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1.
Genet Sel Evol ; 53(1): 76, 2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34551713

RESUMO

BACKGROUND: Backfat thickness is an important carcass composition trait for pork production and is commonly included in swine breeding programmes. In this paper, we report the results of a large genome-wide association study for backfat thickness using data from eight lines of diverse genetic backgrounds. METHODS: Data comprised 275,590 pigs from eight lines with diverse genetic backgrounds (breeds included Large White, Landrace, Pietrain, Hampshire, Duroc, and synthetic lines) genotyped and imputed for 71,324 single-nucleotide polymorphisms (SNPs). For each line, we estimated SNP associations using a univariate linear mixed model that accounted for genomic relationships. SNPs with significant associations were identified using a threshold of p < 10-6 and used to define genomic regions of interest. The proportion of genetic variance explained by a genomic region was estimated using a ridge regression model. RESULTS: We found significant associations with backfat thickness for 264 SNPs across 27 genomic regions. Six genomic regions were detected in three or more lines. The average estimate of the SNP-based heritability was 0.48, with estimates by line ranging from 0.30 to 0.58. The genomic regions jointly explained from 3.2 to 19.5% of the additive genetic variance of backfat thickness within a line. Individual genomic regions explained up to 8.0% of the additive genetic variance of backfat thickness within a line. Some of these 27 genomic regions also explained up to 1.6% of the additive genetic variance in lines for which the genomic region was not statistically significant. We identified 64 candidate genes with annotated functions that can be related to fat metabolism, including well-studied genes such as MC4R, IGF2, and LEPR, and more novel candidate genes such as DHCR7, FGF23, MEDAG, DGKI, and PTN. CONCLUSIONS: Our results confirm the polygenic architecture of backfat thickness and the role of genes involved in energy homeostasis, adipogenesis, fatty acid metabolism, and insulin signalling pathways for fat deposition in pigs. The results also suggest that several less well-understood metabolic pathways contribute to backfat development, such as those of phosphate, calcium, and vitamin D homeostasis.


Assuntos
Tecido Adiposo/anatomia & histologia , Genes , Patrimônio Genético , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Suínos/anatomia & histologia , Suínos/genética , Animais , Genoma , Genômica , Genótipo , Suínos/classificação
2.
Nutrients ; 13(8)2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34444981

RESUMO

AIMS: This systematic review examines the association between maternal lifestyle, diet and physical activity, and epigenetic changes in the offspring. METHODS: A literature search was conducted using multiple science databases: PubMed, Embase and Cochrane Library, on 10 March 2021. RCT and Cohort studies in English or Scandinavian languages were included. Exposure variables included diet, lifestyle, meal patterns or physical activity. Studies using dietary supplements as exposure variables were excluded. Outcome variables included were DNA methylation, microRNA or histone changes in placenta, cord blood or offspring. Two independent authors screened, read and extracted data from the included papers. The Cochrane risk-of-bias tool for randomized trials (RoB2) and The Critical Appraisal Skills Program (CASP) Cohort Study Checklist were used to assess risk of bias in the included studies. A qualitative approach was employed due to heterogeneity of exposures and results of the studies. RESULTS: 16 studies and 3617 participants were included in the final analysis. The exposure variables included physical activity, carbohydrate, low glycemic index diet, added sugar, fat, Mediterranean diet and pro-inflammatory diet. The outcome variables identified were differences in DNA methylation and microRNA. Most studies described epigenetic changes in either placenta or cord blood. Genes reported to be methylated were GR, HSD2, IGF-2, PLAG1, MEG-3, H19 and RXRA. However, not all studies found epigenetic changes strong enough to pass multiple testing, and the study quality varied. CONCLUSION: Despite the variable quality of the included studies, the results in this review suggest that there may be an association between the mother's lifestyle, diet and level of physical activity during pregnancy and epigenetic changes in the offspring.


Assuntos
Dieta , Epigênese Genética , Exercício Físico , Comportamento Alimentar , Desenvolvimento Fetal , Estilo de Vida , Gestantes , Metilação de DNA , Epigenômica , Feminino , Genes , Histonas , Humanos , MicroRNAs , Mães , Gravidez
3.
Nucleic Acids Res ; 49(15): 8471-8487, 2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34313777

RESUMO

There is a pressing need today to mechanistically interpret sets of genomic variants associated with diseases. Here we present a tool called 'VarSAn' that uses a network analysis algorithm to identify pathways relevant to a given set of variants. VarSAn analyzes a configurable network whose nodes represent variants, genes and pathways, using a Random Walk with Restarts algorithm to rank pathways for relevance to the given variants, and reports P-values for pathway relevance. It treats non-coding and coding variants differently, properly accounts for the number of pathways impacted by each variant and identifies relevant pathways even if many variants do not directly impact genes of the pathway. We use VarSAn to identify pathways relevant to variants related to cancer and several other diseases, as well as drug response variation. We find VarSAn's pathway ranking to be complementary to the standard approach of enrichment tests on genes related to the query set. We adopt a novel benchmarking strategy to quantify its advantage over this baseline approach. Finally, we use VarSAn to discover key pathways, including the VEGFA-VEGFR2 pathway, related to de novo variants in patients of Hypoplastic Left Heart Syndrome, a rare and severe congenital heart defect.


Assuntos
Genômica/métodos , Polimorfismo de Nucleotídeo Único , Software , Algoritmos , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Interpretação Estatística de Dados , Feminino , Genes , Humanos , Síndrome do Coração Esquerdo Hipoplásico/genética , Síndrome do Coração Esquerdo Hipoplásico/metabolismo , Masculino , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Transdução de Sinais/genética
4.
Res. soc. adm. pharm ; 17(7): 1347-1355, July. 2021. graf
Artigo em Inglês | Sec. Est. Saúde SP, CONASS, SESSP-IDPCPROD, Sec. Est. Saúde SP | ID: biblio-1283429

RESUMO

BACKGROUND: Familial hypercholesterolemia (FH) is a genetic disease that affects millions of people worldwide. OBJECTIVES: The study protocol FHBGEP was design to investigate the main genomic, epigenomic, and pharmacogenomic factors associated with FH and polygenic hypercholesterolemia (PH). METHODS: FH patients will be enrolled at six research centers in Brazil. An exon-targeted gene strategy will be used to sequence a panel of 84 genes related to FH, PH, pharmacogenomics and coronary artery disease. Variants in coding and regulatory regions will be identified using a proposed variant discovery pipeline and classified according to the American College Medical Genetics guidelines. Functional effects of variants in FH-related genes will be investigated by in vitro studies using lymphocytes and cell lines (HepG2, HUVEC and HEK293FT), CRISPR/Cas9 mutagenesis, luciferase reporter assay and other technologies. Functional studies in silico, such as molecular docking, molecular dynamics, and conformational analysis, will be used to explore the impact of novel variants on protein structure and function. DNA methylation profile and differential expression of circulating non-coding RNAs (miRNAs and lncRNAs) will be analyzed in FH patients and normolipidemic subjects (control group). The influence of genomic and epigenomic factors on metabolic and inflammatory status will be analyzed in FH patients. Pharmacogenomic studies will be conducted to investigate the influence of genomic and epigenomic factors on response to statins in FH patients. SUMMARY: The FHBGEP protocol has the potential to elucidate the genetic basis and molecular mechanisms involved in the pathophysiology of FH and PH, particularly in the Brazilian population. This pioneering approach includes genomic, epigenomic and functional studies, which results will contribute to the improvement of the diagnosis, prognosis and personalized therapy of FH patients.


Assuntos
Farmacogenética , Doença da Artéria Coronariana , Epigenômica , Genes , Hipercolesterolemia
5.
Int J Mol Sci ; 22(11)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34072943

RESUMO

Coronary artery disease remains one of the primary healthcare problems due to the high cost of treatment, increased number of patients, poor clinical outcomes, and lack of effective therapy. Though pharmacological and surgical treatments positively affect symptoms and arrest the disease progression, they generally exhibit a limited effect on the disease outcome. The development of alternative therapeutic approaches towards ischemic disease treatment, especially of decompensated forms, is therefore relevant. Therapeutic angiogenesis, stimulated by various cytokines, chemokines, and growth factors, provides the possibility of restoring functional blood flow in ischemic tissues, thereby ensuring the regeneration of the damaged area. In the current study, based on the clinically approved plasmid vector pVax1, multigenic constructs were developed encoding vascular endothelial growth factor (VEGF), fibroblast growth factors (FGF2), and the DsRed fluorescent protein, integrated via picornaviruses' furin-2A peptide sequences. In vitro experiments demonstrated that genetically modified cells with engineered plasmid constructs expressed the target proteins. Overexpression of VEGF and FGF2 resulted in increased levels of the recombinant proteins. Concomitantly, these did not lead to a significant shift in the general secretory profile of modified HEK293T cells. Simultaneously, the secretome of genetically modified cells showed significant stimulating effects on the formation of capillary-like structures by HUVEC (endothelial cells) in vitro. Our results revealed that when the multicistronic multigene vectors encoding 2A peptide sequences are created, transient transgene co-expression is ensured. The results obtained indicated the mutual synergistic effects of the growth factors VEGF and FGF2 on the proliferation of endothelial cells in vitro. Thus, recombinant multicistronic multigenic constructs might serve as a promising approach for establishing safe and effective systems to treat ischemic diseases.


Assuntos
Doença da Artéria Coronariana/genética , Fator 2 de Crescimento de Fibroblastos/genética , Neovascularização Patológica/genética , Fator A de Crescimento do Endotélio Vascular/genética , Indutores da Angiogênese/farmacologia , Proliferação de Células/genética , Doença da Artéria Coronariana/terapia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Fator 2 de Crescimento de Fibroblastos/farmacologia , Furina/genética , Regulação da Expressão Gênica/genética , Genes/genética , Vetores Genéticos , Células HEK293 , Células Endoteliais da Veia Umbilical Humana , Humanos , Neovascularização Patológica/terapia , Neovascularização Fisiológica/genética , Peptídeos/genética , Peptídeos/farmacologia , Plasmídeos/genética , Plasmídeos/farmacologia , Fator A de Crescimento do Endotélio Vascular/farmacologia
6.
Commun Biol ; 4(1): 706, 2021 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-34108613

RESUMO

Age-related hearing impairment (ARHI) is the most common sensory disorder in older adults. We conducted a genome-wide association meta-analysis of 121,934 ARHI cases and 591,699 controls from Iceland and the UK. We identified 21 novel sequence variants, of which 13 are rare, under either additive or recessive models. Of special interest are a missense variant in LOXHD1 (MAF = 1.96%) and a tandem duplication in FBF1 covering 4 exons (MAF = 0.22%) associating with ARHI (OR = 3.7 for homozygotes, P = 1.7 × 10-22 and OR = 4.2 for heterozygotes, P = 5.7 × 10-27, respectively). We constructed an ARHI genetic risk score (GRS) using common variants and showed that a common variant GRS can identify individuals at risk comparable to carriers of rare high penetrance variants. Furthermore, we found that ARHI and tinnitus share genetic causes. This study sheds a new light on the genetic architecture of ARHI, through several rare variants in both Mendelian deafness genes and genes not previously linked to hearing.


Assuntos
Perda Auditiva/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Feminino , Genes/genética , Predisposição Genética para Doença , Variação Genética/genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
7.
Commun Biol ; 4(1): 736, 2021 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-34127790

RESUMO

Aggregates of hyperphosphorylated tau protein are a pathological hallmark of more than 20 distinct neurodegenerative diseases, including Alzheimer's disease, progressive supranuclear palsy, and frontotemporal dementia. While the exact mechanism of tau aggregation is unknown, the accumulation of aggregates correlates with disease progression. Here we report a genome-wide CRISPR screen to identify modulators of endogenous tau protein for the first time. Primary screens performed in SH-SY5Y cells, identified positive and negative regulators of tau protein levels. Hit validation of the top 43 candidate genes was performed using Ngn2-induced human cortical excitatory neurons. Using this approach, genes and pathways involved in modulation of endogenous tau levels were identified, including chromatin modifying enzymes, neddylation and ubiquitin pathway members, and components of the mTOR pathway. TSC1, a critical component of the mTOR pathway, was further validated in vivo, demonstrating the relevance of this screening strategy. These findings may have implications for treating neurodegenerative diseases in the future.


Assuntos
Redes e Vias Metabólicas/genética , Neurônios/metabolismo , Proteínas tau/metabolismo , Animais , Proteína 9 Associada à CRISPR , Sistemas CRISPR-Cas , Linhagem Celular Tumoral , Edição de Genes , Genes/genética , Genes/fisiologia , Testes Genéticos/métodos , Estudo de Associação Genômica Ampla , Humanos , Camundongos , Neuroblastoma/metabolismo , Ratos , Serina-Treonina Quinases TOR/metabolismo
8.
Genes (Basel) ; 12(5)2021 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069634

RESUMO

Variability is the source on which selective pressure acts, allowing genome evolution and adaptation [...].


Assuntos
Genes/genética , Genoma Humano/genética , Adaptação Fisiológica/genética , Animais , Evolução Molecular , Humanos , Fenótipo , Plantas/genética
9.
Nucleic Acids Res ; 49(W1): W153-W161, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34125897

RESUMO

As a result of the advent of high-throughput technologies, there has been rapid progress in our understanding of the genetics underlying biological processes. However, despite such advances, the genetic landscape of human diseases has only marginally been disclosed. Exploiting the present availability of large amounts of biological and phenotypic data, we can use our current understanding of disease genetics to train machine learning models to predict novel genetic factors associated with the disease. To this end, we developed DGLinker, a webserver for the prediction of novel candidate genes for human diseases given a set of known disease genes. DGLinker has a user-friendly interface that allows non-expert users to exploit biomedical information from a wide range of biological and phenotypic databases, and/or to upload their own data, to generate a knowledge-graph and use machine learning to predict new disease-associated genes. The webserver includes tools to explore and interpret the results and generates publication-ready figures. DGLinker is available at https://dglinker.rosalind.kcl.ac.uk. The webserver is free and open to all users without the need for registration.


Assuntos
Doença/genética , Software , Esclerose Amiotrófica Lateral/genética , Gráficos por Computador , Genes , Humanos , Aprendizado de Máquina
10.
Nucleic Acids Res ; 49(W1): W317-W325, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34086934

RESUMO

Gene set enrichment (GSE) analysis plays an essential role in extracting biological insight from genome-scale experiments. ORA (overrepresentation analysis), FCS (functional class scoring), and PT (pathway topology) approaches are three generations of GSE methods along the timeline of development. Previous versions of KOBAS provided services based on just the ORA method. Here we presented version 3.0 of KOBAS, which is named KOBAS-i (short for KOBAS intelligent version). It introduced a novel machine learning-based method we published earlier, CGPS, which incorporates seven FCS tools and two PT tools into a single ensemble score and intelligently prioritizes the relevant biological pathways. In addition, KOBAS has expanded the downstream exploratory visualization for selecting and understanding the enriched results. The tool constructs a novel view of cirFunMap, which presents different enriched terms and their correlations in a landscape. Finally, based on the previous version's framework, KOBAS increased the number of supported species from 1327 to 5944. For an easier local run, it also provides a prebuilt Docker image that requires no installation, as a supplementary to the source code version. KOBAS can be freely accessed at http://kobas.cbi.pku.edu.cn, and a mirror site is available at http://bioinfo.org/kobas.


Assuntos
Genes , Software , Expressão Gênica , Ontologia Genética , Aprendizado de Máquina , Proteínas/genética
11.
PLoS Genet ; 17(5): e1009548, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-34014919

RESUMO

Fisher's partitioning of genotypic values and genetic variance is highly relevant in the current era of genome-wide association studies (GWASs). However, despite being more than a century old, a number of persistent misconceptions related to nonadditive genetic effects remain. We developed a user-friendly web tool, the Falconer ShinyApp, to show how the combination of gene action and allele frequencies at causal loci translate to genetic variance and genetic variance components for a complex trait. The app can be used to demonstrate the relationship between a SNP effect size estimated from GWAS and the variation the SNP generates in the population, i.e., how locus-specific effects lead to individual differences in traits. In addition, it can also be used to demonstrate how within and between locus interactions (dominance and epistasis, respectively) usually do not lead to a large amount of nonadditive variance relative to additive variance, and therefore, that these interactions usually do not explain individual differences in a population.


Assuntos
Genes/genética , Variação Genética , Estudo de Associação Genômica Ampla , Internet , Software , Epistasia Genética , Frequência do Gene , Genes Dominantes , Loci Gênicos/genética , Genótipo , Humanos , Modelos Genéticos , Polimorfismo de Nucleotídeo Único
12.
Nature ; 594(7862): 283-288, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33981036

RESUMO

Homologous recombination (HR) repairs DNA double-strand breaks (DSBs) in the S and G2 phases of the cell cycle1-3. Several HR proteins are preferentially recruited to DSBs at transcriptionally active loci4-10, but how transcription promotes HR is poorly understood. Here we develop an assay to assess the effect of local transcription on HR. Using this assay, we find that transcription stimulates HR to a substantial extent. Tethering RNA transcripts to the vicinity of DSBs recapitulates the effects of local transcription, which suggests that transcription enhances HR through RNA transcripts. Tethered RNA transcripts stimulate HR in a sequence- and orientation-dependent manner, indicating that they function by forming DNA-RNA hybrids. In contrast to most HR proteins, RAD51-associated protein 1 (RAD51AP1) only promotes HR when local transcription is active. RAD51AP1 drives the formation of R-loops in vitro and is required for tethered RNAs to stimulate HR in cells. Notably, RAD51AP1 is necessary for the DSB-induced formation of DNA-RNA hybrids in donor DNA, linking R-loops to D-loops. In vitro, RAD51AP1-generated R-loops enhance the RAD51-mediated formation of D-loops locally and give rise to intermediates that we term 'DR-loops', which contain both DNA-DNA and DNA-RNA hybrids and favour RAD51 function. Thus, at DSBs in transcribed regions, RAD51AP1 promotes the invasion of RNA transcripts into donor DNA, and stimulates HR through the formation of DR-loops.


Assuntos
DNA/genética , DNA/metabolismo , Recombinação Homóloga/genética , Estruturas R-Loop/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transcrição Genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Linhagem Celular , DNA/química , Quebras de DNA de Cadeia Dupla , Reparo do DNA , Proteínas de Ligação a DNA/metabolismo , Genes/genética , Genes Reporter/genética , Proteínas de Fluorescência Verde/genética , Humanos , Técnicas In Vitro , RNA Mensageiro/química , Proteínas de Ligação a RNA/metabolismo , Rad51 Recombinase/metabolismo
13.
Nature ; 594(7861): 77-81, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33953399

RESUMO

The divergence of chimpanzee and bonobo provides one of the few examples of recent hominid speciation1,2. Here we describe a fully annotated, high-quality bonobo genome assembly, which was constructed without guidance from reference genomes by applying a multiplatform genomics approach. We generate a bonobo genome assembly in which more than 98% of genes are completely annotated and 99% of the gaps are closed, including the resolution of about half of the segmental duplications and almost all of the full-length mobile elements. We compare the bonobo genome to those of other great apes1,3-5 and identify more than 5,569 fixed structural variants that specifically distinguish the bonobo and chimpanzee lineages. We focus on genes that have been lost, changed in structure or expanded in the last few million years of bonobo evolution. We produce a high-resolution map of incomplete lineage sorting and estimate that around 5.1% of the human genome is genetically closer to chimpanzee or bonobo and that more than 36.5% of the genome shows incomplete lineage sorting if we consider a deeper phylogeny including gorilla and orangutan. We also show that 26% of the segments of incomplete lineage sorting between human and chimpanzee or human and bonobo are non-randomly distributed and that genes within these clustered segments show significant excess of amino acid replacement compared to the rest of the genome.


Assuntos
Evolução Molecular , Genoma/genética , Genômica , Pan paniscus/genética , Filogenia , Animais , Fator de Iniciação 4A em Eucariotos/genética , Feminino , Genes , Gorilla gorilla/genética , Anotação de Sequência Molecular/normas , Pan troglodytes/genética , Pongo/genética , Duplicações Segmentares Genômicas , Análise de Sequência de DNA
14.
Nat Commun ; 12(1): 2224, 2021 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-33850126

RESUMO

Prioritizing genes for translation to therapeutics for common diseases has been challenging. Here, we propose an approach to identify drug targets with high probability of success by focusing on genes with both gain of function (GoF) and loss of function (LoF) mutations associated with opposing effects on phenotype (Bidirectional Effect Selected Targets, BEST). We find 98 BEST genes for a variety of indications. Drugs targeting those genes are 3.8-fold more likely to be approved than non-BEST genes. We focus on five genes (IGF1R, NPPC, NPR2, FGFR3, and SHOX) with evidence for bidirectional effects on stature. Rare protein-altering variants in those genes result in significantly increased risk for idiopathic short stature (ISS) (OR = 2.75, p = 3.99 × 10-8). Finally, using functional experiments, we demonstrate that adding an exogenous CNP analog (encoded by NPPC) rescues the phenotype, thus validating its potential as a therapeutic treatment for ISS. Our results show the value of looking for bidirectional effects to identify and validate drug targets.


Assuntos
Genes , Preparações Farmacêuticas , Descoberta de Drogas , Nanismo/genética , Estudos de Associação Genética , Humanos , Peptídeo Natriurético Tipo C/genética , Fenótipo , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Receptor IGF Tipo 1/genética , Receptores do Fator Natriurético Atrial/genética , Proteína de Homoeobox de Baixa Estatura/genética
15.
Nat Genet ; 53(5): 638-649, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33859415

RESUMO

A central question in the post-genomic era is how genes interact to form biological pathways. Measurements of gene dependency across hundreds of cell lines have been used to cluster genes into 'co-essential' pathways, but this approach has been limited by ubiquitous false positives. In the present study, we develop a statistical method that enables robust identification of gene co-essentiality and yields a genome-wide set of functional modules. This atlas recapitulates diverse pathways and protein complexes, and predicts the functions of 108 uncharacterized genes. Validating top predictions, we show that TMEM189 encodes plasmanylethanolamine desaturase, a key enzyme for plasmalogen synthesis. We also show that C15orf57 encodes a protein that binds the AP2 complex, localizes to clathrin-coated pits and enables efficient transferrin uptake. Finally, we provide an interactive webtool for the community to explore our results, which establish co-essentiality profiling as a powerful resource for biological pathway identification and discovery of new gene functions.


Assuntos
Redes Reguladoras de Genes , Genes , Genoma , Clatrina/metabolismo , Endocitose , Epigênese Genética , Regulação da Expressão Gênica , Células HeLa , Humanos , Anotação de Sequência Molecular , Neoplasias/genética , Plasmalogênios/biossíntese , Transdução de Sinais/genética
16.
Int J Mol Sci ; 22(6)2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33809541

RESUMO

Liquid-liquid phase separation (LLPS) is a molecular process that leads to the formation of membraneless organelles, representing functionally specialized liquid-like cellular condensates formed by proteins and nucleic acids. Integrating the data on LLPS-associated proteins from dedicated databases revealed only modest agreement between them and yielded a high-confidence dataset of 89 human LLPS drivers. Analysis of the supporting evidence for our dataset uncovered a systematic and potentially concerning difference between protein concentrations used in a good fraction of the in vitro LLPS experiments, a key parameter that governs the phase behavior, and the proteomics-derived cellular abundance levels of the corresponding proteins. Closer scrutiny of the underlying experimental data enabled us to offer a sound rationale for this systematic difference, which draws on our current understanding of the cellular organization of the proteome and the LLPS process. In support of this rationale, we find that genes coding for our human LLPS drivers tend to be dosage-sensitive, suggesting that their cellular availability is tightly regulated to preserve their functional role in direct or indirect relation to condensate formation. Our analysis offers guideposts for increasing agreement between in vitro and in vivo studies, probing the roles of proteins in LLPS.


Assuntos
Dosagem de Genes , Genes , Transição de Fase , Proteínas/química , Bases de Dados Factuais , Humanos , Anotação de Sequência Molecular , Organelas , Proteoma/metabolismo
17.
Salud(i)ciencia (Impresa) ; 24(5): 238-244, mar.-abr. 2021. tab.
Artigo em Espanhol | LILACS, BINACIS | ID: biblio-1283917

RESUMO

Se realizó una revisión narrativa sobre la genética del hipotiroidismo congénito (HC). Se utilizaron las bases de datos Medline/PubMed, LILACS-BIREME y SciELO. Se identificaron los estudios originales publicados entre 2000 y agosto de 2020. Las palabras clave utilizadas durante la búsqueda fueron las siguientes: "hipotiroidismo congénito (congenital hypothyroidism)", "genética (genetic)", "polimorfismos de nucleótido único (SNP) (single polymorphisms nucleotid)". Se revisaron 58 estudios originales que informan las bases moleculares del HC. Se ha definido el concepto básico del HC, así como las bases moleculares que están asociados con la aparición de dicho trastorno. La revisión de la literatura ha permitido identificar al menos 12 genes que codifican las proteínas, las cuales, al producirse mutaciones, están implicadas en el HC. De los 12 genes informados que desempeñan un papel importante en el HC, errores en 6 genes se han vinculado con el HC con disgenesia tiroidea, lo cual implica alteraciones en la morfogénesis de la glándula tiroides, mientras que mutaciones en otros 6 genes se han asociado con dishormonogénesis, que genera un bloqueo total o parcial de los procesos bioquímicos implicados en la síntesis y secreción de hormonas tiroideas. La prevalencia en Sudamérica varía aproximadamente desde 1 por cada 1170 hasta 1 por cada 8285 neonatos. El estudio de la genética molecular pone de manifiesto que, en el futuro, aportará datos importantes en cuanto a la identificación de nuevas mutaciones y asociaciones con fenotipos clínicos que podrían relacionarse con el HC, para, de esta manera, potenciar el diagnóstico y tratamiento


A narrative review was conducted on the genetics of congenital hypothyroidism. The Medline/PubMed, LILACS-BIREME, and SciELO databases were used. Original studies published between 2000 and August 2020 were identified. The keywords used during the search were as follows: "congenital hypothyroidism", "genetics", "polymorphisms SNPs". Fifty-eight original studies reviewing the molecular basis of congenital hypothyroidism were reviewed. The basic concept of congenital hypothyroidism has been defined as well as the molecular bases that are associated with the development of this disorder. The literature review has identified at least 12 genes encoding proteins that, when mutations occur, are involved in congenital hypothyroidism. Of the 12 genes reported to play an important role in congenital hypothyroidism, errors in 6 genes have been associated with congenital hypothyroidism with thyroid dysgenesis, which implies alterations in the morphogenesis of the thyroid gland. On the other hand, mutations in 6 other genes have been associated with dyshormonogenesis that generates a total or partial blockage of the biochemical processes involved in the synthesis and secretion of thyroid hormones. The prevalence in South America is reported to vary from approximately 1 per 1000 to 1 per 8000 newborns. The study of molecular genetics shows that in the future it will contribute to the identification of new mutations and associations with clinical phenotypes that could be related to congenital hypothyroidism, thus enhancing diagnosis and treatment


Assuntos
Terapêutica , Glândula Tireoide , Hormônios Tireóideos , Epidemiologia , Hipotireoidismo Congênito , Genes , Genética , Bases de Dados Bibliográficas
18.
Biochem Biophys Res Commun ; 556: 163-170, 2021 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-33845307

RESUMO

Although efficient methods of gene silencing have been established in eukaryotes, many different techniques are still used in bacteria due to the lack of a standardized tool. Here, we developed a convenient and efficient method to downregulate the expression of a specific gene using ∼140 nucleotide RNA with a 24-nucleotide antisense region from an arabinose-inducible expression plasmid by taking Escherichia coli lacZ and phoA genes encoding ß-galactosidase and alkaline phosphatase, respectively, as target genes to evaluate the model. We examined the antisense RNA (asRNA) design, including targeting position, uORF stability elements at the 5'-end, and Hfq-binding module at the 3'-end, and inducer amount required to obtain effective experimental conditions for gene silencing. Furthermore, we constructed multiplexed dual-acting asRNA genes in the plasmid, which were transcribed as polycistronic RNA and were able to knockdown multiple target genes simultaneously. We observed the highest inhibition level of 98.6% when lacZ was targeted using the pMKN104 asRNA expression plasmid, containing a five times stronger PBAD -10 promoter sequence with no requirement of the Hfq protein for repression. These features allow the system to be utilized as an asRNA expression platform in many bacteria, besides E. coli, for gene regulation.


Assuntos
Escherichia coli/genética , Regulação Bacteriana da Expressão Gênica , Técnicas de Silenciamento de Genes/métodos , Inativação Gênica , Genes/genética , RNA Antissenso/genética , Arabinose/metabolismo , Arabinose/farmacologia , Sequência de Bases , Códon de Iniciação/genética , Escherichia coli/efeitos dos fármacos , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Inativação Gênica/efeitos dos fármacos , Genes/efeitos dos fármacos , Genes Reporter , Plasmídeos/efeitos dos fármacos , Plasmídeos/genética , Regiões Promotoras Genéticas/efeitos dos fármacos , Regiões Promotoras Genéticas/genética , RNA Antissenso/biossíntese
19.
J Mol Biol ; 433(11): 166913, 2021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-33676929

RESUMO

Non-coding RNA (ncRNA) genes assume increasing biological importance, with growing associations with diseases. Many ncRNA sources are transcript-centric, but for non-coding variant analysis and disease decipherment it is essential to transform this information into a comprehensive set of genome-mapped ncRNA genes. We present GeneCaRNA, a new all-inclusive gene-centric ncRNA database within the GeneCards Suite. GeneCaRNA information is integrated from four community-backed data structures: the major transcript database RNAcentral with its 20 encompassed databases, and the ncRNA entries of three major gene resources HGNC, Ensembl and NCBI Gene. GeneCaRNA presents 219,587 ncRNA gene pages, a 7-fold increase from those available in our three gene mining sources. Each ncRNA gene has wide-ranging annotation, mined from >100 worldwide sources, providing a powerful GeneCards-leveraged search. The latter empowers VarElect, our disease-gene interpretation tool, allowing one to systematically decipher ncRNA variants. The combined power of GeneCaRNA with GeneHancer, our regulatory elements database, facilitates wide-ranging scrutiny of the non-coding terra incognita of gene networks and whole genome analyses.


Assuntos
Bases de Dados de Ácidos Nucleicos , Genes , RNA não Traduzido/genética , Software , Redes Reguladoras de Genes , Predisposição Genética para Doença , Humanos
20.
BMC Bioinformatics ; 22(1): 165, 2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33781206

RESUMO

BACKGROUND: Exploring the relationship between disease and gene is of great significance for understanding the pathogenesis of disease and developing corresponding therapeutic measures. The prediction of disease-gene association by computational methods accelerates the process. RESULTS: Many existing methods cannot fully utilize the multi-dimensional biological entity relationship to predict disease-gene association due to multi-source heterogeneous data. This paper proposes FactorHNE, a factor graph-aggregated heterogeneous network embedding method for disease-gene association prediction, which captures a variety of semantic relationships between the heterogeneous nodes by factorization. It produces different semantic factor graphs and effectively aggregates a variety of semantic relationships, by using end-to-end multi-perspectives loss function to optimize model. Then it produces good nodes embedding to prediction disease-gene association. CONCLUSIONS: Experimental verification and analysis show FactorHNE has better performance and scalability than the existing models. It also has good interpretability and can be extended to large-scale biomedical network data analysis.


Assuntos
Doença , Genes , Semântica , Doença/genética , Predisposição Genética para Doença , Humanos
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