-wide association studies have identified numerous disease-associated variants, but a vast majority are located in non-coding regions, making it challenging to understand their functional impact. This complexity necessitates new techniques to identify causal variants in non-coding regions and elucidate their specific cellular contexts and mechanisms of action. Here we present work i) examining mutations that create nullomers in the human genome to explore its potential utility in identifying pathogenic mutations and ii) a single-cell multi-omic study identifying the transcriptome and regulome of the human and mouse hypothalamus to identify regulatory regions of obesity-associated variants.Methods: (i) We generated all possible mutations of the human genome that can lead to emergence of a nullomer, and examine where in the genome they emerge. (ii) We apply single-cell RNA and ATAC sequencing to adult hypothalamus samples.Results and Conclusions: (i) Our findings highlight CpG hypermutability and methylated cytosines as key elements leading to resurfacing of nullomers in individuals. We also showcase that nullomers can have applications in disease annotation and pathogenic variant identification. (ii) We identified regulatory elements of hypothalamus cell types and mapped obesity-associated variants to cell-type specific peaks. We validated these regions to be enhancers using CRISPR editing and CRISPRi.
- Published
- 2024
4. Identification of molecular subtypes of ischaemic stroke based on immune‐related genes and weighted co‐expression network analysis
- Author
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Duncan Wei, Xiaopu Chen, Jing Xu, and Wenzhen He
- Subjects
bioinformatics ,biology ,genetics ,genomics ,Biology (General) ,QH301-705.5 - Abstract
Abstract Immune system has been reported to play a key role in the development of ischaemic stroke (IS). Nevertheless, its exact immune‐related mechanism has not yet been fully revealed. Gene expression data of IS and healthy control samples was downloaded from Gene Expression Omnibus database and differentially expressed genes (DEGs) was obtained. Immune‐related genes (IRGs) data was downloaded from the ImmPort database. The molecular subtypes of IS were identified based on IRGs and weighted co‐expression network analysis (WGCNA). 827 DEGs and 1142 IRGs were obtained in IS. Based on 1142 IRGs, 128 IS samples were clustered into two molecular subtypes: clusterA and clusterB. Based on the WGCNA, the authors found that the blue module had the highest correlation with IS. In the blue module, 90 genes were screened as candidate genes. The top 55 genes were selected as the central nodes according to gene degree in protein–protein interactions network of all genes in blue module. Through taking overlap, nine real hub genes were obtained that might distinguish between clusterA subtype and clusterB subtype of IS. The real hub genes (IL7R, ITK, SOD1, CD3D, LEF1, FBL, MAF, DNMT1, and SLAMF1) may be associated with molecular subtypes and immune regulation of IS.
- Published
- 2023
- Full Text
- View/download PDF
5. Influence of inherited genetic variants on risk, biology and prognosis of common cancers
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Xiong, Lingyun, Bond, Gareth, and Church, David
- Subjects
616.99 ,Cancer ,Epidemiology ,Genetics ,Biology ,Bioinformatics - Abstract
Cancer is a complex disease affected by both inherited risk variants and somatic alterations. Recent studies showed that inherited genetic variants and somatic driver mutations converge in cancer hallmark pathways, and that inherited genetic variants were associated with specific somatic driver mutations in tumours. However, it is unclear whether common inherited genetic variants interact with somatic driver mutations to influence cancer risk and prognosis. In this study, I analyse multi-cancer datasets to investigate germline by somatic interaction in cancer and to evaluate the role of inherited genetic variants on risk, prognosis, nearby gene expression, response to anti-cancer therapy and adaptive immune response in common cancers. I describe how the p53 poly(A) SNP, rs78378222 (17p13.1; TP53), interacts with p53 mutational status in tumours to influence cancer risk, response to therapy and prognosis in common cancers. I find that a known colorectal cancer risk locus at 10p14 (rs10795668; ATP5C1) interacts with KRAS mutational status in tumours to associate with colorectal cancer risk. I identify two loci at 15q26.2 (rs72767781; NR2F2-AS1) and 15q22.2 (rs11447843; VPS13C) associated with prognosis in early-stage colorectal cancer at genome-wide significance, together with numerous suggestive loci. In particular, rs184423256 (8q22.3; RRM2B) and rs114887409 (4p16.1; ABLIM2) interact with KRAS mutational status in colorectal cancer to associate with clinical outcomes. Furthermore, I identify 22 loci associated with infiltrating CD8+ T cell density in colorectal cancer, which are used to infer the causal relationship between adaptive immune trait and prognosis in early-stage colorectal cancer. In summary, this study constitutes an integrative analysis of germline by somatic interaction on risk, biology, and prognosis of common cancers. The findings provide supportive evidence that inherited genetic variants can play an active role during tumour development, thus offering insight into the genetic basis of cancer susceptibility and practical guidance for personalised disease prediction.
- Published
- 2021
6. A meta-analysis of microarray datasets to identify biological regulatory networks in Alzheimer’s disease
- Author
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Kimia Sadat Hashemi, Mohadese Koohi Aliabadi, Arian Mehrara, Elham Talebi, Ali Akbar Hemmati, Radin Dabbagh Rezaeiye, Mohammad Javad Ghanbary, Maryam Motealleh, Behnaz Dayeri, and Shayan Khalili Alashti
- Subjects
Alzheimer’s disease ,gene expression profiling ,microarray analysis ,bioinformatics ,biology ,Genetics ,QH426-470 - Abstract
Background: Alzheimer’s Disease (AD) is an age-related progressive neurodegenerative disorder characterized by mental deterioration, memory deficit, and multiple cognitive abnormalities, with an overall prevalence of ∼2% among industrialized countries. Although a proper diagnosis is not yet available, identification of miRNAs and mRNAs could offer valuable insights into the molecular pathways underlying AD’s prognosis.Method: This study aims to utilize microarray bioinformatic analysis to identify potential biomarkers of AD, by analyzing six microarray datasets (GSE4757, GSE5281, GSE16759, GSE28146, GSE12685, and GSE1297) of AD patients, and control groups. Furthermore, this study conducted gene ontology, pathways analysis, and protein-protein interaction network to reveal major pathways linked to probable biological events. The datasets were meta-analyzed using bioinformatics tools, to identify significant differentially expressed genes (DEGs) and hub genes and their targeted miRNAs’.Results: According to the findings, CXCR4, TGFB1, ITGB1, MYH11, and SELE genes were identified as hub genes in this study. The analysis of DEGs using GO (gene ontology) revealed that these genes were significantly enriched in actin cytoskeleton regulation, ECM-receptor interaction, and hypertrophic cardiomyopathy. Eventually, hsa-mir-122-5p, hsa-mir-106a-5p, hsa-mir-27a-3p, hsa-mir16-5p, hsa-mir-145-5p, hsa-mir-12-5p, hsa-mir-128-3p, hsa-mir 3200-3p, hsa-mir-103a-3p, and hsa-mir-9-3p exhibited significant interactions with most of the hub genes.Conclusion: Overall, these genes can be considered as pivotal biomarkers for diagnosing the pathogenesis and molecular functions of AD.
- Published
- 2023
- Full Text
- View/download PDF
7. Identification of molecular subtypes of ischaemic stroke based on immune‐related genes and weighted co‐expression network analysis.
- Author
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Wei, Duncan, Chen, Xiaopu, Xu, Jing, and He, Wenzhen
- Subjects
ISCHEMIC stroke ,GENE expression ,GENES ,GENE regulatory networks ,DOWNLOADING ,IDENTIFICATION - Abstract
Immune system has been reported to play a key role in the development of ischaemic stroke (IS). Nevertheless, its exact immune‐related mechanism has not yet been fully revealed. Gene expression data of IS and healthy control samples was downloaded from Gene Expression Omnibus database and differentially expressed genes (DEGs) was obtained. Immune‐related genes (IRGs) data was downloaded from the ImmPort database. The molecular subtypes of IS were identified based on IRGs and weighted co‐expression network analysis (WGCNA). 827 DEGs and 1142 IRGs were obtained in IS. Based on 1142 IRGs, 128 IS samples were clustered into two molecular subtypes: clusterA and clusterB. Based on the WGCNA, the authors found that the blue module had the highest correlation with IS. In the blue module, 90 genes were screened as candidate genes. The top 55 genes were selected as the central nodes according to gene degree in protein–protein interactions network of all genes in blue module. Through taking overlap, nine real hub genes were obtained that might distinguish between clusterA subtype and clusterB subtype of IS. The real hub genes (IL7R, ITK, SOD1, CD3D, LEF1, FBL, MAF, DNMT1, and SLAMF1) may be associated with molecular subtypes and immune regulation of IS. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
8. SEARCH FOR GENETIC FACTORS UNDERLYING PROTECTION AGAINST OR RISK FOR COGNITIVE IMPAIRMENT IN THE MIDWESTERN AMISH
- Author
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Main, Leighanne Regina
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- Aging, Bioinformatics, Biology, Biostatistics, Genetics, Neurobiology, Cognitive preservation, cognitive resistance, cognitive resilience, genetics, Alzheimer Disease, founder population
- Abstract
Alzheimer disease (AD) affects more than 6 million individuals in the US, and accountsfor 60-80% of dementia cases. AD demonstrates mixed pathologies of amyloid beta andtau tangle accumulation, leading to symptoms such as cognitive impairment andmemory loss. Taking advantage of a closed, isolated population, the Midwestern Amish,variants both in protection against AD as well as risk for AD were explored. Thecomparative reduction in incidence of AD within the Amish versus a general Europeanpopulation led to the examination cognitive preservation, rather than AD, as thediagnosis of interest. A genome-wide association study (GWAS) was performed on theAmish to identify protective loci for AD via the GENESIS R Package. PC-AiR and PC-Relatewere used for principal component analysis to assist in correcting for the highly relatedsample. Linkage analyses across the entire genome, once again for cognitivepreservation, were used to supplement and corroborate GWAS findings. These analyseswere initially completed in MERLIN, but certain regions demonstrating repeated16significance were run through MORGAN, an MCMC linkage analysis software. Theseanalyses highlighted one region on chromosome 2p11.2-13.1 that demonstrated aprotective effect against AD. This region was previously associated with risk for AD inthe Midwestern Amish, potentially indicating both protective and risk variants withinthis locus. Further evaluations of genetic loci implicated in AD took advantage of thisunique sample population to examine a potential risk factor. The MGMT locus waspreviously associated with increased risk for AD in the Hutterites, who are anotherclosed, isolated population of European decent. In the Midwestern Amish, one SNP inthe MGMT locus was significantly associated with AD diagnosis. However, this SNP wasa novel result, distinct from those detected in a previous study and not in linkagedisequilibrium with previously associated MGMT SNPs for AD. We argue that this is anew association for the MGMT region, not previously detected, possibly indicatingpopulation-specific variants impacting AD risk. Given these findings, this Amish population demonstrates a unique opportunity for identifying new variants for bothprotection against and risk for AD, and merits continued investigation.
- Published
- 2024
9. GenPress: A Novel Dictionary Based Method to Compress DNA Data of Various Species
- Author
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Lehotay-Kéry, Péter, Kiss, Attila, Hutchison, David, Editorial Board Member, Kanade, Takeo, Editorial Board Member, Kittler, Josef, Editorial Board Member, Kleinberg, Jon M., Editorial Board Member, Mattern, Friedemann, Editorial Board Member, Mitchell, John C., Editorial Board Member, Naor, Moni, Editorial Board Member, Pandu Rangan, C., Editorial Board Member, Steffen, Bernhard, Editorial Board Member, Terzopoulos, Demetri, Editorial Board Member, Tygar, Doug, Editorial Board Member, Goos, Gerhard, Founding Editor, Hartmanis, Juris, Founding Editor, Nguyen, Ngoc Thanh, editor, Gaol, Ford Lumban, editor, Hong, Tzung-Pei, editor, and Trawiński, Bogdan, editor
- Published
- 2019
- Full Text
- View/download PDF
10. High-Performance In-Memory Genome Data Analysis How In-Memory Database Technology Accelerates Personalized Medicine /
- Author
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Plattner, Hasso, 1944, Schapranow, Matthieu-P., SpringerLink (Online service), Unknown, Plattner, Hasso, 1944, Schapranow, Matthieu-P., and SpringerLink (Online service)
- Subjects
Bioinformatics ,Biology ,Business Information Systems ,Computational Biology/Bioinformatics ,Computer Appl. in Life Sciences ,Data processing ,Genetics ,Genetics and Population Dynamics ,Life sciences ,Management information systems ,Mathematical statistics ,Mathematics ,Medical informatics ,Medical records ,Statistics and Computing/Statistics Programs - Published
- 2014
11. Inferring evolutionary history from whole genomes: outlier tests and methods based on the coalescent with recombination
- Author
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Yoshihara Caldeira Brandt, Débora
- Subjects
Genetics ,Bioinformatics ,Biology - Abstract
Whole genome sequences allow for new, powerful inferences of evolutionary history. In addition to increasing the scale of application of traditional population genetic inferences by using them on an enormous amount of loci, genomic data also provide valuable information about the location of those sites and correlations among them, which can be leveraged for inference of evolutionary parameters. In this dissertation, I explore three types of evolutionary inferences that are thriving with the increasing availability of genomic data and new methods. In Chapter 1, I use simulations to evaluate methods for inference of ancestral recombination graphs. In Chapter 2, I apply a new method based on the pairwise sequential Markovian coalescent to infer population split times and migration rates from a pair of diploid genomes. In Chapter 3, I use population-level genomic data from the population of a rural village in Ecuador to infer signatures of selection possibly related to the beneficial effects of diet on their cardiovascular health.
- Published
- 2022
12. Genome-Wide Analysis of the Impact of Diet on Liver and Intestines in Mouse and SNPs in Human HNF4a Binding Sites
- Author
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Martinez Lomeli, Jose
- Subjects
Bioinformatics ,Genetics ,Biology ,aaSNPs ,Alternative splicing ,High Fat Diets ,HNF4a ,intestines ,liver - Abstract
The use of next-generation sequencing technology has been extremely useful for genome-wide analysis in many different organisms. For example, transcriptomic analysis based on RNA-seq can identify all changes in gene expression in a given tissue in a single experiment. Other types of experiments, such as ChIP-seq, allow mapping of transcription factor binding sites across the genome. Much of the work in this dissertation focuses on the transcription factor hepatocyte nuclear factor 4a (HNF4a) which is a member of the nuclear receptor superfamily of ligand-dependent transcription factors and abundantly expressed in the liver and intestines. HNF4a has been linked to several diseases including diabetes, liver and colon cancer, inflammatory bowel disease and others. The expression of HNF4a is driven by two promoters (P1 and P2) which result in the expression of 12 different isoforms. Additionally, HNF4a has as its endogenous ligand an essential fatty acid (linoleic acid, LA) that must be obtained from the diet and is known to play a role in gluconeogenesis during fasting. Therefore, we examine fasted vs fed conditions as well as high fat diets with different amounts of LA on gene expression in the liver and intestines, respectively. Finally, HNF4a target genes have been extensively studied and mutations in HNF4a binding sites in regulatory regions of select target genes associated with disease have been identified. However, to date, there has been no systematic approach to identify variants in HNF4a binding sites of target genes on a genome-wide scale.In Chapter 1 of this dissertation, we provide an introduction to the biological and research problems addressed in the remainder of the dissertation and review the relevant literature. In Chapter 2, we analyze transcriptomic (RNA-seq) data from male mice fed three different high fat diets (HFDs) with different amounts of LA from four different tissues across the mouse intestinal tract. We found that different portions of the intestines have unique gene profiles, especially in terms of nuclear receptor signaling, xenobiotic and drug metabolism, and intestinal epithelial barrier function. We found that different types of HFDs impact gene expression in the intestinal tract in different ways, including genes linked to diseases such as inflammatory bowel disease and colon cancer. A network analysis revealed that mice fed the HFDs had altered expression of intestinal genes involved in crucial body functions such as the immune system and the intestinal microbiome which could facilitate bacterial and viral infections such as SARS-CoV-2. To our knowledge, this is the most comprehensive dataset including multiple diets and multiple parts of the intestines and should provide an excellent resource for the scientific community for some time to come.In Chapter 3, we compared the impact of fasting and HNF4a isoforms on liver gene expression and alternative splicing, comparing and contrasting two RNA-seq datasets from male and female mice. We also compared wild type mice (express predominantly P1-HNF4a isoforms) to exon swap mice (a7HMZ) which express only the P2 isoforms of HNF4a which are typically not expressed in the adult liver. We found that a 12-hour fast has a significant effect on alternative splicing and that the P2-HNF4a isoforms seem to play a role. Interestingly, there was a different pattern of alternative splicing in female livers.In Chapter 4, we analyze the impact of single nucleotide polymorphisms (SNPs) on HNF4a binding sites using publicly available datasets of HNF4a ChIP-seq (chromatin immunoprecipitation) from human liver and the liver cancer cell line HepG2 which expresses HNF4a and exhibits a hepatocyte phenotype. For this purpose, we trained a support vector machine (SVM) to predict binding affinity scores based on DNA sequences known to bind HNF4a from protein binding microarray (PBM) data. This model allowed us to identify 10 putative affinity altering SNPs (aaSNPs) in the human liver HNF4a ChIP-seq and six in the HepG2 ChIP-seq that impact the binding of HNF4a to the chromatin. Additionally, some of these identified SNPs were found in genes related to cancer, suggesting a potential role in personalized medicine. These results present a proof concept of affinity disruption in binding between HNF4a and some target genes in a genome-wide analysis.Finally, in Chapter 5, we provide an example of how transcriptomic data could be used to generate new biological hypotheses and test them. Additionally, we provide future directions for Chapter 3 and Chapter 4.
- Published
- 2022
13. A Multi-omics Approach to Annotate the Horse Genome
- Author
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Peng, Sichong
- Subjects
Biology ,Genetics ,Bioinformatics ,Annotation ,Epigenomics ,Equine ,Transcriptomics - Abstract
The genomic sequence of the horse has been available since 2007, providing critical resources for discovering important genomic variants regarding both animal health and population structure. However, to fully understand the functional implications of these variants, detailed annotation of the horse genome is required. Currently, the horse genome is annotated using the limited available RNA-seq data, as well as through comparative genomics by translating human and mouse genome annotation. While this approach has served the equine researchers well and led to a number of discoveries improving the care and management of horses, many important questions remain unanswered. The limitation of the current annotation is two pronged. First, a comparative genomics approach is insufficient to identify many genes that are less evolutionarily conserved, especially those that are noncoding. The sole reliance on short-read RNA-seq data also meant that alternate isoforms could not be accurately resolved. Second, epigenomic regulatory elements are crucial to detailed understanding of gene expression network but are yet to be systemically identified in the horse. Many regulatory elements, including enhancers, promoters, and insulators, are not transcribed or transcribed at a very low level, necessitating alternate approaches to identify them. To solve these problems, the Functional Annotation of the Animal Genomes (FAANG) project proposed a systemic approach to tissue collection, phenotyping, and data generation, adopting the blueprint laid out by the Encyclopedia of DNA Elements (ENCODE) project. This thesis describes the equine FAANG team’s effort to map tissue-specific gene expression and regulation in the horse genome. Chapter 1 provides an overview of the equine FAANG project’s approach to functional annotation. Chapter 2 describes an improved transcriptome that includes novel genes and alternate isoforms compared to the current annotation. In Chapter 3, we use ATAC-seq to create a catalog of tissue-specific open chromatin regions, which can serve as proxies to active regulatory elements. Chapter 4 provides a complete annotation of chromatin states across nine tissues. The Addendum detailed our effort to validate assays for transposase accessible chromatin using sequencing (ATAC-seq) in both frozen tissues and cryopreserved nuclei from fresh tissues. This thesis presents the first comprehensive overview of gene expression and their regulation in the horse, enabling interrogation of complex gene regulatory network and further studies of complex traits in horses. Future work should focus on both widening the scope of the equine FAANG project by including more tissue types and developmental stages, as well as refining gene network at single-cell resolution.
- Published
- 2022
14. Characterization of primate structural variation using diverse sequencing technologies
- Author
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Soto, Daniela Catalina
- Subjects
Genetics ,Bioinformatics ,Biology ,Long-read sequencing ,Segmental duplications ,Structural variation - Abstract
Elucidating the genetic changes underlying the evolution of human traits remains an unfinished puzzle. Structural variants (SVs) account for more genetic differences than single-nucleotide polymorphisms between humans and our closest living relatives, chimpanzees, and are a hallmark of great ape evolution. The genomes of great apes are enriched in large interspersed segmental duplications (SDs), defined as duplications larger than 1 kbp with over 90% sequence identity, that sensitize the genome to further genomic rearrangements, including copy-number variation, via non- allelic homologous recombination. Despite their relevance, the identification and characterization of these SVs has been hindered by short reads lengths as they lack enough sequence context to discover breakpoints and cannot unequivocally be mapped to highly identical duplicates. Long-read sequencing technologies overcome these limitations by providing reads thousands of bases long, but the availability of population cohorts remains limited.This thesis studies primate SVs and SDs characterized using diverse sequencing technologies and assesses their representation in reference genomes, variation across modern populations, their putative molecular impacts, and their roles in evolution and adaptation. We found novel SVs, including 88 deletions and 36 inversions, in two chimpanzee individuals sequenced with nanopore and optical mapping. Deletions and inversion breakpoints were depleted within topologically associated domains but enriched in differentially expressed genes between the two species. Focusing on human SDs, we identified eight Mbp of erroneously collapsed duplications in the human reference genome, impacting 48 protein coding and ten medically relevant genes, that are corrected in the first complete sequence of a human genome, T2T-CHM13. Leveraging this new reference, we identified 417 genes embedded in SDs with over 98% sequence identity (SD-98) that are near copy-number (CN) fixed in modern humans (1000 Genomes Project; 1KGP), 205 genes showing stratification between diverse modern populations (VST>95th percentile), and 22 protein-encoding genes showing consistent Tajima’s D outlier values across all humans examined. Our approach highlighted potential relevant human gene duplications, which are priority candidates for functional studies. Finally, we provide a compendium of tools and practices that we recommend be adopted by computational biologists to increase reproducibility in the field.
- Published
- 2022
15. Human Genome Data Protection Using PostgreSQL DBMS
- Author
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Lehotay-Kéry, Péter, Kiss, Attila, Barbosa, Simone Diniz Junqueira, Series Editor, Filipe, Joaquim, Series Editor, Kotenko, Igor, Series Editor, Sivalingam, Krishna M., Series Editor, Washio, Takashi, Series Editor, Yuan, Junsong, Series Editor, Zhou, Lizhu, Series Editor, Ghosh, Ashish, Series Editor, and Stephanidis, Constantine, editor
- Published
- 2018
- Full Text
- View/download PDF
16. Genome-wide analysis of selection in mammals, insects and fungi
- Author
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Ridout, Kate E. and Filatov, Dmitry A.
- Subjects
572.838 ,Bioinformatics (life sciences) ,Biology ,Genetics (life sciences) ,Evolution,ecology and systematics ,Evolution (zoology) ,Bioinformatics ,genetics ,genomics ,evolution ,selection ,protein structure ,next generation sequencing ,NGS assembly ,Microbotryum - Abstract
Characterising and understanding factors that affect the rate of molecular evolution in proteins has played a major part in the development of evolutionary theory. The early analyses of amino acid substitutions stimulated the development of the neutral theory of molecular evolution, which later evolved into the nearly neutral theory. More recent work has lead to a better understanding of the role selection plays at the molecular level, but there is still limited understanding of how higher levels of protein organisation affect the way natural selection acts. The investigation of this question is the central aim of this thesis, which is addressed via the analysis of selective pressures in secondary protein structures in insects, mammals and fungi. The analyses for the first two groups were conducted using publically available datasets. To conduct the analyses in fungi, genome sequence data from the fungal genus Microbotryum (sequenced in our laboratory) was assembled and annotated, resulting in the development of a number of bioinformatics tools which are described here. The fungal, insect and mammalian datasets were interrogated with regard to a number of structural features, such as protein secondary structure, position of a site with regard to adaptively evolving sites, hydropathy and solvent-accessibility. These features were correlated with the signals of positive and purifying selection detected using phylogenetic maximum likelihood and Bayesian approaches. I conclude that all of the factors examined can have an effect on the rate of molecular evolution. In particular, disordered and hydrophilic regions of the protein are found to experience fewer physiochemical constraints and contain a higher proportion of adaptively evolving sites. It is also revealed that positively selected residues are ‘clustered’ together spatially, and these trends persist in the three taxa. Finally, I show that this variation in adaptive evolution is a result of both selective events and physiochemical constraint.
- Published
- 2012
17. Exploring Non-Canonical Regulatory Small RNAs in Mammals
- Author
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Shi, Junchao
- Subjects
Bioinformatics ,Genetics ,Biology ,Lung cancer ,rRNA-derived small RNA ,small RNA annotation ,small RNA library construction ,tRNA-derived small RNA ,yRNA-derived small RNA - Abstract
Small RNAs are short, non-coding RNA molecules that have been identified in a wide range of species across all three domains of life. In mammals, canonical small RNAs such as microRNAs (miRNAs) and Piwi-interacting RNAs (piRNAs) are tissue-specifically distributed and can regulate gene expression at both transcriptional and post-transcriptional levels, associating with various fundamental functions such as gene silencing and retrotransposon control. While miRNAs and piRNAs have been extensively investigated, the existence and mechanism of other non-canonical mammalian small RNAs remain underexplored.With the extensive use of high-throughput sequencing technologies in the past decade, small RNA diversity is rapidly growing. However, the conventional small RNA library construction method lacks the detection capability for non-canonical small RNAs that carry specific terminal and internal modifications, especially for tRNA-derived small RNAs (tsRNAs) and rRNA-derived small RNAs (rsRNAs). In addition, existing downstream bioinformatics tools are mostly focused on analyzing canonical small RNAs such as miRNAs and piRNAs, while the annotation of other small RNAs remains rudimentary or ignored.To reveal a panoramic view of small RNAs, a small RNA annotation pipeline (that is, SPORTS) is developed to simultaneously and comparatively annotate both canonical and non-canonical small RNAs, along with RNA modification prediction capacity. Moreover, a small RNA library preparation procedure (that is, PANDORA-seq) is optimized to comprehensively capture modified small RNAs such as tsRNAs and rsRNAs.The improved RNA-seq and bioinformatics strategy leads to a new and surprising small RNA landscape that tsRNAs and rsRNAs have a higher abundance than canonical small RNAs in a majority of mouse and human tissues/cells that have been examined. Those mammalian tsRNAs and rsRNAs also exhibit tissue- and cell-specific patterns and the expression level of those small RNAs are dynamically altered during the generation of induced pluripotent stem cells (iPSCs) based on PANDORA-seq. Those newly identified small RNAs also display translational regulation during embryonic stem cell differentiation and have a role in regulating embryonic stem cell lineage fate based on the transcriptomic changes after their transfection.
- Published
- 2021
18. Frontiers of Plant Cell Biology: Signals and Pathways, System-Based Approaches 22nd Symposium in Plant Biology (University of California-Riverside)
- Author
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Minorsky, Peter
- Published
- 2003
19. Federal University Alagoas Researchers Report on Findings in Bioinformatics (Homeostatic status of thyroid hormones and brain water movement as determinant factors in biology of cerebral gliomas: a pilot study using a bioinformatics approach).
- Subjects
THYROID hormones ,HYDROCEPHALUS ,GLIOMAS ,RESEARCH personnel ,BIOLOGY ,BIOINFORMATICS - Abstract
Researchers from Federal University Alagoas in Brazil have conducted a pilot study using a bioinformatics approach to investigate the role of thyroid hormones and brain water movement in the biology of cerebral gliomas. The study found that aquaporins (AQPs), which are water channel transporters, are overexpressed in patients with glioma. The researchers also identified a correlation between the expression of genes involved in the tyrosine and thyroid hormone pathways and AQPs. These findings suggest that thyroid hormone pathways and AQPs 1 and 4 could be potential targets for new anti-tumor drugs and therapeutic biomarkers for malignant gliomas. [Extracted from the article]
- Published
- 2024
20. Complete Genome and Plasmid Sequence Data of Three Strains of Xanthomonas arboricola pv. corylina, the Bacterium Responsible for Bacterial Blight of Hazelnut
- Author
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Fabio Rezzonico, Andjelka Prokić, Joël F. Pothier, Monika Kałużna, and Aleksa Obradović
- Subjects
0106 biological sciences ,complete genome ,Genomics ,Plant Science ,Biology ,microbe-genome sequencing ,01 natural sciences ,Genome ,03 medical and health sciences ,Plasmid ,bacterial pathogens ,genomics ,hazelnut ,Bacterial blight ,Xanthomonas arboricola pv. corylina ,bacteria ,Pathogen ,030304 developmental biology ,Genetics ,0303 health sciences ,bioinformatics ,Xanthomonas arboricola ,biology.organism_classification ,PEST analysis ,Agronomy and Crop Science ,Bacteria ,010606 plant biology & botany - Abstract
Xanthomonas arboricola pv. corylina is the causal agent of bacterial blight of hazelnut. The bacterium has been listed as an A2 quarantine pathogen in Europe since 1978 and on the regulated non-quarantine pest list since 2019. Three isolates from various geographic regions and isolated at different times were sequenced using a hybrid approach with short- and long-read technologies to generate closed genome and plasmid sequences in order to better understand the biology of this pathogen.
- Published
- 2022
21. DIMPLE: deep insertion, deletion, and missense mutation libraries for exploring protein variation in evolution, disease, and biology
- Author
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Christian B. Macdonald, David Nedrud, Patrick Rockefeller Grimes, Donovan Trinidad, James S. Fraser, and Willow Coyote-Maestas
- Subjects
INDEL Mutation ,Bioinformatics ,Information and Computing Sciences ,Mutation ,Genetics ,Proteins ,Missense ,Biological Sciences ,Biology ,Environmental Sciences - Abstract
Insertions and deletions (indels) enable evolution and cause disease. Due to technical challenges, indels are left out of most mutational scans, limiting our understanding of them in disease, biology, and evolution. We develop a low cost and bias method, DIMPLE, for systematically generating deletions, insertions, and missense mutations in genes, which we test on a range of targets, including Kir2.1. We use DIMPLE to study how indels impact potassium channel structure, disease, and evolution. We find deletions are most disruptive overall, beta sheets are most sensitive to indels, and flexible loops are sensitive to deletions yet tolerate insertions.
- Published
- 2023
22. Detecting structural variants in the DNA of the inbred Scandinavian wolf
- Author
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Huson, Lars
- Subjects
snakemake ,population genomics ,CNV ,grey wolf ,inbreeding ,Bioinformatik och systembiologi ,Evolutionsbiologi ,structural variant ,wolf ,endangered population ,evolution ,genomics ,Genetics ,animal ,Genetik ,Evolutionary Biology ,Bioinformatics and Systems Biology ,biology ,extinction ,biological sciences ,pedigree ,population genetics ,SV ,bioinformatics ,DNA ,endangered species ,genetic diversity ,Canis lupus ,wolves ,copy-number variation ,conservation genetics ,conservation genomics ,indel ,genetic variation ,Scandinavia ,smoove ,mutation ,genomes ,animal population ,inbreeding depression - Abstract
Only 40 years ago, just three individuals made the journey from Finland/Russia to found the current wolf population in the southwest of Sweden. This population, that to this date descends from less than 10 founders, has a substantial increased extinction risk due to inbreeding. Several previous studies have used SNPs to monitor the level of inbreeding and homozygosity in the population, as well as measure immigration and the inflow of new genetic material. This study uses both short- and long-read data to discover structural variants (SVs) and small indels in the population, so that they may be used to extend the analyses and provide more insight into the current state of the Scandinavian wolf population. After the calling of the SVs, strict filtering and manual curation were applied to the data, thereby removing many false positive calls and increasing confidence in the remaining SVs. Short-read and long-read SV-callers found 31,800 and 57,821 SVs respectively, with relatively little overlap between the two sets. By far, the most common SV-types were deletions and insertions, at about 30,000 each with varying length ranging from a 50 base pairs to several tens of Mbp. Analyses on the data, such as PCAs and parent-offspring trio analyses, reveal high-confidence calls and consistent results between SV-types and SV-callers, as well as a low estimated genotyping error rate. PCAs performed on the SVs resembled those performed on SNPs, which strengthens the credibility of the identified variants. Finally, this study suggests several alternative steps for possible improvement to the dataset, along with some proposals for subsequent research topics that may use the variants discovered in this study.
- Published
- 2023
23. Understanding the cellular heterogeneity in fetal-like and adult tissues to study cell-type-specific functional genetic variation
- Author
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Donovan, Margaret Kathleen Rose
- Subjects
Genetics ,Bioinformatics ,Biology ,Cellular heterogeneity ,Development ,eQTLs ,Induced pluripotent stem cells - Abstract
Genome-wide association studies (GWAS) have suggested that the underlying genetic basis of complex traits and disease is driven by large numbers of non-coding variants with modest effects that likely act by modifying gene regulation. Towards understanding the regulatory impact of genetic variation, expression quantitative trait loci (eQTL) analyses have been performed across dozens of human tissues to link the influence of genetic variants on gene expression levels. While these eQTL studies have provided important biological insights, they are still limited by not considering the contexts in which these variants function, including the stage of development and cell type. Specifically, others have shown increased disease risk in adulthood has links to fetal origins, suggesting that characterizing gene expression in fetal-like cells could identify genetic variants that are associated with adult traits, but function primarily or solely during development. Additionally, as eQTL studies are typically performed across bulk tissues, unaccounted for cellular heterogeneity present in bulk gene expression measurements can affect genotype-gene expression associations. Thus, it is important to identify regulatory variants that alter gene expression in both primitive and adult cell types and to characterize cellular heterogeneity across tissues to comprehensively understand the genetic basis of complex traits and disease.Here, I present two studies, which utilize gene expression data from fetal-like and adult tissues to characterize cellular heterogeneity at distinct stages of human development. I have examined the cellular heterogeneity in fetal-like induced pluripotent stem cell (iPSC)-derived cardiovascular progenitor cells (CVPCs) using single cell (sc)RNA-seq data to identify cell populations that emerge as a result of the cardiac differentiation. Further, I deconvoluted 180 iPSC-CVPCs and identified factors innate to iPSCs that impacted cardiac fate. Next, I showed that mouse scRNA-seq can be used as an alternative to human scRNA-seq for the deconvolution of adult GTEx bulk tissues and considering cell composition eQTL studies powered the discovery of novel eQTLs, some of which were cell-type-associated and colocalized with GWAS disease loci.
- Published
- 2019
24. The RNA encoding the microtubule-associated protein tau has extensive structure that affects its biology.
- Author
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Chen, Jonathan L., Moss, Walter N., Spencer, Adam, Zhang, Peiyuan, Childs-Disney, Jessica L., and Disney, Matthew D.
- Subjects
- *
TAU proteins , *MICROTUBULE-associated proteins , *RNA , *BIOLOGY , *PATHOLOGY , *ALZHEIMER'S disease - Abstract
Tauopathies are neurodegenerative diseases that affect millions of people worldwide including those with Alzheimer’s disease. While many efforts have focused on understanding the role of tau protein in neurodegeneration, there has been little done to systematically analyze and study the structures within tau’s encoding RNA and their connection to disease pathology. Knowledge of RNA structure can provide insights into disease mechanisms and how to affect protein production for therapeutic benefit. Using computational methods based on thermodynamic stability and evolutionary conservation, we identified structures throughout the tau pre-mRNA, especially at exon-intron junctions and within the 5′ and 3′ untranslated regions (UTRs). In particular, structures were identified at twenty exon-intron junctions. The 5′ UTR contains one structured region, which lies within a known internal ribosome entry site. The 3′ UTR contains eight structured regions, including one that contains a polyadenylation signal. A series of functional experiments were carried out to assess the effects of mutations associated with mis-regulation of alternative splicing of exon 10 and to identify regions of the 3′ UTR that contain cis-regulatory elements. These studies defined novel structural regions within the mRNA that affect stability and pre-mRNA splicing and may lead to new therapeutic targets for treating tau-associated diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
25. Complete Genome Resources for Xylella fastidiosa Strains AlmaEM3 and BB08-1 Reveal Prophage-Associated Structural Variation Among Blueberry-Infecting Strains
- Author
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Blanca B. Landa, Lindsey P. Burbank, Luis F. Arias-Giraldo, Leonardo De La Fuente, Michael O'Leary, Department of Agriculture (US), and National Institutes of Health (US)
- Subjects
Genetics ,biology ,Bioinformatics ,Strain (biology) ,Leaf scorch ,Genomics ,Plant Science ,Subspecies ,biology.organism_classification ,medicine.disease ,Genome ,Structural variation ,Microbe-genome sequencing ,medicine ,Bacterial pathogens ,Xylella fastidiosa ,Agronomy and Crop Science ,Prophage - Abstract
This work was funded by the United States Department of Agriculture–Agricultural Research Service appropriated project 2034-22000-012-00D and the Xylella fastidiosa Active Containment Through a Multidisciplinary-Oriented Research Strategy (XF-ACTORS) project. Illumina sequencing for BB08-1 was carried out at the University of California, Davis, Genome Center DNA Technologies and Expression Analysis Cores, supported by National Institute of Health Shared Instrumentation Grant 1S10OD010786-01.
- Published
- 2022
26. Identification of CHMP4C as a new risk gene for inherited dilated cardiomyopathy
- Author
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Zilong Qiu, Shengmei Qin, Junbo Ge, Xuejie Li, Bo Yuan, Xianhong Shu, Nianwei Zhou, Shifang Shan, Cuizhen Pan, Xiaolin Wang, Yingying Jiang, and Lu Tang
- Subjects
Cardiomyopathy, Dilated ,Genetics ,MEDLINE ,medicine ,Humans ,Risk gene ,Identification (biology) ,Dilated cardiomyopathy ,Biology ,Bioinformatics ,medicine.disease ,Molecular Biology ,HeLa Cells - Published
- 2022
27. Identification of the key genes and immune infiltrating cells determined by sex differences in ischaemic stroke through co‐expression network module
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Haipeng Xu, Rong Hu, Qianqian Liu, Yanzhi Ge, Yang Liu, Yang Zheng, and Conglin Ren
- Subjects
Male ,sex differences ,Cell type ,QH301-705.5 ,Biology ,Bioinformatics ,Genome ,Brain Ischemia ,differently expressed genes ,Immune system ,Genetics ,medicine ,Animals ,Humans ,Gene Regulatory Networks ,KEGG ,Biology (General) ,Molecular Biology ,Gene ,Stroke ,Ischemic Stroke ,Sex Characteristics ,ischaemic stroke ,WGCNA ,Gene Expression Profiling ,RNA ,Cell Biology ,medicine.disease ,Rats ,Modeling and Simulation ,Female ,CD8 ,Biotechnology - Abstract
Stroke is one of the leading causes of patients' death and long‐term disability worldwide, and ischaemic stroke (IS) accounts for nearly 80% of all strokes. Differential genes and weighted gene co‐expression network analysis (WGCNA) in male and female patients with IS were compared. The authors used cell type identification by estimating relative subsets of RNA transcripts (CIBERSORT) to analyse the distribution pattern of immune subtypes between male and female patients. In this study, 141 up‐regulated and 61 down‐regulated genes were gathered and distributed into five modules in response to their correlation degree to clinical traits. The criterion for Gene Ontology (GO) term and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway indicated that detailed analysis had the potential to enhance clinical prediction and to identify the gender‐related mechanism. After that, the expression levels of hub genes were measured via the quantitative real‐time PCR (qRT‐PCR) method. Finally, CCL20, ICAM1 and PTGS2 were identified and these may be some promising targets for sex differences in IS. Besides, the hub genes were further verified by rat experiments. Furthermore, these CIBERSORT results showed that T cells CD8 and Monocytes may be the target for the treatment of male and female patients, respectively.
- Published
- 2022
28. Combination therapy and noncoding RNAs: a new era of cancer personalized medicine
- Author
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Perla Pucci
- Subjects
Cancer Research ,RNA, Untranslated ,Combination therapy ,business.industry ,medicine.medical_treatment ,Cancer ,Biology ,Bioinformatics ,medicine.disease ,Targeted therapy ,Neoplasms ,microRNA ,Genetics ,medicine ,Animals ,Humans ,Personalized medicine ,Precision Medicine ,business - Published
- 2022
29. The adducin saga: pleiotropic genomic targets for precision medicine in human hypertension—vascular, renal, and cognitive diseases
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Wenjun Gao, Ezekiel Gonzalez-Fernandez, Kirby N Thomas, Fan Fan, Letao Fan, Yedan Liu, Shaoxun Wang, and Richard J. Roman
- Subjects
Candidate gene ,Hypertension, Renal ,Heart disease ,Physiology ,Blood Pressure ,Review ,Disease ,Biology ,Bioinformatics ,Renal Circulation ,Genetics ,medicine ,Animals ,Homeostasis ,Humans ,Cognitive Dysfunction ,Genetic Predisposition to Disease ,Precision Medicine ,Nephritis ,medicine.disease ,Rats ,Disease Models, Animal ,Blood pressure ,ADD1 ,ADD3 ,Renal blood flow ,Hypertension ,Mutation ,Calmodulin-Binding Proteins ,Kidney disease - Abstract
Hypertension is a leading risk factor for stroke, heart disease, chronic kidney disease, vascular cognitive impairment, and Alzheimer’s disease. Previous genetic studies have nominated hundreds of genes linked to hypertension, and renal and cognitive diseases. Some have been advanced as candidate genes by showing that they can alter blood pressure or renal and cerebral vascular function in knockout animals; however, final validation of the causal variants and underlying mechanisms has remained elusive. This review chronicles 40 years of work, from the initial identification of adducin (ADD) as an ACTIN-binding protein suggested to increase blood pressure in Milan hypertensive rats, to the discovery of a mutation in ADD1 as a candidate gene for hypertension in rats that were subsequently linked to hypertension in man. More recently, a recessive K572Q mutation in ADD3 was identified in Fawn-Hooded Hypertensive (FHH) and Milan Normotensive (MNS) rats that develop renal disease, which is absent in resistant strains. ADD3 dimerizes with ADD1 to form functional ADD protein. The mutation in ADD3 disrupts a critical ACTIN-binding site necessary for its interactions with actin and spectrin to regulate the cytoskeleton. Studies using Add3 KO and transgenic strains, as well as a genetic complementation study in FHH and MNS rats, confirmed that the K572Q mutation in ADD3 plays a causal role in altering the myogenic response and autoregulation of renal and cerebral blood flow, resulting in increased susceptibility to hypertension-induced renal disease and cerebral vascular and cognitive dysfunction.
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- 2022
30. The KiSS-1/GPR54 system: Essential roles in physiological homeostasis and cancer biology
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Mengxiang Zhao, Liang Ding, Nisha Zhu, Yanhong Ni, and Yuxian Song
- Subjects
0301 basic medicine ,endocrine system ,Medicine (General) ,Kisspeptin ,Endogeny ,Review Article ,Biology ,QH426-470 ,Bioinformatics ,Biochemistry ,Metastasis ,03 medical and health sciences ,0302 clinical medicine ,R5-920 ,medicine ,Genetics ,Receptor ,Molecular Biology ,Gene ,Regulators in vivo and in vitro ,Genetics (clinical) ,Physiological homeostasis ,Trophoblast ,Cell Biology ,medicine.disease ,Biomarker ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,KiSS-1/GPR54 ,Identification (biology) ,human activities ,Homeostasis ,hormones, hormone substitutes, and hormone antagonists ,Tumor metastasis - Abstract
KiSS-1, first identified as an anti-metastasis gene in melanoma, encodes C-terminally amidated peptide products, including kisspeptin-145, kisspeptin-54, kisspeptin-14, kisspeptin-13 and kisspeptin-10. These products are endogenous ligands coupled to G protein-coupled receptor 54 (GPR54)/hOT7T175/AXOR12. To date, the regulatory activities of the KiSS-1/GPR54 system, such as puberty initiation, antitumor metastasis, fertility in adulthood, hypothalamic-pituitary-gonadal axis (HPG axis) feedback, and trophoblast invasion, have been investigated intensively. Accumulating evidence has demonstrated that KiSS-1 played a key role in reproduction and served as a promising biomarker relative to the diagnosis, identification of therapeutic targets and prognosis in various carcinomas, while few studies have systematically summarized its subjective factors and concluded the functions of KiSS-1/GPR54 signaling in physiology homeostasis and cancer biology. In this review, we retrospectively summarized the regulators of the KiSS-1/GPR54 system in different animal models and reviewed its functions according to physiological homeostasis regulations and above all, cancer biology, which provided us with a profound understanding of applying the KiSS-1/GPR54 system into medical applications.
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- 2022
31. Strategies for characterizing the regulatory code of the human genome
- Author
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Javed, Nauman Muhammad
- Subjects
- base editing, computational biology, deep learning, regulatory genomics, Bioinformatics, Genetics, Biology
- Abstract
The regulatory code of the genome refers to the mechanisms that govern differential gene expression across diverse cell-types in the human body. Epigenome profiling has nominated millions of regulatory elements (REs) within the non-coding genome as potential mediators of this context-dependent gene regulation. However, how genomic sequence encodes for the function of these REs remains poorly understood. In this thesis, I describe computational and experimental strategies related to the characterization of these sequence determinants, with a focus on the use and development of machine learning models for regulatory genomics, and CRISPR-based perturbations. In chapter 1, we introduce a tool for detecting sample-swaps within large-scale, multi-donor functional genomics databases, which can confound integrative genomics analyses and machine learning model development. This approach quantifies the sample-relatedness of diverse sequencing datasets by utilizing linkage disequilibrium between genetic variants, allowing comparison between non-overlapping reads. By combining this approach with ancestry-agnostic haplotype maps, we achieve reliable sample-swap detection across different assays and sample read-depths. Application of this method led to the identification and correction of sample-swaps in nearly 1\% of ENCODE datasets. This tool is scalable for the systematic validation of the rapidly expanding body of genomic data that can provide a foundation for deep learning- and experimentally-based investigations of the genome's regulatory code, as proposed in the subsequent chapters. In chapter 2, we describe a framework for dissecting regulatory elements at base resolution, using a combination of genetic and epigenetic CRISPR-based perturbations, as well as a sequence based deep learning model. We use these complementary strategies to characterize a differentially accessible enhancer upstream of the key T-cell activation gene, CD69. These approaches converge on a $\sim$ 170 base interval critical for CD69 induction in stimulated Jurkat T cells. Individual cytosine-to-thymine base edits within the interval reduce element accessibility and acetylation, with a corresponding reduction of CD69 expression. The most potent base edits likely impact regulatory interactions between the transcriptional activators, GATA3 and TAL1, and the repressor BHLHE40. Systematic analysis suggests that interplay between GATA3 and BHLHE40 plays a general role in rapid T cell transcriptional responses. This chapter provides a framework for parsing regulatory elements in their endogenous chromatin contexts and identifying operative artificial variants. Furthermore, it demonstrates the utility of sequence based deep learning models for parsing regulatory element function and provides early benchmarking against experimental data for these emerging tools. In chapter 3, we build upon the sequence-based deep learning model utilized in chapter 2. A limitation of this model is that it cannot generalize to cell-types unobserved during training. To address this, we introduce a multi-modal transformer based neural network and propose a novel masking based pre-training objective to learn joint representations of sequence and cell-type specific ATAC-seq signal. We demonstrate that this approach yields useful embeddings that can be used for downstream tasks including gene expression prediction in de novo cellular contexts.
- Published
- 2023
32. Brain Repair by Cell Replacement via In Situ Neuronal Reprogramming
- Author
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Xiang-Dong Fu and Hao Qian
- Subjects
Neurons ,Symptom management ,Neurogenesis ,Cell replacement ,Brain ,Neurodegenerative Diseases ,Biology ,Bioinformatics ,Brain repair ,Genetics ,Humans ,Treatment strategy ,Reprogramming - Abstract
Neurodegenerative diseases, characterized by progressive neural loss, have been some of the most challenging medical problems in aging societies. Treatment strategies such as symptom management have little impact on disease progression, while intervention with specific disease mechanisms may only slow down disease progression. One therapeutic strategy that has the potential to reverse the disease phenotype is to replenish neurons and rebuild the pathway lost to degeneration. Although it is generally believed that the central nervous system has lost the capability to regenerate, increasing evidence indicates that the brain is more plastic than previously thought, containing perhaps the biggest repertoire of cells with latent neurogenic programs in the body. This review focuses on key advances in generating new neurons through in situ neuronal reprogramming, which is tied to fundamental questions regarding adult neurogenesis, cell source, and mechanisms for neuronal reprogramming, as well as the ability of new neurons to integrate into the existing circuitry.
- Published
- 2021
33. Current and future treatment approaches for Barth syndrome
- Author
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Hilary J. Vernon, Reid C. Thompson, Michael T. Chin, John L. Jefferies, Clifford Takemoto, Brittany Hornby, Andrea Heyman, William T. Pu, and Suya Wang
- Subjects
medicine.medical_specialty ,Neutropenia ,Cardiolipins ,Peroxisome Proliferator-Activated Receptors ,Tafazzin ,Cardiomyopathy ,Enzyme Therapy ,Peroxisome proliferator-activated receptor ,Disease ,Bioinformatics ,Mice ,chemistry.chemical_compound ,Muscular Diseases ,Internal medicine ,Genetics ,Cardiolipin ,medicine ,Animals ,Humans ,Genetics (clinical) ,chemistry.chemical_classification ,Clinical Trials as Topic ,Hematology ,biology ,business.industry ,Barth syndrome ,Genetic Therapy ,Elamipretide ,medicine.disease ,chemistry ,Barth Syndrome ,biology.protein ,Bezafibrate ,Cardiomyopathies ,business ,Oligopeptides ,Acyltransferases - Abstract
Barth Syndrome is an X-linked disorder of mitochondrial cardiolipin metabolism caused by pathogenic variants in TAFAZZIN with pleiotropic effects including cardiomyopathy, neutropenia, growth delay, and skeletal myopathy. Management requires a multidisciplinary approach to the organ-specific manifestations including specialists from cardiology, hematology, nutrition, physical therapy, genetics, and metabolism. Currently, treatment is centered on management of specific clinical features, and is not targeted towards remediating the underlying biochemical defect. However, two clinical trials have been recently undertaken which target the mitochondrial pathology of this disease: a study to examine the effects of elamipretide, a cardiolipin targeted agent, and a study to examine the effects of bezafibrate, a peroxisome proliferator-activated receptor (PPAR) agonist. Treatments to directly target the defective TAFAZZIN pathway are under development, including enzyme and gene therapies. This article is protected by copyright. All rights reserved.
- Published
- 2021
34. PRNCR1: a long non-coding RNA with a pivotal oncogenic role in cancer
- Author
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Abhishek Bardhan, Keya Basu, Anwesha Banerjee, Amlan Ghosh, and Dilipkumar Pal
- Subjects
Male ,Genotype ,Carcinogenesis ,Single-nucleotide polymorphism ,Review ,Biology ,Bioinformatics ,Polymorphism, Single Nucleotide ,Prostate cancer ,Neoplasms ,microRNA ,Biomarkers, Tumor ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,Alleles ,Genetics (clinical) ,Cancer ,Prognosis ,medicine.disease ,Molecular medicine ,Long non-coding RNA ,Human genetics ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,RNA, Long Noncoding - Abstract
Long non-coding RNAs (lncRNAs) have been gaining importance in the field of cancer research in recent years. PRNCR1 (prostate cancer-associated non-coding RNA1) is a 12.7 kb, intron-less lncRNA found to play an oncogenic role in malignancy of diverse organs including prostate, breast, lung, oral cavity, colon and rectum. Single-nucleotide polymorphisms (SNPs) of PRNCR1 locus have been found to be associated with cancer susceptibility in different populations. In this review, an attempt has been made for the first time to summarize all sorts of available data on PRNCR1 to date from relevant databases (GeneCard, LncExpDB, Ensembl genome browser, and PubMed). As functional roles of PRNCR1, miRNA (microRNA) sponging was mostly highlighted in the pathogenesis of different cancer; in addition, an association of the lncRNA with chromatin-modifying complex to enhance androgen receptor-mediated gene transcription was reported in prostate cancer. Diagnostic and prognostic importance of PRNCR1 was found in some malignancies suggesting potency of the lncRNA to serve as a clinical biomarker. For PRNCR1 SNPs, although cancer susceptibility of the risk alleles/genotypes was reported in different populations, majorities of the findings were not replicated and underlying molecular mechanisms remained unexplored. Therapeutic implication of PRNCR1 was not studied well and future research may come up in this direction for intervening novel strategies to fight against cancer.
- Published
- 2021
35. The European Bioinformatics Institute (EMBL-EBI) in 2021
- Author
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Gaia Cantelli, Rahuman S Malik-Sheriff, Paul Flicek, Ewan Birney, Cath Brooksbank, Alex Bateman, Johanna McEntyre, Anton I. Petrov, Henning Hermjakob, Michele Ide-Smith, and Rolf Apweiler
- Subjects
InterPro ,Service (systems architecture) ,RNA, Untranslated ,Databases, Factual ,AcademicSubjects/SCI00010 ,Databases, Pharmaceutical ,Information Storage and Retrieval ,Biology ,Bioinformatics ,Data type ,Artificial Intelligence ,Component (UML) ,Genetics ,Ensembl ,Database Issue ,Humans ,Databases, Protein ,Balanced scorecard ,Genome, Human ,SARS-CoV-2 ,Academies and Institutes ,COVID-19 ,Computational Biology ,Metadata ,Europe ,UniProt - Abstract
The European Bioinformatics Institute (EMBL-EBI) maintains a comprehensive range of freely available and up-to-date molecular data resources, which includes over 40 resources covering every major data type in the life sciences. This year's service update for EMBL-EBI includes new resources, PGS Catalog and AlphaFold DB, and updates on existing resources, including the COVID-19 Data Platform, trRosetta and RoseTTAfold models introduced in Pfam and InterPro, and the launch of Genome Integrations with Function and Sequence by UniProt and Ensembl. Furthermore, we highlight projects through which EMBL-EBI has contributed to the development of community-driven data standards and guidelines, including the Recommended Metadata for Biological Images (REMBI), and the BioModels Reproducibility Scorecard. Training is one of EMBL-EBI’s core missions and a key component of the provision of bioinformatics services to users: this year's update includes many of the improvements that have been developed to EMBL-EBI’s online training offering.
- Published
- 2021
36. Role of Neurotransmitter System Genes in Chronic Obstructive Pulmonary Disease
- Author
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S. M. Izmaǐlova, L. Z. Akhmadishina, Sh. R. Zulkarneev, T. V. Victorova, Sh. Z. Zagidullin, O. V. Kochetova, Timur R. Nasibullin, Gulnaz F. Korytina, and Yu. G. Aznabaeva
- Subjects
chemistry.chemical_compound ,chemistry ,Genetics ,Pulmonary disease ,Biology ,Bioinformatics ,Neurotransmitter ,Gene - Published
- 2021
37. Genome-wide analysis of 53,400 people with irritable bowel syndrome highlights shared genetic pathways with mood and anxiety disorders
- Author
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Eijsbouts, Chris, Zheng, Tenghao, Kennedy, Nicholas A., Bonfiglio, Ferdinando, Anderson, Carl A., Moutsianas, Loukas, Holliday, Joanne, Shi, Jingchunzi, Shringarpure, Suyash, Voda, Alexandru-Ioan, Farrugia, Gianrico, Franke, Andre, H��benthal, Matthias, Abecasis, Gon��alo, Zawistowski, Matthew, Skogholt, Anne Heidi, Ness-Jensen, Eivind, Hveem, Kristian, Esko, T��nu, Teder-Laving, Maris, Zhernakova, Alexandra, Camilleri, Michael, Boeckxstaens, Guy, Whorwell, Peter J., Spiller, Robin, McVean, Gil, D���Amato, Mauro, Jostins, Luke, Parkes, Miles, Agee, Michelle, Aslibekyan, Stella, Auton, Adam, Bell, Robert K., Bryc, Katarzyna, Clark, Sarah K., Elson, Sarah L., Fletez-Brant, Kipper, Fontanillas, Pierre, Furlotte, Nicholas A., Gandhi, Pooja M., Heilbron, Karl, Hicks, Barry, Hinds, David A., Huber, Karen E., Jewett, Ethan M., Jiang, Yunxuan, Kleinman, Aaron, Lin, Keng-Han, Litterman, Nadia K., Luff, Marie K., McCreight, Jey C., McIntyre, Matthew H., McManus, Kimberly F., Mountain, Joanna L., Mozaffari, Sahar V., Nandakumar, Priyanka, Noblin, Elizabeth S., Northover, Carrie A. M., O���Connell, Jared, Petrakovitz, Aaron A., Pitts, Steven J., Poznik, G. David, Sathirapongsasuti, J. Fah, Shastri, Anjali J., Shelton, Janie F., Tian, Chao, Tung, Joyce Y., Tunney, Robert J., Vacic, Vladimir, Wang, Xin, Zare, Amir S., Kashyap, Purna, Chang, Lin, Mayer, Emeran, Heitkemper, Margaret, Sayuk, Gregory S., Ringel-Kulka, Tamar, Ringel, Yehuda, Chey, William D., Eswaran, Shanti, Merchant, Juanita L., Shulman, Robert J., Bujanda, Luis, Garcia-Etxebarria, Koldo, Dlugosz, Aldona, Lindberg, Greger, Schmidt, Peter T., Karling, Pontus, Ohlsson, Bodil, Walter, Susanna, Faresj��, ��shild O., Simren, Magnus, Halfvarson, Jonas, Portincasa, Piero, Barbara, Giovanni, Usai-Satta, Paolo, Neri, Matteo, Nardone, Gerardo, Cuomo, Rosario, Galeazzi, Francesca, Bellini, Massimo, Latiano, Anna, Houghton, Lesley, Jonkers, Daisy, Kurilshikov, Alexander, Weersma, Rinse K., Netea, Mihai, Tesarz, Jonas, Gauss, Annika, Goebel-Stengel, Miriam, Andresen, Viola, Frieling, Thomas, Pehl, Christian, Schaefert, Rainer, Niesler, Beate, Lieb, Wolfgang, Hanevik, Kurt, Langeland, Nina, Wensaas, Knut-Arne, Litleskare, Sverre, Gabrielsen, Maiken E., Thomas, Laurent, Thijs, Vincent, Lemmens, Robin, Van Oudenhove, Lukas, Wouters, Mira, Eijsbouts C., Zheng T., Kennedy N.A., Bonfiglio F., Anderson C.A., Moutsianas L., Holliday J., Shi J., Shringarpure S., Agee M., Aslibekyan S., Auton A., Bell R.K., Bryc K., Clark S.K., Elson S.L., Fletez-Brant K., Fontanillas P., Furlotte N.A., Gandhi P.M., Heilbron K., Hicks B., Hinds D.A., Huber K.E., Jewett E.M., Jiang Y., Kleinman A., Lin K.-H., Litterman N.K., Luff M.K., McCreight J.C., McIntyre M.H., McManus K.F., Mountain J.L., Mozaffari S.V., Nandakumar P., Noblin E.S., Northover C.A.M., O'Connell J., Petrakovitz A.A., Pitts S.J., Poznik G.D., Sathirapongsasuti J.F., Shastri A.J., Shelton J.F., Tian C., Tung J.Y., Tunney R.J., Vacic V., Wang X., Zare A.S., Voda A.-I., Kashyap P., Chang L., Mayer E., Heitkemper M., Sayuk G.S., Ringel-Kulka T., Ringel Y., Chey W.D., Eswaran S., Merchant J.L., Shulman R.J., Bujanda L., Garcia-Etxebarria K., Dlugosz A., Lindberg G., Schmidt P.T., Karling P., Ohlsson B., Walter S., Faresjo A.O., Simren M., Halfvarson J., Portincasa P., Barbara G., Usai-Satta P., Neri M., Nardone G., Cuomo R., Galeazzi F., Bellini M., Latiano A., Houghton L., Jonkers D., Kurilshikov A., Weersma R.K., Netea M., Tesarz J., Gauss A., Goebel-Stengel M., Andresen V., Frieling T., Pehl C., Schaefert R., Niesler B., Lieb W., Hanevik K., Langeland N., Wensaas K.-A., Litleskare S., Gabrielsen M.E., Thomas L., Thijs V., Lemmens R., Van Oudenhove L., Wouters M., Farrugia G., Franke A., Hubenthal M., Abecasis G., Zawistowski M., Skogholt A.H., Ness-Jensen E., Hveem K., Esko T., Teder-Laving M., Zhernakova A., Camilleri M., Boeckxstaens G., Whorwell P.J., Spiller R., McVean G., D'Amato M., Jostins L., Parkes M., Eijsbouts, Chris [0000-0001-5179-0653], Anderson, Carl A. [0000-0003-1719-7009], Moutsianas, Loukas [0000-0001-5453-345X], Holliday, Joanne [0000-0003-4568-7320], Shringarpure, Suyash [0000-0001-6464-2668], Voda, Alexandru-Ioan [0000-0003-2974-6992], Farrugia, Gianrico [0000-0003-3473-5235], Hübenthal, Matthias [0000-0002-5956-3006], Abecasis, Gonçalo [0000-0003-1509-1825], Zawistowski, Matthew [0000-0002-3005-083X], Ness-Jensen, Eivind [0000-0001-6005-0729], Teder-Laving, Maris [0000-0002-5872-1850], Camilleri, Michael [0000-0001-6472-7514], Whorwell, Peter J. [0000-0002-5220-8474], Spiller, Robin [0000-0001-6371-4500], McVean, Gil [0000-0002-5012-4162], D’Amato, Mauro [0000-0003-2743-5197], Jostins, Luke [0000-0002-2475-3969], Parkes, Miles [0000-0002-6467-0631], Apollo - University of Cambridge Repository, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Translational Immunology Groningen (TRIGR), Eijsbouts, C., Zheng, T., Kennedy, N. A., Bonfiglio, F., Anderson, C. A., Moutsianas, L., Holliday, J., Shi, J., Shringarpure, S., Agee, M., Aslibekyan, S., Auton, A., Bell, R. K., Bryc, K., Clark, S. K., Elson, S. L., Fletez-Brant, K., Fontanillas, P., Furlotte, N. A., Gandhi, P. M., Heilbron, K., Hicks, B., Hinds, D. A., Huber, K. E., Jewett, E. M., Jiang, Y., Kleinman, A., Lin, K. -H., Litterman, N. K., Luff, M. K., Mccreight, J. C., Mcintyre, M. H., Mcmanus, K. F., Mountain, J. L., Mozaffari, S. V., Nandakumar, P., Noblin, E. S., Northover, C. A. M., O'Connell, J., Petrakovitz, A. A., Pitts, S. J., Poznik, G. D., Sathirapongsasuti, J. F., Shastri, A. J., Shelton, J. F., Tian, C., Tung, J. Y., Tunney, R. J., Vacic, V., Wang, X., Zare, A. S., Voda, A. -I., Kashyap, P., Chang, L., Mayer, E., Heitkemper, M., Sayuk, G. S., Ringel-Kulka, T., Ringel, Y., Chey, W. D., Eswaran, S., Merchant, J. L., Shulman, R. J., Bujanda, L., Garcia-Etxebarria, K., Dlugosz, A., Lindberg, G., Schmidt, P. T., Karling, P., Ohlsson, B., Walter, S., Faresjo, A. O., Simren, M., Halfvarson, J., Portincasa, P., Barbara, G., Usai-Satta, P., Neri, M., Nardone, G., Cuomo, R., Galeazzi, F., Bellini, M., Latiano, A., Houghton, L., Jonkers, D., Kurilshikov, A., Weersma, R. K., Netea, M., Tesarz, J., Gauss, A., Goebel-Stengel, M., Andresen, V., Frieling, T., Pehl, C., Schaefert, R., Niesler, B., Lieb, W., Hanevik, K., Langeland, N., Wensaas, K. -A., Litleskare, S., Gabrielsen, M. E., Thomas, L., Thijs, V., Lemmens, R., Van Oudenhove, L., Wouters, M., Farrugia, G., Franke, A., Hubenthal, M., Abecasis, G., Zawistowski, M., Skogholt, A. H., Ness-Jensen, E., Hveem, K., Esko, T., Teder-Laving, M., Zhernakova, A., Camilleri, M., Boeckxstaens, G., Whorwell, P. J., Spiller, R., Mcvean, G., D'Amato, M., Jostins, L., and Parkes, M.
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Male ,Molecular Chaperone ,Mood Disorder ,631/208/205/2138 ,Biology ,692/699/1503/1502/2071 ,Bioinformatics ,Polymorphism, Single Nucleotide ,Genetic pathways ,38/43 ,Irritable Bowel Syndrome ,Cytoskeletal Protein ,Genetics ,medicine ,Genetic predisposition ,Aged ,Anxiety Disorders ,CD56 Antigen ,Cell Adhesion Molecules ,Cytoskeletal Proteins ,Female ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Guanine Nucleotide Exchange Factors ,Homeodomain Proteins ,Humans ,Middle Aged ,Molecular Chaperones ,Mood Disorders ,United Kingdom ,Polymorphism ,692/699/476 ,Irritable bowel syndrome ,Depression (differential diagnoses) ,article ,Homeodomain Protein ,Single Nucleotide ,Guanine Nucleotide Exchange Factor ,medicine.disease ,Neuroticism ,Biobank ,Mood ,Cell Adhesion Molecule ,Anxiety ,medicine.symptom ,Anxiety Disorder ,Human - Abstract
Funder: Kennedy Trust Rheumatology Research Prize Studentship, Funder: DFG Cluster of Excellence ���Precision Medicine in Chronic In-flammation��� (PMI; ID: EXC2167), Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: ���Ideas��� Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); doi: https://doi.org/10.13039/100011199; Grant(s): 715772, Funder: NWO-VIDI grant 016.178.056, the Netherlands Heart Foundation CVON grant 2018-27, and NWO Gravitation grant ExposomeNL, Funder: Li Ka Shing Foundation (Li Ka Shing Foundation Limited); doi: https://doi.org/10.13039/100007421, Irritable bowel syndrome (IBS) results from disordered brain���gut interactions. Identifying susceptibility genes could highlight the underlying pathophysiological mechanisms. We designed a digestive health questionnaire for UK Biobank and combined identified cases with IBS with independent cohorts. We conducted a genome-wide association study with 53,400 cases and 433,201 controls and replicated significant associations in a 23andMe panel (205,252 cases and 1,384,055 controls). Our study identified and confirmed six genetic susceptibility loci for IBS. Implicated genes included NCAM1, CADM2, PHF2/FAM120A, DOCK9, CKAP2/TPTE2P3 and BAG6. The first four are associated with mood and anxiety disorders, expressed in the nervous system, or both. Mirroring this, we also found strong genome-wide correlation between the risk of IBS and anxiety, neuroticism and depression (rg > 0.5). Additional analyses suggested this arises due to shared pathogenic pathways rather than, for example, anxiety causing abdominal symptoms. Implicated mechanisms require further exploration to help understand the altered brain���gut interactions underlying IBS.
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- 2021
38. Bioinformatics analysis of rhinovirus capsid proteins VP1-4 sequences for cross-serotype vaccine development
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Shuaibu Abdullahi Hudu, Alreshidi Mateg Ali, Abdul Rahman Omar, Chin V. Kin, Ahmed Subeh Alshrari, Syed Mohammed Basheeruddin Asdaq, Chong P. Pei, and Zamberi Sekawi
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Serotype ,Rhinovirus ,Bioinformatics ,viruses ,Infectious and parasitic diseases ,RC109-216 ,Serogroup ,medicine.disease_cause ,Genome ,Homology (biology) ,Antibodies ,medicine ,Humans ,Genetics ,biology ,Strain (biology) ,Reverse vaccinology ,Public Health, Environmental and Occupational Health ,Computational Biology ,General Medicine ,Asthma ,Infectious Diseases ,Receptors, LDL ,Capsid ,Rhinoviruses ,biology.protein ,Capsid Proteins ,Antibody ,Public aspects of medicine ,RA1-1270 ,Cell Adhesion Molecules ,Cross-protection ,Vaccine - Abstract
Background Rhinoviruses (RV) are associated with the development and exacerbations of asthma and chronic obstructive pulmonary disease. They've also been linked to more severe diseases like pneumonia, acute bronchiolitis, croup, and otitis media. Because of the hypervariable sequences in the same serotypes, no effective vaccine against rhinoviruses has been developed to date. With the availability of new full-length genome sequences for all RV-A and RV-B serotyped strains, this study used bioinformatics to find a suitable RV strain with the highest similarity matrices to the other strains. Methods The full genomic sequences of all known different RV-A and -B prototypes were downloaded from the National Centre for Biotechnology Information (NCBI) and divided into minor low-density lipoprotein receptor (LDLR) and major intercellular adhesion molecule groups (ICAM). The sequences were edited using Biological Sequence Alignment Editor, v 7.2.0 (BioEdit software) to study each capsid protein (VP1, VP2, VP3, and VP4) and analyzed using the EMBL-EBI ClustalW server and the more current Clustal Omega tool for the calculation of the identities and similarities. Results We analyzed and predicted immunogenic motifs from capsid proteins that are conserved across distinct RV serotypes using a bioinformatics technique. The amino acid sequences of VP3 were found to be the most varied, while VP4 was the most conserved protein among all RV-A and RV-B strains. Among all strains studied, RV-74 demonstrated the highest degree of homology to other strains and could be a potential genetic source for recombinant protein production. Nine highly conserved regions with a minimum length of 9-mers were identified, which could serve as potential immune targets against rhinoviruses. Conclusion Therefore, bioinformatics analysis conducted in the current study has paved the way for the selection of immunogenic targets. Bioinformatically, the ideal strain’s capsid protein is suggested to contain the most common RVs immunogenic sites.
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- 2021
39. The critical roles of m6A modification in metabolic abnormality and cardiovascular diseases
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Hao Jiang, Ge Junbo, Zhen Dong, Aijun Sun, and Beijian Zhang
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0301 basic medicine ,Medicine (General) ,Methyltransferase ,RNA methylation ,Heart failure ,Review Article ,030204 cardiovascular system & hematology ,QH426-470 ,Bioinformatics ,Biochemistry ,RNA epigenetics ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,R5-920 ,Genetics ,Medicine ,Epigenetics ,Molecular Biology ,Genetics (clinical) ,biology ,business.industry ,N6-methyladenosine ,Cell Biology ,medicine.disease ,Cardiovascular disease ,Metabolic syndrome ,Biomarker (cell) ,Myocardial infarction ,030104 developmental biology ,chemistry ,biology.protein ,Demethylase ,METTL3 ,Abnormality ,N6-Methyladenosine ,business ,FTO - Abstract
N6-methyladenosine (m6A) RNA methylation is an emerging area of epigenetics, which is a reversible and dynamic modification mediating by 'writers' (methylase, adding methyl groups, METTL3, METTL14, and WTAP), 'erasers' (demethylase, deleting methyl groups, FTO and ALKBH5), and 'readers' (YTHDF1-3, YTHDC1 and YTHDC2). Recent studies in human, animal models and cell levels have disclosed a critical role of m6A modification in regulating the homeostasis of metabolic processes and cardiovascular function. Evidence from these studies identify m6A as a candidate of biomarker and therapeutic target for metabolic abnormality and cardiovascular diseases (CVD). Comprehensive understanding of the complexity of m6A regulation in metabolic diseases and CVD will be helpful for us to understand the pathogenesis of CVD. In this review, we discuss the regulatory role of m6A in metabolic abnormality and CVD. We will emphasize the clinical relevance of m6A dysregulation in CVD.
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- 2021
40. Bioinformatic Annotation of Genes for Alzheimer’s Disease and Coronary Heart Disease
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E. E. Chizhik, A. A. Bobrysheva, and N. Yu. Chasovskikh
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Annotation ,Genetics ,Disease ,Biology ,Bioinformatics ,Gene ,Coronary heart disease - Published
- 2021
41. Spatial and temporal dynamics of microbiomes and resistomes in broiler litter stockpiles
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Xin‑Yuan Zhou, Ran Avidov, Yael Laor, Chhedi Lal Gupta, Jian-Qiang Su, Vempalli Sudharsan Varma, Yong-Guan Zhu, Karuppasamy Kattusamy, Shlomo E. Blum, Ibrahim Saadi, and Eddie Cytryn
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Antibiotic resistance bacteria ,Tetracycline ,Bioinformatics ,Biophysics ,Antibiotic resistance gene ,Biochemistry ,Microbiology ,Antibiotic resistance ,Enterococcaceae ,Structural Biology ,Genetics ,medicine ,Microbiome ,Broiler litter ,Long-read sequencing ,Staphylococcaceae ,ComputingMethodologies_COMPUTERGRAPHICS ,biology ,biology.organism_classification ,Computer Science Applications ,Resistome ,Litter ,TP248.13-248.65 ,Biotechnology ,medicine.drug ,Enterococcus faecium ,Research Article - Abstract
Graphical abstract, Farmers apply broiler chicken litter to soils to enrich organic matter and provide crops with nutrients, following varying periods of stockpiling. However, litter frequently harbors fecal-derived microbial pathogens and associated antibiotic resistance genes (ARGs), and may be a source of microbial contamination of produce. We coupled a cutting-edge Loop Genomics long-read 16S rRNA amplicon-sequencing platform with high-throughput qPCR that targeted a suite of ARGs, to assess temporal (five time points over a 60-day period) and spatial (top, middle and bottom layers) microbiome and resistome dynamics in a broiler litter stockpile. We focused on potentially pathogenic species from the Enterobacteriaceae, Enterococcaceae and Staphylococcaceae families associated with food-borne disease. Bacterial diversity was significantly lower in the middle of the stockpile, where targeted pathogens were lowest and Bacillaceae were abundant. E. coli was the most abundant Enterobacteriaceae species, and high levels of the opportunistic pathogen Enterococcus faecium were detected. Correlation analyses revealed that the latter was significantly associated with aminoglycoside (aac(6′)-Ib(aka aacA4), aadA5), tetracycline (tetG), vancomycin (vanC), phenicol (floR) and MLSB (mphB) resistance genes. Staphylococcaceae were primarily non-pathogenic, but extremely low levels of the opportunistic pathogen S. aureus were detected, as was the opportunistic pathogen S. saprophyticus, which was linked to vancomycin (vanSA, vanC1), MLSB (vatE, ermB) and tetracycline (tetK) resistance genes. Collectively, we found that stockpile microbiomes and resistomes are strongly dictated by temporal fluctuations and spatial heterogeneity. Insights from this study can be exploited to improve stockpile management practice to support sustainable antimicrobial resistance mitigation policies in the future.
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- 2021
42. Identification of Key Pathways and Genes in SARS-CoV-2 Infecting Human Intestines by Bioinformatics Analysis
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Yi-Qing Li, Tian-Ao Xie, Ji-Chun Chen, Yu-Fei Xie, Xu-Guang Guo, Zhen-Zong Lin, and Zhong-Wei Li
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SARS-CoV-2 ,Bioinformatics ,Gene Expression Profiling ,COVID-19 ,Computational Biology ,General Medicine ,Disease ,Computational biology ,Biology ,BUB1B ,Biochemistry ,Virus ,Human genetics ,Intestines ,Infectious disease (medical specialty) ,Gene expression ,Genetics ,Humans ,Original Article ,KEGG ,Molecular Biology ,Gene ,Ecology, Evolution, Behavior and Systematics - Abstract
COVID-19 is a serious infectious disease that has recently swept the world, and research on its causative virus, SARS-CoV-2, remains insufficient. Therefore, this study uses bioinformatics analysis techniques to explore the human digestive tract diseases that may be caused by SARS-CoV-2 infection. The gene expression profile data set, numbered GSE149312, is from the Gene Expression Omnibus (GEO) database and is divided into a 24-h group and a 60-h group. R software is used to analyze and screen out differentially expressed genes (DEGs) and then gene ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses are performed. In KEGG, the pathway of non-alcoholic fatty liver disease exists in both the 24-h group and 60-h group. STRING is used to establish a protein–protein interaction (PPI) network, and Cytoscape is then used to visualize the PPI and define the top 12 genes of the node as the hub genes. Through verification, nine statistically significant hub genes are identified: AKT1, TIMP1, NOTCH, CCNA2, RRM2, TTK, BUB1B, KIF20A, and PLK1. In conclusion, the results of this study can provide a certain direction and basis for follow-up studies of SARS-CoV-2 infection of the human digestive tract and provide new insights for the prevention and treatment of diseases caused by SARS-CoV-2. Supplementary Information The online version contains supplementary material available at 10.1007/s10528-021-10144-w.
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- 2021
43. Identification of variant APL translocations PRKAR1A-RARα and ZBTB16-RARα (PLZF-RARα) through the MI-ONCOSEQ platform
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Charles E. Foucar, Rupali Roy Bhave, Darren King, Bernard L. Marini, Dan R. Robinson, Dale L. Bixby, Anthony J. Perissinotti, Lydia L. Benitez, and Vincent Ma
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Adult ,Acute promyelocytic leukemia ,Cancer Research ,medicine.medical_specialty ,Oncogene Proteins, Fusion ,Cyclic AMP-Dependent Protein Kinase RIalpha Subunit ,Retinoic acid ,Chromosomal translocation ,Biology ,Bioinformatics ,Translocation, Genetic ,Young Adult ,chemistry.chemical_compound ,Leukemia, Promyelocytic, Acute ,Genetics ,medicine ,Humans ,Molecular Biology ,Exome ,PRKAR1A ,Aged ,Gene Rearrangement ,Retinoic Acid Receptor alpha ,Prognosis ,medicine.disease ,Regimen ,medicine.anatomical_structure ,chemistry ,Female ,Bone marrow ,Hematopathology - Abstract
The cornerstone of management in patients with acute promyelocytic leukemia (APL) is early diagnosis and prompt initiation of treatment with an all-trans retinoic acid (ATRA)-based regimen. Identification of the t(15;17)(PML-RARA) chromosomal translocation through conventional cytogenetics fluorescence in-situ hybridization (FISH) or detection of the promyelocytic leukemia-retinoic acid receptor alpha (PML-RARα) fusion through RT-PCR represent the current standard of care for diagnosing APL. However, about 1–2% of patients with APL have a variant translocation involving other fusion partners with RARα besides PML. These patients present a unique diagnostic and clinical challenge in that conventional cytogenetics in addition to FISH and/or RT-PCR for PML-RARα may fail to identify these clinically relevant genetic lesions leading to an inappropriate diagnosis and treatment. We present two cases of patients who had APL with variant translocations whose bone marrow specimens were sent to the University of Michigan for enrollment in the MI-ONCOSEQ study (HUM00067928) after standard testing failed to identify PML-RARα or t(15;17) despite a phenotypic concern for this diagnosis. In these two patients, whole exome and transcriptome profiling via the MI-ONCOSEQ platform identified a PRKAR1A-RARα fusion in one patient and ZBTB16-RARα fusion in another patient. These cases illustrate the utility of whole exome and transcriptome profiling in diagnosing variant translocations in patients in whom there is a high clinical suspicion for APL based on hematopathology review.
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- 2021
44. Transcriptional characterization of subcutaneous adipose tissue in obesity affected women highlights metabolic dysfunction and implications for lncRNAs
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Raffaella Cancello, Stephana Carelli, Letizia Messa, Cristina Cereda, Bianca Barzaghini, Federica Rey, Cecilia Pandini, Simona Bertoli, Giancarlo Micheletto, Gian Vincenzo Zuccotti, and Manuela Teresa Raimondi
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Adipogenesis ,In silico ,Subcutaneous Fat ,Adipose tissue ,RNA-Seq ,Biology ,Bioinformatics ,Transcriptome ,Adipose Tissue ,Gene expression ,Adipocytes ,Genetics ,Humans ,Female ,RNA, Long Noncoding ,Obesity ,Transcription factor ,Function (biology) - Abstract
Obesity is a complex disease with multifactorial causes, and its prevalence is becoming a serious health crisis. For this reason, there is a crucial need to identify novel targets and players. With this aim in mind, we analyzed via RNA-sequencing the subcutaneous adipose tissue of normal weight and obesity-affected women, highlighting the differential expression in the two tissues. We specifically focused on long non-coding RNAs, as 6 of these emerged as dysregulated in the diseased-tissue (COL4A2-AS2, RPS21-AS, PELATON, ITGB2-AS1, ACER2-AS and CTEPHA1). For each of them, we performed both a thorough in silico dissection and in vitro validation, to predict their function during adipogenesis. We report the lncRNAs expression during adipose derived stem cells differentiation to adipocytes as model of adipogenesis and their potential modulation by adipogenesis-related transcription factors (C/EBPs and PPARγ). Moreover, inhibiting CTEPHA1 expression we investigated its impact on adipogenesis-related transcription factors, showing its significative dysregulation of C/EBPα expression. Lastly, we dissected the subcellular localization, pathway involvement and disease-correlation for coding differentially expressed genes. Together, these findings highlight a transcriptional deregulation at the basis of obesity, impacted by both coding and long non-coding RNAs.
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- 2021
45. Rare germline variants in childhood cancer patients suspected of genetic predisposition to cancer
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Dianne Sylvester, Robyn V. Jamieson, Federica Saletta, Jennifer A. Byrne, Michael Krivanek, Liang Qiao, Nicole Graf, Natalie Grima, Mandy L. Ballinger, Olivier Latchoumanin, Li Zhou, Dale Wright, Luciano Dalla-Pozza, David Thomas, Judy Kirk, Daniel Catchpoole, Bruce Bennetts, Yuyan Chen, and Bhavna Padhye
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Cancer Research ,Adolescent ,Genomics ,Biology ,Bioinformatics ,Germline ,Frameshift mutation ,Cohort Studies ,Neoplasms ,Exome Sequencing ,Genetics ,medicine ,Genetic predisposition ,Humans ,Genetic Predisposition to Disease ,Child ,Germ-Line Mutation ,Exome sequencing ,Aged ,business.industry ,Infant, Newborn ,Infant ,Cancer ,medicine.disease ,CpG site ,Child, Preschool ,Personalized medicine ,business - Abstract
Identification of cancer-predisposing germline variants in childhood cancer patients is important for therapeutic decisions, disease surveillance and risk assessment for patients, and potentially, also for family members. We investigated the spectrum and prevalence of pathogenic germline variants in selected childhood cancer patients with features suggestive of genetic predisposition to cancer. Germline DNA was subjected to exome sequencing to filter variants in 1048 genes of interest including 176 known cancer predisposition genes (CPGs). An enrichment burden analysis compared rare deleterious germline CPG variants in the patient cohort with those in a healthy aged control population. A subset of predicted deleterious variants in novel candidate CPGs was investigated further by examining matched tumor samples, and the functional impact of AXIN1 variants was analyzed in cultured cells. Twenty-two pathogenic/likely pathogenic (P/LP) germline variants detected in 13 CPGs were identified in 19 of 76 patients (25.0%). Unclear association with the diagnosed cancer types was observed in 11 of 19 patients carrying P/LP CPG variants. The burden of rare deleterious germline variants in autosomal dominant CPGs was significantly higher in study patients versus healthy aged controls. A novel AXIN1 frameshift variant (Ser321fs) may impact the regulation of β-catenin levels. Selection of childhood cancer patients for germline testing based on features suggestive of an underlying genetic predisposition could help to identify carriers of clinically relevant germline CPG variants, and streamline the integration of germline genomic testing in the pediatric oncology clinic.
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- 2021
46. SOX10: 20 years of phenotypic plurality and current understanding of its developmental function
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Lisa Zerad, William Bertani-Torres, Veronique Pingault, and Nadege Bondurand
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nervous system diseases ,Cell type ,Kallmann syndrome ,Hearing loss ,SOX10 ,human genetics ,Embryonic Development ,Review ,Biology ,Bioinformatics ,Enteric Nervous System ,Neoplasms ,Genetics ,medicine ,Animals ,Humans ,Waardenburg Syndrome ,Hirschsprung Disease ,Hearing Loss ,Genetics (clinical) ,SOXE Transcription Factors ,Waardenburg syndrome ,Gene Expression Regulation, Developmental ,Neural crest ,Kallmann Syndrome ,medicine.disease ,Human genetics ,Phenotype ,Testis determining factor ,Neural Crest ,Mutation ,embryonic structures ,Melanocytes ,medicine.symptom - Abstract
SOX10 belongs to a family of 20 SRY (sex-determining region Y)-related high mobility group box-containing (SOX) proteins, most of which contribute to cell type specification and differentiation of various lineages. The first clue that SOX10 is essential for development, especially in the neural crest, came with the discovery that heterozygous mutations occurring within and around SOX10 cause Waardenburg syndrome type 4. Since then, heterozygous mutations have been reported in Waardenburg syndrome type 2 (Waardenburg syndrome type without Hirschsprung disease), PCWH or PCW (peripheral demyelinating neuropathy, central dysmyelination, Waardenburg syndrome, with or without Hirschsprung disease), intestinal manifestations beyond Hirschsprung (ie, chronic intestinal pseudo-obstruction), Kallmann syndrome and cancer. All of these diseases are consistent with the regulatory role of SOX10 in various neural crest derivatives (melanocytes, the enteric nervous system, Schwann cells and olfactory ensheathing cells) and extraneural crest tissues (inner ear, oligodendrocytes). The recent evolution of medical practice in constitutional genetics has led to the identification of SOX10 variants in atypical contexts, such as isolated hearing loss or neurodevelopmental disorders, making them more difficult to classify in the absence of both a typical phenotype and specific expertise. Here, we report novel mutations and review those that have already been published and their functional consequences, along with current understanding of SOX10 function in the affected cell types identified through in vivo and in vitro models. We also discuss research options to increase our understanding of the origin of the observed phenotypic variability and improve the diagnosis and medical care of affected patients.
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- 2021
47. Positive selection in noncoding genomic regions of vocal learning birds is associated with genes implicated in vocal learning and speech functions in humans
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Carolyn J. Khoury, David Haussler, Joel Armstrong, Alden Deran, James A. Cahill, Benedict Paten, and Erich D. Jarvis
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Vocal communication ,Bioinformatics ,Autism ,Intellectual and Developmental Disabilities (IDD) ,education ,Biology ,Basic Behavioral and Social Science ,Medical and Health Sciences ,Vocalization ,Songbirds ,Behavioral and Social Science ,otorhinolaryngologic diseases ,Genetics ,medicine ,Animals ,Humans ,Learning ,Speech ,Gene ,Genetics (clinical) ,Animal ,Research ,Tumor Suppressor Proteins ,Positive selection ,Brain ,FOXP2 ,Genomics ,Biological Sciences ,medicine.disease ,Brain Disorders ,Repressor Proteins ,Mental Health ,Evolutionary biology ,Vocal learning ,Vocalization, Animal ,Spoken language - Abstract
Vocal learning, the ability to imitate sounds from conspecifics and the environment, is a key component of human spoken language and learned song in three independently evolved avian groups—oscine songbirds, parrots, and hummingbirds. Humans and each of these three bird clades exhibit specialized behavioral, neuroanatomical, and brain gene expression convergence related to vocal learning, speech, and song. To understand the evolutionary basis of vocal learning gene specializations and convergence, we searched for and identified accelerated genomic regions (ARs), a marker of positive selection, specific to vocal learning birds. We found avian vocal learner-specific ARs, and they were enriched in noncoding regions near genes with known speech functions or brain gene expression specializations in humans and vocal learning birds, including FOXP2, NEUROD6, ZEB2, and MEF2C, and near genes with major neurodevelopmental functions, including NR2F1, NRP2, and BCL11B. We also found enrichment near the SFARI class S genes associated with syndromic vocal communication forms of autism spectrum disorders. These findings reveal strong candidate noncoding regions near genes for the evolutionary adaptations that distinguish vocal learning species from their close vocal nonlearning relatives and provide further evidence of molecular convergence between birdsong and human spoken language.
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- 2021
48. Genome-Wide Identification of LRR-RLK Family in Saccharum and Expression Analysis in Response to Biotic and Abiotic Stress
- Author
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Zhoutao Wang, Fu Xu, Wei Cheng, Yachun Su, Guilong Lu, Waqar Ahmad, and Liping Xu
- Subjects
Microbiology (medical) ,Genetics ,gene expression analysis ,Phylogenetic tree ,biology ,molecular evolution ,QH301-705.5 ,Abiotic stress ,Saccharum ,fungi ,Saccharum spontaneum ,bioinformatics ,stress response ,General Medicine ,Biotic stress ,biology.organism_classification ,Microbiology ,Genome ,Arabidopsis ,Gene family ,LRR-RLK gene family ,Biology (General) ,Molecular Biology ,Gene - Abstract
The leucine-rich repeat receptor-like protein kinase (LRR-RLK) gene family is the largest family of the receptor-like protein kinases (RLKs) superfamily in higher plants, which is involved in regulating the plant growth and development, stress responses, signal transduction and so on. However, no comprehensive analyses of LRR-RLKs have been reported in sugarcane. Here, we performed a comprehensive analysis of the LRR-RLK gene family in sugarcane ancestor species Saccharum spontaneum. A total of 437 LRR-RLK genes were identified and categorized into 14 groups based on a maximum likelihood phylogenetic tree. The chromosome location showed an uneven distribution on all 32 chromosomes in sugarcane. Subsequently, the exon–intron organization structure and conserved motif arrangement were relatively conserved among the same groups or subgroups and between Arabidopsis and S. spontaneum genomes. Furthermore, the promoter sequences analyses showed that sugarcane LRR-RLK genes (SsLRR-RLKs) were strongly regulated by various environmental stimuli, phytohormonal factors and transcription factors (TFs). Eventually, the expression profiles of SsLRR-RLK genes at different stresses were analyzed based on RNA-seq data, suggesting their potential roles in the regulation of sugarcane responses to diverse abiotic and biotic stress. Overall, the findings provide insight into the potential functional roles and lay the foundation for further functional study.
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- 2021
49. Genetic predisposition of SNPs in miRNA-149 (rs2292832) and FOXE1 (rs3758249) in thyroid Cancer
- Author
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Shazia Fatima, Samina Asghar Abbasi, Ruqia Mehmood Baig, Ayesha Ammar, Rashida Khan, Humaira Shaheen, and Qaisar Mansoor
- Subjects
Single-nucleotide polymorphism ,General Medicine ,Biology ,medicine.disease ,Bioinformatics ,Penetrance ,Thyroid carcinoma ,Genotype ,Genetics ,medicine ,Genetic predisposition ,Molecular Biology ,Thyroid cancer ,FOXE1 ,Genetic association - Abstract
Many efforts have been made in recent years to investigate the alterations in protein-coding genes as well as non-coding RNAs that are playing an emerging role in the development and progression of cancers. These miRNAs are short non-coding functional RNAs that are involved in the regulation of transcriptome. In different studies, it was found that human miRNA-149 is an important microRNA that is functioning either as onco-miRNAs or acting as tumor suppressors, in different conditions. Many of the miRNAs are regulating different SNPs of FOXE1 in different studies which are causing low-to-moderate penetrance of genes that initiates the development of thyroid cancer. The involvement of SNPs in miRNA-149 gene rs2292832 and FOXE1 rs3758249 with PTC for better disease prognosis and management was determined in this study and the relation between these SNPs at the genotypic level was also evaluated. PTC patients with age and gender-matched controls were recruited in the present study. Blood samples were collected in EDTA vacutainer followed by DNA extraction by the organic method. Genotyping of rs2292832 and rs3758249 was done by ARMS-PCR and PCR- RFLP respectively. Statistical analyses were carried out by using SPSS software (version 20). The mutation T>C in miRNA-149 rs2292832 was significantly associated with thyroid cancer (p-value 0.0004, C did not show significant association with the disease (p-value 0.124244, > 0.05). Moreover, no correlation of rs2292832 at the genotype level was observed with rs3758249. miRNA-149 gene SNP rs2292832 was observed in strong association with thyroid cancer. Lack of genetic association of rs3758249 of FOXE1 gene has been ruled for the disease. The statistically significant association of rs2292832 with thyroid cancer depicts its mechanistic involvement at the cellular level in Papillary Thyroid Carcinoma.
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- 2021
50. Rare neurological manifestations in a Saudi Arabian patient with <scp>Ehlers–Danlos</scp> syndrome and a novel homozygous variant in the <scp> TNXB </scp> gene
- Author
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Naif Al-Zahrani, Walid Dridi, Hakon Hakonarson, Patrick M. A. Sleiman, Talal Al-Harbi, Haya Al-Rammah, and Yichuan Liu
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dbSNP ,biology ,business.industry ,medicine.disease ,Myotonia ,Bioinformatics ,Tenascin X ,Myotonic dystrophy ,Exon ,Ehlers–Danlos syndrome ,Genetics ,biology.protein ,medicine ,business ,Genetics (clinical) ,Exome sequencing ,Reference genome - Abstract
We report a 38-year-old Saudi male with Ehlers-Danlos Syndrome (EDS). The patient presented with rare and unusual neurological manifestations, including but not limited to ophthalmoplegia and myopathic pattern on his electromyography. In addition to hand weakness, there was skin hyperextensibility, joint hyperflexibility, and frontal baldness. Next-generation sequencing was performed on target exon sequences, using whole exome sequencing and Burrows-Wheeler Aligner for alignment/base calling. Genome Analysis Toolkit and reference genome Homo sapiens (UCSC hg19) were used for sequence processing and analysis. Variant classification was done according to standard international recommendations. A novel homozygous variant, NM_019105.6: c.8488C>T p.(Gln2830*), was detected in the TNXB gene. This variant is not reported in the literature nor dbSNP or gnomAD databases. Additionally, this variant is predicted to create a premature stop codon and produce a truncated protein or nonsense-mediated mRNA decay. Hence, it is classified as a likely pathogenic variant. The same point variant was found in a heterozygous state in the patient's father and sister. Both presented with milder symptoms associated with Ehlers-Danlos syndromes and heritable connective tissue disorders. Therefore, the patient was diagnosed as a tenascin-X (TNX) deficient type of EDS known as classical-like Ehlers-Danlos syndrome. TNX deficient patients may present with clinical and electrophysiological manifestations that are unusual in EDS like frontal baldness, ophthalmoplegia, and myotonia, which mimic myotonic dystrophy type I. Clinicians should be aware of the potential overlap of symptoms among these two diseases to ensure correct diagnosis is made.
- Published
- 2021
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