Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 54.974
Filtrar
1.
Nature ; 584(7820): 244-251, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32728217

RESUMO

DNase I hypersensitive sites (DHSs) are generic markers of regulatory DNA1-5 and contain genetic variations associated with diseases and phenotypic traits6-8. We created high-resolution maps of DHSs from 733 human biosamples encompassing 438 cell and tissue types and states, and integrated these to delineate and numerically index approximately 3.6 million DHSs within the human genome sequence, providing a common coordinate system for regulatory DNA. Here we show that these maps highly resolve the cis-regulatory compartment of the human genome, which encodes unexpectedly diverse cell- and tissue-selective regulatory programs at very high density. These programs can be captured comprehensively by a simple vocabulary that enables the assignment to each DHS of a regulatory barcode that encapsulates its tissue manifestations, and global annotation of protein-coding and non-coding RNA genes in a manner orthogonal to gene expression. Finally, we show that sharply resolved DHSs markedly enhance the genetic association and heritability signals of diseases and traits. Rather than being confined to a small number of distal elements or promoters, we find that genetic signals converge on congruently regulated sets of DHSs that decorate entire gene bodies. Together, our results create a universal, extensible coordinate system and vocabulary for human regulatory DNA marked by DHSs, and provide a new global perspective on the architecture of human gene regulation.


Assuntos
Cromatina/genética , DNA/metabolismo , Desoxirribonuclease I/metabolismo , Anotação de Sequência Molecular , Cromatina/química , Cromatina/metabolismo , DNA/química , DNA/genética , Regulação da Expressão Gênica , Genes/genética , Genoma Humano/genética , Humanos , Regiões Promotoras Genéticas/genética , Sequências Reguladoras de Ácido Nucleico/genética
2.
Medicine (Baltimore) ; 99(29): e21286, 2020 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-32702920

RESUMO

Calcific aortic valve disease (CAVD) is highly prevalent in our aging world and has no effective pharmaceutical treatment. Intense efforts have been made but the underlying molecular mechanisms of CAVD are still unclear.This study was designed to identify the critical genes and pathways in CAVD by bioinformatics analysis. Microarray datasets of GSE12644, GSE51472, and GSE83453 were obtained from Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified and functional and pathway enrichment analysis was performed. Subsequently, the protein-protein interaction network (PPI) was constructed with Search Tool for the Retrieval of Interacting Genes and was visualized with Cytoscape to identify the most significant module. Hub genes were identified by Cytoscape plugin cytoHubba.A total of 179 DEGs, including 101 upregulated genes and 78 downregulated genes, were identified. The enriched functions and pathways of the DEGs include inflammatory and immune response, chemotaxis, extracellular matrix (ECM) organization, complement and coagulation cascades, ECM receptor interaction, and focal adhesion. The most significant module in the PPI network was analyzed and genes among it were mainly enriched in chemotaxis, locomotory behavior, immune response, chemokine signaling pathway, and extracellular space. In addition, DEGs, with degrees ≥ 10 and the top 10 highest Maximal Chique Centrality (MCC) score, were identified as hub genes. CCR1, MMP9, VCAM1, and ITGAX, which were of the highest degree or MCC score, were manually reviewed.The DEGs and hub genes identified in the present study help us understand the molecular mechanisms underlying the pathogenesis of CAVD and might serve as candidate therapeutic targets for CAVD.


Assuntos
Estenose da Valva Aórtica/genética , Valva Aórtica/patologia , Calcinose/genética , Genes/genética , Predisposição Genética para Doença/genética , Estenose da Valva Aórtica/etiologia , Calcinose/etiologia , Estudos de Casos e Controles , Biologia Computacional , Genes/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos
3.
Nat Commun ; 11(1): 3255, 2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32591531

RESUMO

Mendelian randomisation (MR) analysis is an important tool to elucidate the causal relevance of environmental and biological risk factors for disease. However, causal inference is undermined if genetic variants used to instrument a risk factor also influence alternative disease-pathways (horizontal pleiotropy). Here we report how the 'no horizontal pleiotropy assumption' is strengthened when proteins are the risk factors of interest. Proteins are typically the proximal effectors of biological processes encoded in the genome. Moreover, proteins are the targets of most medicines, so MR studies of drug targets are becoming a fundamental tool in drug development. To enable such studies, we introduce a mathematical framework that contrasts MR analysis of proteins with that of risk factors located more distally in the causal chain from gene to disease. We illustrate key model decisions and introduce an analytical framework for maximising power and evaluating the robustness of analyses.


Assuntos
Sistemas de Liberação de Medicamentos , Genes , Análise da Randomização Mendeliana , Intervalos de Confiança , Doença das Coronárias/genética , Genoma Humano , Humanos , Desequilíbrio de Ligação/genética , Lipídeos/química , Modelos Genéticos , Razão de Chances , Fenômica , Polimorfismo de Nucleotídeo Único/genética , Proteínas/genética , Locos de Características Quantitativas/genética , Reprodutibilidade dos Testes
4.
Hum Genet ; 139(6-7): 769-776, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32405658

RESUMO

Over the last decade next generation sequencing (NGS) has been extensively used to identify new pathogenic mutations and genes causing rare genetic diseases. The efficient analyses of NGS data is not trivial and requires a technically and biologically rigorous pipeline that addresses data quality control, accurate variant filtration to minimize false positives and false negatives, and prioritization of the remaining genes based on disease genomics and physiological knowledge. This review provides a pipeline including all these steps, describes popular software for each step of the analysis, and proposes a general framework for the identification of causal mutations and genes in individual patients of rare genetic diseases.


Assuntos
Biologia Computacional/métodos , Genes/genética , Doenças Genéticas Inatas/etiologia , Genoma Humano , Mutação , Medicina de Precisão , Doenças Raras/etiologia , Doenças Genéticas Inatas/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Doenças Raras/patologia , Software
5.
BMC Bioinformatics ; 21(1): 151, 2020 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-32312224

RESUMO

BACKGROUND: Molecular characters have been added in integrative taxonomic approaches in recent years. Nevertheless, taxon diagnoses are still widely restricted to morphological characters. The inclusion of molecular characters into taxon diagnoses is not only hampered by problems, such as their definition and the designation of their positions in a reference alignment, but also by the technical effort. RESULTS: DeSignate is a tool for character-based taxon diagnoses that includes a novel ranking scheme. It detects and classifies individual and combined signature characters (diagnostic molecular characters) based on so-called character state vectors. An intuitive web application guides the user through the analysis process and provides the results at a glance. Further, formal definitions and a uniform terminology of characters are introduced. CONCLUSIONS: DeSignate facilitates the inclusion of diagnostic molecular characters and their positions to complement taxon diagnoses. Compared to previous solutions, the tool simplifies the workflow and improves reproducibility and traceability of the results. The tool is freely available as a web application at (https://designate.dbresearch.uni-salzburg.at/) and is open source (https://github.com/DatabaseGroup/DeSignate/).


Assuntos
Genes , Filogenia , Alinhamento de Sequência , Software , Sequência de Bases , Reprodutibilidade dos Testes
6.
Adv Exp Med Biol ; 1236: 1-38, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32304067

RESUMO

The laboratory mouse has become the model organism of choice in numerous areas of biological and biomedical research, including the study of congenital birth defects. The appeal of mice for these experimental studies stems from the similarities between the physiology, anatomy, and reproduction of these small mammals with our own, but it is also based on a number of practical reasons: mice are easy to maintain in a laboratory environment, are incredibly prolific, and have a relatively short reproductive cycle. Another compelling reason for choosing mice as research subjects is the number of tools and resources that have been developed after more than a century of working with these small rodents in laboratory environments. As will become obvious from the reading of the different chapters in this book, research in mice has already helped uncover many of the genes and processes responsible for congenital birth malformations and human diseases. In this chapter, we will provide an overview of the methods, scientific advances, and serendipitous circumstances that have made these discoveries possible, with a special emphasis on how the use of genetics has propelled scientific progress in mouse research and paved the way for future discoveries.


Assuntos
Pesquisa Biomédica , Modelos Animais de Doenças , Genes , Camundongos/genética , Mutação , Animais , Humanos , Reprodução
7.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(4): 373-377, 2020 Apr 10.
Artigo em Chinês | MEDLINE | ID: mdl-32219816

RESUMO

OBJECTIVE: To determine the type and carrier rate of deafness-related variants in Dongguan, China. METHODS: A total of 16 182 subjects were screened. Heel blood samples were collected from newborns, while peripheral venous blood samples were collected from the remainders. For each individual, 100 variations of 18 deafness susceptibility genes were detected. RESULTS: In total 1631 deafness-related variants (including 5 homozygous mutations) were detected, which gave a detection rate of 10.08%. The detection rate of SLC26A4 gene variants was the highest (845 cases, 5.22%), which was followed by GJB2 (673 cases, 4.16%), GJB3 (100 cases, 0.62%), TMC1 (12 cases, 0.07%), and MYO15A (1 case, 0.01%). The detection rate for GJB2 c.235delC variant was the highest (524 cases, 3.24%), which was followed by SLC26A4 IVS7-2A>G variant (270 cases, 1.67%). Thirty three individuals (0.20%) carried two variants at the same time, 7 of them (0.04%) carried compound heterozygous variants of the same gene. CONCLUSION: To expand the range of screening can help with determination of the carrier status and provision of early intervention and genetic counseling for the examinees.


Assuntos
Surdez/genética , Genes , Predisposição Genética para Doença , China , Análise Mutacional de DNA , Aconselhamento Genético , Testes Genéticos , Variação Genética , Humanos , Recém-Nascido , Mutação , RNA Ribossômico
10.
Environ Int ; 137: 105530, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32062310

RESUMO

INTRODUCTION: Inhalation of asbestos induces lung cancer via different cellular mechanisms. Together with the increased production of carbon nanotubes (CNTs) grows the concern about adverse effects on the lungs given the similarities with asbestos. While it has been established that CNT and asbestos induce epigenetic alterations, it is currently not known whether alterations at epigenetic level remain stable after withdrawal of the exposure. Identification of DNA methylation changes after a low dose of CNT and asbestos exposure and recovery can be useful to determine the fibre/particle toxicity and adverse outcome. METHODS: Human bronchial epithelial cells (16HBE) were treated with a low and non-cytotoxic dose (0.25 µg/ml) of multi-walled carbon nanotubes (MWCNTs-NM400) or single-walled carbon nanotubes (SWCNTs-SRM2483) and 0.05 µg/ml amosite (brown) asbestos for the course of four weeks (sub-chronic exposure). After this treatment, the cells were further incubated (without particle/fibre) for two weeks, allowing recovery from the exposure (recovery period). Nuclear depositions of the CNTs were assessed using femtosecond pulsed laser microscopy in a label-free manner. DNA methylation alterations were analysed using microarrays that assess more than 850 thousand CpG sites in the whole genome. RESULTS: At non-cytotoxic doses, CNTs were noted to be incorporated with in the nucleus after a four weeks period. Exposure to MWCNTs induced a single hypomethylation at a CpG site and gene promoter region. No change in DNA methylation was observed after the recovery period for MWCNTs. Exposure to SWCNTs or amosite induced hypermethylation at CpG sites after sub-chronic exposure which may involve in 'transcription factor activity' and 'sequence-specific DNA binding' gene ontologies. After the recovery period, hypermethylation and hypomethylation were noted for both SWCNTs and amosite. Hippocalcinlike 1 (HPCAL1), protease serine 3 (PRSS3), kallikrein-related peptidase 3 (KLK3), kruppel like factor 3 (KLF3) genes were hypermethylated at different time points in either SWCNT-exposed or amosite-exposed cells. CONCLUSION: These results suggest that the specific SWCNT (SRM2483) and amosite fibres studied induce hypo- or hypermethylation on CpG sites in DNA after very low-dose exposure and recovery period. This effect was not seen for the studied MWCNT (NM400).


Assuntos
Asbestos , Metilação de DNA , Nanotubos de Carbono , Asbestos/toxicidade , Brônquios , Células Epiteliais , Genes , Humanos , Pulmão , Nanotubos de Carbono/toxicidade , Tripsina
11.
Mol Genet Genomics ; 295(3): 591-606, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32006176

RESUMO

Achaete-scute complex (ASC) genes play essential roles in regulating neurogenesis of metazoans. Various metazoan species have greatly different numbers of genes in ASCa, ASCb and ASCc families. To explore evolutionary mechanisms of metazoan ASC genes, Blast (basic local alignment search tool) searches and phylogenetic analyses were conducted to identify ASC genes in metazoan species and to infer phylogenetic relationship between various ASC genes. As a result, 2784 ASC genes were identified in 804 metazoan species. The phylogenetic tree constructed using 1237 unique bHLH motifs shows that metazoan ASCa, ASCb and ASCc families contain six (a1-a6), five (b1-b5) and three (c1-c3) bHLH genes, respectively. Further phylogenetic analyses suggest that ASC genes in metazoans are derived from a primitive c gene, those in insects are derived from c2 gene, and those in chordates are derived from a2 and a3 genes. Data of gene linkage demonstrate that insect a6 is derived from a4 but not from a5, and chordate a2 is ancestral to b5 only, whilst a3 is ancestral to both b3 and b5. It is concluded that current ASC gene families in metazoans were established through a series of sub- and/or neo-functionalization to duplicated ancestral ASC gene(s). These results provide good references for exploring evolutionary mechanisms of other bHLH genes in metazoans. Besides, gene subtyping is considered as an efficient method for evolutionary studies on closely related homologous genes.


Assuntos
Região do Genoma do Complexo Achaete-Scute/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Evolução Molecular , Genes/genética , Filogenia , Animais , Genômica
12.
PLoS One ; 15(1): e0228456, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31999769

RESUMO

The combination of a fluorescent reporter and enzymatic reporter provides a flexible and versatile way for the study of diverse biological processes, such as the detection of transcription and translation. Thus, there is an urgent need to develop this novel bifunctional reporter system. This study reports the design, construction, and validation of a new dicistronic mCherry-lacZα reporter system by artificial lac operon and pbr operon models in lacZM15-producing E. coli. It allows two reporter genes to be co-transcribed into a dicistronic mRNA strand, followed by coupled expression of mCherry and lacZα. In artificial lac operons, expression of the downstream lacZα was demonstrated to be positively related to expression of the upstream ORF. In artificial pbr operons, compared with the insertion of downstream full-length lacZ, the insertion of downstream lacZα exerted a slight effect on the response from the upstream mCherry. Furthermore, the downstream lacZα reporter showed stronger response to Pb(II) than the downstream full-length lacZ. Importantly, the response sensitivity of downstream lacZα was still higher than that of upstream mCherry in a dual RFP-lacZα reporter construct. The highly efficient expression profile of the reporter lacZα peptide makes it a preferred downstream reporter in polycistronic constructs. This novel bifunctional reporter system offers a robust tool for biological studies.


Assuntos
Escherichia coli/genética , Genes Reporter , Chumbo/análise , Técnicas Biossensoriais , Expressão Gênica , Genes , Óperon Lac , Proteínas Luminescentes/genética , RNA Mensageiro/metabolismo
13.
Hum Genet ; 139(6-7): 733-743, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31932884

RESUMO

The unique vulnerability to infection of newborns and young infants is generally explained by a constellation of differences between early-life immune responses and immune responses at later ages, often referred to as neonatal immune immaturity. This developmental view, corroborated by robust evidence, offers a plausible, population-level description of the pathogenesis of life-threatening infectious diseases during the early-life period, but provides little explanation on the wide inter-individual differences in susceptibility and resistance to specific infections during the first months of life. In this context, the role of individual human genetic variation is increasingly recognized. A life-threatening infection caused by an opportunistic pathogen in an otherwise healthy infant likely represents the first manifestation of an inborn error of immunity. Single-gene disorders may also underlie common infections in full-term infants with no comorbidities or in preterm infants. In addition, there is increasing evidence of a possible role for common genetic variation in the pathogenesis of infection in preterm infants. Over the past years, a unified theory of infectious diseases emerged, supporting a hypothetical, age-dependent general model of genetic architecture of human infectious diseases. We discuss here how the proposed genetic model can be reconciled with the widely accepted developmental view of early-life infections in humans.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Genes/genética , Doenças Genéticas Inatas/complicações , Predisposição Genética para Doença , Variação Genética , Infecções/etiologia , Doenças Genéticas Inatas/genética , Genética Humana , Humanos , Infecções/patologia
14.
Nucleic Acids Res ; 48(5): 2694-2708, 2020 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-31919519

RESUMO

Diplonemids are highly abundant heterotrophic marine protists. Previous studies showed that their strikingly bloated mitochondrial genome is unique because of systematic gene fragmentation and manifold RNA editing. Here we report a comparative study of mitochondrial genome architecture, gene structure and RNA editing of six recently isolated, phylogenetically diverse diplonemid species. Mitochondrial gene fragmentation and modes of RNA editing, which include cytidine-to-uridine (C-to-U) and adenosine-to-inosine (A-to-I) substitutions and 3' uridine additions (U-appendage), are conserved across diplonemids. Yet as we show here, all these features have been pushed to their extremes in the Hemistasiidae lineage. For example, Namystynia karyoxenos has its genes fragmented into more than twice as many modules than other diplonemids, with modules as short as four nucleotides. Furthermore, we detected in this group multiple A-appendage and guanosine-to-adenosine (G-to-A) substitution editing events not observed before in diplonemids and found very rarely elsewhere. With >1,000 sites, C-to-U and A-to-I editing in Namystynia is nearly 10 times more frequent than in other diplonemids. The editing density of 12% in coding regions makes Namystynia's the most extensively edited transcriptome described so far. Diplonemid mitochondrial genome architecture, gene structure and post-transcriptional processes display such high complexity that they challenge all other currently known systems.


Assuntos
Euglenozoários/genética , Genes , Genoma Mitocondrial , Edição de RNA/genética , Sequência de Bases , Cromossomos/genética , Sequência Conservada , DNA Mitocondrial/genética , Filogenia
15.
BMC Genomics ; 21(1): 63, 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31959106

RESUMO

BACKGROUND: As a major threat to the oyster industry, Pacific Oyster Mortality Syndrome (POMS) is a polymicrobial disease affecting the main oyster species farmed across the world. POMS affects oyster juveniles and became panzootic this last decade, but POMS resistance in some oyster genotypes has emerged. While we know some genetic loci associated with resistance, the underlying mechanisms remained uncharacterized. So, we developed a comparative transcriptomic approach using basal gene expression profiles between different oyster biparental families with contrasted phenotypes when confronted to POMS (resistant or susceptible). RESULTS: We showed that POMS resistant oysters show differential expression of genes involved in stress responses, protein modifications, maintenance of DNA integrity and repair, and immune and antiviral pathways. We found similarities and clear differences among different molecular pathways in the different resistant families. These results suggest that the resistance process is polygenic and partially varies according to the oyster genotype. CONCLUSIONS: We found differences in basal expression levels of genes related to TLR-NFκB, JAK-STAT and STING-RLR pathways. These differences could explain the best antiviral response, as well as the robustness of resistant oysters when confronted to POMS. As some of these genes represent valuable candidates for selective breeding, we propose future studies should further examine their function.


Assuntos
Crassostrea/genética , Crassostrea/microbiologia , Animais , Crassostrea/imunologia , Crassostrea/metabolismo , Genes , RNA-Seq , Estresse Fisiológico/genética , Transcriptoma
16.
Hum Genet ; 139(1): 95-102, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31317254

RESUMO

A central goal in human genetics is the identification of variants and genes that influence the risk of polygenic diseases. In the past decade, genome-wide association studies (GWAS) have identified tens of thousands of genetic loci associated with various diseases. Since the majority of such loci lie within non-coding regions and have many candidate variants in linkage disequilibrium, it has been challenging to accurately identify specific causal variants and genes. To aid in their discovery a variety of statistical and experimental approaches have been developed. These approaches often borrow information from functional genomics assays such as ATAC-seq, ChIP-seq and RNA-seq to annotate functional variants and identify regulatory relationships between variants and genes. While such approaches are powerful, given the diversity of cell types and environments, it is paramount to select disease-relevant contexts for follow-up analyses. In this review, we discuss the latest developments, challenges, and best practices for determining the causal mechanisms of polygenic disease risk variants with functional genomics data from specialized cell types.


Assuntos
Linhagem da Célula/genética , Genes/genética , Genoma Humano , Estudo de Associação Genômica Ampla , Genômica/métodos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Predisposição Genética para Doença , Humanos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA