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1.
Nature ; 604(7905): 310-315, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35388217

RESUMEN

Comprehensive genome annotation is essential to understand the impact of clinically relevant variants. However, the absence of a standard for clinical reporting and browser display complicates the process of consistent interpretation and reporting. To address these challenges, Ensembl/GENCODE1 and RefSeq2 launched a joint initiative, the Matched Annotation from NCBI and EMBL-EBI (MANE) collaboration, to converge on human gene and transcript annotation and to jointly define a high-value set of transcripts and corresponding proteins. Here, we describe the MANE transcript sets for use as universal standards for variant reporting and browser display. The MANE Select set identifies a representative transcript for each human protein-coding gene, whereas the MANE Plus Clinical set provides additional transcripts at loci where the Select transcripts alone are not sufficient to report all currently known clinical variants. Each MANE transcript represents an exact match between the exonic sequences of an Ensembl/GENCODE transcript and its counterpart in RefSeq such that the identifiers can be used synonymously. We have now released MANE Select transcripts for 97% of human protein-coding genes, including all American College of Medical Genetics and Genomics Secondary Findings list v3.0 (ref. 3) genes. MANE transcripts are accessible from major genome browsers and key resources. Widespread adoption of these transcript sets will increase the consistency of reporting, facilitate the exchange of data regardless of the annotation source and help to streamline clinical interpretation.


Asunto(s)
Biología Computacional , Bases de Datos Genéticas , Genómica , Genoma , Humanos , Difusión de la Información , Anotación de Secuencia Molecular , National Library of Medicine (U.S.) , Estados Unidos
2.
PLoS Biol ; 22(5): e3002405, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38713717

RESUMEN

We report a new visualization tool for analysis of whole-genome assembly-assembly alignments, the Comparative Genome Viewer (CGV) (https://ncbi.nlm.nih.gov/genome/cgv/). CGV visualizes pairwise same-species and cross-species alignments provided by National Center for Biotechnology Information (NCBI) using assembly alignment algorithms developed by us and others. Researchers can examine large structural differences spanning chromosomes, such as inversions or translocations. Users can also navigate to regions of interest, where they can detect and analyze smaller-scale deletions and rearrangements within specific chromosome or gene regions. RefSeq or user-provided gene annotation is displayed where available. CGV currently provides approximately 800 alignments from over 350 animal, plant, and fungal species. CGV and related NCBI viewers are undergoing active development to further meet needs of the research community in comparative genome visualization.


Asunto(s)
Genoma , Programas Informáticos , Animales , Genoma/genética , Alineación de Secuencia/métodos , Genómica/métodos , Algoritmos , Estados Unidos , Humanos , Eucariontes/genética , Bases de Datos Genéticas , National Library of Medicine (U.S.) , Anotación de Secuencia Molecular/métodos
3.
Genome Res ; 32(1): 175-188, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34876495

RESUMEN

Eukaryotic genomes contain many nongenic elements that function in gene regulation, chromosome organization, recombination, repair, or replication, and mutation of those elements can affect genome function and cause disease. Although numerous epigenomic studies provide high coverage of gene regulatory regions, those data are not usually exposed in traditional genome annotation and can be difficult to access and interpret without field-specific expertise. The National Center for Biotechnology Information (NCBI) therefore provides RefSeq Functional Elements (RefSeqFEs), which represent experimentally validated human and mouse nongenic elements derived from the literature. The curated data set is comprised of richly annotated sequence records, descriptive records in the NCBI Gene database, reference genome feature annotation, and activity-based interactions between nongenic regions, target genes, and each other. The data set provides succinct functional details and transparent experimental evidence, leverages data from multiple experimental sources, is readily accessible and adaptable, and uses a flexible data model. The data have multiple uses for basic functional discovery, bioinformatics studies, genetic variant interpretation; as known positive controls for epigenomic data evaluation; and as reference standards for functional interactions. Comparisons to other gene regulatory data sets show that the RefSeqFE data set includes a wider range of feature types representing more areas of biology, but it is comparatively smaller and subject to data selection biases. RefSeqFEs thus provide an alternative and complementary resource for experimentally assayed functional elements, with future data set growth expected.


Asunto(s)
Biología Computacional , Genoma , Animales , Bases de Datos Genéticas , Eucariontes/genética , Humanos , Ratones , Estándares de Referencia
4.
Proc Natl Acad Sci U S A ; 119(51): e2214957119, 2022 12 20.
Artículo en Inglés | MEDLINE | ID: mdl-36508673

RESUMEN

Secretory proteins and lipids are biosynthesized in the endoplasmic reticulum (ER). The "protein quality control" system (PQC) monitors glycoprotein folding and supports the elimination of terminally misfolded polypeptides. A key component of the PQC system is Uridine diphosphate glucose:glycoprotein glucosyltransferase 1 (UGGT1). UGGT1 re-glucosylates unfolded glycoproteins, to enable the re-entry in the protein-folding cycle and impede the aggregation of misfolded glycoproteins. In contrast, a complementary "lipid quality control" (LQC) system that maintains lipid homeostasis remains elusive. Here, we demonstrate that cytotoxic phosphatidic acid derivatives with saturated fatty acyl chains are one of the physiological substrates of UGGT2, an isoform of UGGT1. UGGT2 produces lipid raft-resident phosphatidylglucoside regulating autophagy. Under the disruption of lipid metabolism and hypoxic conditions, UGGT2 inhibits PERK-ATF4-CHOP-mediated apoptosis in mouse embryonic fibroblasts. Moreover, the susceptibility of UGGT2 KO mice to high-fat diet-induced obesity is elevated. We propose that UGGT2 is an ER-localized LQC component that mitigates saturated lipid-associated ER stress via lipid glucosylation.


Asunto(s)
Fibroblastos , Glucosiltransferasas , Animales , Ratones , Fibroblastos/metabolismo , Glucosiltransferasas/metabolismo , Estrés del Retículo Endoplásmico , Glicoproteínas/metabolismo , Lípidos
5.
Nature ; 563(7732): 501-507, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30429615

RESUMEN

Female Aedes aegypti mosquitoes infect more than 400 million people each year with dangerous viral pathogens including dengue, yellow fever, Zika and chikungunya. Progress in understanding the biology of mosquitoes and developing the tools to fight them has been slowed by the lack of a high-quality genome assembly. Here we combine diverse technologies to produce the markedly improved, fully re-annotated AaegL5 genome assembly, and demonstrate how it accelerates mosquito science. We anchored physical and cytogenetic maps, doubled the number of known chemosensory ionotropic receptors that guide mosquitoes to human hosts and egg-laying sites, provided further insight into the size and composition of the sex-determining M locus, and revealed copy-number variation among glutathione S-transferase genes that are important for insecticide resistance. Using high-resolution quantitative trait locus and population genomic analyses, we mapped new candidates for dengue vector competence and insecticide resistance. AaegL5 will catalyse new biological insights and intervention strategies to fight this deadly disease vector.


Asunto(s)
Aedes/genética , Infecciones por Arbovirus/virología , Arbovirus , Genoma de los Insectos/genética , Genómica/normas , Control de Insectos , Mosquitos Vectores/genética , Mosquitos Vectores/virología , Aedes/virología , Animales , Infecciones por Arbovirus/transmisión , Arbovirus/aislamiento & purificación , Variaciones en el Número de Copia de ADN/genética , Virus del Dengue/aislamiento & purificación , Femenino , Variación Genética/genética , Genética de Población , Glutatión Transferasa/genética , Resistencia a los Insecticidas/efectos de los fármacos , Masculino , Anotación de Secuencia Molecular , Familia de Multigenes/genética , Piretrinas/farmacología , Estándares de Referencia , Procesos de Determinación del Sexo/genética
6.
Environ Res ; 250: 118515, 2024 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-38373547

RESUMEN

Telomeres are inert DNA sequences (TTAGGG) at the end of chromosomes that protect genetic information and maintain DNA integrity. Emerging evidence has demonstrated that telomere alteration can be closely related to occupational exposure and the development of various disease conditions, including cancer. However, the functions and underlying molecular mechanisms of telomere alteration and shelterin dysregulation after welding fume exposures have not been broadly defined. In this study, we analyzed telomere length and shelterin complex proteins in peripheral blood mononuclear cells (PBMCs) and in lung tissue recovered from male Sprague-Dawley rats following exposure by intratracheal instillation (ITI) to 2 mg/rat of manual metal arc-stainless steel (MMA-SS) welding fume particulate or saline (vehicle control). PBMCs and lung tissue were harvested at 30 d after instillation. Our study identified telomere elongation and shelterin dysregulation in PBMCs and lung tissue after welding fume exposure. Mechanistically, telomere elongation was independent of telomerase reverse transcriptase (TERT) activation. Collectively, our findings demonstrated that welding fume-induced telomere elongation was (a) TERT-independent and (b) associated with shelterin complex dysregulation. It is possible that an alteration of telomere length and its regulatory proteins may be utilized as predictive biomarkers for various disease conditions after welding fume exposure. This needs further investigation.


Asunto(s)
Pulmón , Ratas Sprague-Dawley , Acero Inoxidable , Telomerasa , Soldadura , Animales , Masculino , Ratas , Contaminantes Ocupacionales del Aire/toxicidad , Exposición por Inhalación/efectos adversos , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patología , Acero Inoxidable/toxicidad , Telomerasa/genética , Telomerasa/metabolismo , Telómero/efectos de los fármacos , Proteínas de Unión a Telómeros/genética , Proteínas de Unión a Telómeros/metabolismo
7.
Environ Res ; 180: 108900, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31711660

RESUMEN

Inhalation of welding fume (WF) can result in the deposition of toxic metals, such as manganese (Mn), in the brain and may cause neurological changes in exposed workers. Alterations in telomere length are indicative of cellular aging and, possibly, neurodegeneration. Here, we investigated the effect of WF inhalation on telomere length and markers of neurodegeneration in whole brain tissue in rats. Male Fischer-344 (F-344) rats were exposed by inhalation to stainless steel WF (20 mg/m3 x 3 h/d x 4 d/wk x 5 wk) or filtered air (control). Telomere length, DNA-methylation, gene expression of Trf1, Trf2, ATM, and APP, protein expression of p-Tau, α-synuclein, and presenilin 1 and 2 were assessed in whole brain tissue at 12 wk after WF exposure ended. Results suggest that WF inhalation increased telomere length without affecting telomerase in whole brain. Moreover, we observed that components of the shelterin complex, Trf1 and Trf2, play an important role in telomere end protection, and their regulation may be responsible for the increase in telomere length. In addition, expression of different neurodegeneration markers, such as p-Tau, presenilin 1-2 and α-synuclein proteins, were increased in brain tissue from the WF-exposed rats as compared to control. These findings suggest a possible correlation between epigenetic modifications, telomere length alteration, and neurodegeneration because of the presence of factors in serum after WF exposure that may cause extra-pulmonary effects as well as the translocation of potentially neurotoxic metals associated with WF to the central nervous system (CNS). Further studies are needed to investigate the brain region specificity and temporal response of these effects.


Asunto(s)
Contaminantes Ocupacionales del Aire , Regulación de la Expresión Génica/efectos de los fármacos , Exposición por Inhalación , Telómero , Soldadura , Contaminantes Ocupacionales del Aire/toxicidad , Animales , Encéfalo , Gatos , Metilación de ADN , Células Endoteliales , Humanos , Masculino , Ratas , Ratas Sprague-Dawley
8.
Part Fibre Toxicol ; 17(1): 60, 2020 11 26.
Artículo en Inglés | MEDLINE | ID: mdl-33243293

RESUMEN

BACKGROUND: Inhalation of multi-walled carbon nanotubes (MWCNTs) poses a potential risk to human health. In order to safeguard workers and consumers, the toxic properties of MWCNTs need to be identified. Functionalization has been shown to either decrease or increase MWCNT-related pulmonary injury, depending on the type of modification. We, therefore, investigated both acute and chronic pulmonary toxicity of a library of MWCNTs derived from a common pristine parent compound (NC7000). METHODS: MWCNTs were thermally or chemically purified and subsequently surface functionalized by carboxylation or amination. To evaluate pulmonary toxicity, male C57BL6 mice were dosed via oropharyngeal aspiration with either 1.6 or 4 mg/kg of each MWCNT type. Mitsui-7 MWCNT was used as a positive control. Necropsy was performed at days 3 and 60 post-exposure to collect bronchoalveolar lavage fluid (BALF) and lungs. RESULTS: At day 3 all MWCNTs increased the number of neutrophils in BALF. Chemical purification had a greater effect on pro-inflammatory cytokines (IL-1ß, IL-6, CXCL1) in BALF, while thermal purification had a greater effect on pro-fibrotic cytokines (CCL2, OPN, TGF-ß1). At day 60, thermally purified, carboxylated MWCNTs had the strongest effect on lymphocyte numbers in BALF. Thermally purified MWCNTs caused the greatest increase in LDH and total protein in BALF. Furthermore, the thermally purified and carboxyl- or amine-functionalized MWCNTs caused the greatest number of granulomatous lesions in the lungs. The physicochemical characteristics mainly associated with increased toxicity of the thermally purified derivatives were decreased surface defects and decreased amorphous content as indicated by Raman spectroscopy. CONCLUSIONS: These data demonstrate that the purification method is an important determinant of lung toxicity induced by carboxyl- and amine-functionalized MWCNTs.


Asunto(s)
Contaminantes Atmosféricos/toxicidad , Pulmón/efectos de los fármacos , Nanotubos de Carbono/toxicidad , Administración por Inhalación , Animales , Líquido del Lavado Bronquioalveolar/química , Citocinas/metabolismo , Exposición por Inhalación , Lesión Pulmonar , Ratones , Ratones Endogámicos C57BL , Factor de Crecimiento Transformador beta1/metabolismo
9.
Nucleic Acids Res ; 46(D1): D221-D228, 2018 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-29126148

RESUMEN

The Consensus Coding Sequence (CCDS) project provides a dataset of protein-coding regions that are identically annotated on the human and mouse reference genome assembly in genome annotations produced independently by NCBI and the Ensembl group at EMBL-EBI. This dataset is the product of an international collaboration that includes NCBI, Ensembl, HUGO Gene Nomenclature Committee, Mouse Genome Informatics and University of California, Santa Cruz. Identically annotated coding regions, which are generated using an automated pipeline and pass multiple quality assurance checks, are assigned a stable and tracked identifier (CCDS ID). Additionally, coordinated manual review by expert curators from the CCDS collaboration helps in maintaining the integrity and high quality of the dataset. The CCDS data are available through an interactive web page (https://www.ncbi.nlm.nih.gov/CCDS/CcdsBrowse.cgi) and an FTP site (ftp://ftp.ncbi.nlm.nih.gov/pub/CCDS/). In this paper, we outline the ongoing work, growth and stability of the CCDS dataset and provide updates on new collaboration members and new features added to the CCDS user interface. We also present expert curation scenarios, with specific examples highlighting the importance of an accurate reference genome assembly and the crucial role played by input from the research community.


Asunto(s)
Secuencia de Consenso , Bases de Datos Genéticas , Sistemas de Lectura Abierta , Animales , Curaduría de Datos/métodos , Curaduría de Datos/normas , Bases de Datos Genéticas/normas , Guías como Asunto , Humanos , Ratones , Anotación de Secuencia Molecular , National Library of Medicine (U.S.) , Estados Unidos , Interfaz Usuario-Computador
10.
PLoS Biol ; 13(10): e1002277, 2015 10.
Artículo en Inglés | MEDLINE | ID: mdl-26469762

RESUMEN

Although glucose uniquely stimulates proinsulin biosynthesis in ß cells, surprisingly little is known of the underlying mechanism(s). Here, we demonstrate that glucose activates the unfolded protein response transducer inositol-requiring enzyme 1 alpha (IRE1α) to initiate X-box-binding protein 1 (Xbp1) mRNA splicing in adult primary ß cells. Using mRNA sequencing (mRNA-Seq), we show that unconventional Xbp1 mRNA splicing is required to increase and decrease the expression of several hundred mRNAs encoding functions that expand the protein secretory capacity for increased insulin production and protect from oxidative damage, respectively. At 2 wk after tamoxifen-mediated Ire1α deletion, mice develop hyperglycemia and hypoinsulinemia, due to defective ß cell function that was exacerbated upon feeding and glucose stimulation. Although previous reports suggest IRE1α degrades insulin mRNAs, Ire1α deletion did not alter insulin mRNA expression either in the presence or absence of glucose stimulation. Instead, ß cell failure upon Ire1α deletion was primarily due to reduced proinsulin mRNA translation primarily because of defective glucose-stimulated induction of a dozen genes required for the signal recognition particle (SRP), SRP receptors, the translocon, the signal peptidase complex, and over 100 other genes with many other intracellular functions. In contrast, Ire1α deletion in ß cells increased the expression of over 300 mRNAs encoding functions that cause inflammation and oxidative stress, yet only a few of these accumulated during high glucose. Antioxidant treatment significantly reduced glucose intolerance and markers of inflammation and oxidative stress in mice with ß cell-specific Ire1α deletion. The results demonstrate that glucose activates IRE1α-mediated Xbp1 splicing to expand the secretory capacity of the ß cell for increased proinsulin synthesis and to limit oxidative stress that leads to ß cell failure.


Asunto(s)
Empalme Alternativo , Proteínas de Unión al ADN/metabolismo , Endorribonucleasas/metabolismo , Hiperglucemia/metabolismo , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Estrés Oxidativo , Proteínas Serina-Treonina Quinasas/metabolismo , Factores de Transcripción/metabolismo , Adolescente , Adulto , Animales , Células Cultivadas , Cruzamientos Genéticos , Proteínas de Unión al ADN/genética , Endorribonucleasas/genética , Femenino , Humanos , Hiperglucemia/sangre , Hiperglucemia/patología , Secreción de Insulina , Células Secretoras de Insulina/patología , Células Secretoras de Insulina/ultraestructura , Masculino , Ratones Noqueados , Ratones Transgénicos , Persona de Mediana Edad , Proteínas Serina-Treonina Quinasas/genética , Proteínas Recombinantes/metabolismo , Factores de Transcripción del Factor Regulador X , Transducción de Señal , Donantes de Tejidos , Factores de Transcripción/genética , Proteína 1 de Unión a la X-Box , Adulto Joven
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