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1.
Arq. ciências saúde UNIPAR ; 26(2): 159-174, maio-ago. 2022.
Artículo en Portugués | LILACS | ID: biblio-1372969

RESUMEN

A obesidade é definida pelo excesso de gordura corporal acumulada no tecido adiposo quando o indivíduo atinge valores de IMC igual ou superior a 30 Kg/m2. Constitui um dos principais fatores de risco para várias doenças não transmissíveis (DNTs) como por exemplo, diabetes mellitus tipo 2 (DM2), doenças cardiovasculares, hipertensão arterial, acidente vascular cerebral e até mesmo o câncer. Embora a obesidade esteja diretamente relacionada com o consumo calórico excessivo em relação ao gasto energético diário, sua etiologia pode estar associada aos baixos níveis de atividade física, às alterações neuroendócrinas e aos fatores genéticos. Considerando o componente genético, esta pode ser classificada como sindrômicas e estar associada às alterações cromossômicas estruturais ou numéricas, ou como não sindrômica, quando relacionada, principalmente, com os polimorfismos de nucleotídeos simples (SNPs) em alelos que atuam como herança monogênica, ou ainda com a interação vários genes (poligênica multifatorial). Apesar de existirem muitas etiologias diferentes, normalmente a obesidade é tratada a partir da mesma abordagem, desconsiderando a fisiologia que a desencadeou. Dessa forma, o objetivo do presente trabalho foi abordar a obesidade genética não sindrômica por meio a) da descrição breve de perspectiva histórica sobre seu entendimento; b) da exposição dos principais mecanismos moleculares envolvidos com o controle de peso; c) da compilação dos principais genes e SNPs relacionados; d) da definição dos principais genes; e e) da abordagem das principais perspectivas de intervenção.


Obesity is defined as excess body fat accumulated in the adipose tissue when the individual reaches BMI values equal to or greater than 30 kg/m2. It is one of the main risk factors for several non-communicable diseases (NCDs), such as Type 2 Diabetes mellitus (T2D), cardiovascular diseases, high blood pressure, stroke and even cancer. Although obesity is directly related to excessive calorie intake in relation to daily energy expenditure, its etiology may be associated with low levels of physical activity, neuroendocrine changes, and genetic factors. Considering the genetic component, it can be classified as syndromic and be associated with chromosomal or numerical changes, or as non-syndromic and being related mainly to single nucleotide polymorphisms (SNPs) in alleles that act as monogenic inheritance, or with an interaction of several genes (multifactorial polygenic). Although there are many different etiologies, obesity is usually treated using the same approach, disregarding the physiology that triggered it. Thus, the aim of this study was to address non-syndromic genetic obesity through a) a brief description of a historical perspective on its understanding; b) the exposure of the main molecular mechanisms involved in weight control, c) the compilation of the key genes and related SNPs, d) the definition of the key genes and e) the approach of the main intervention representations.


Asunto(s)
Humanos , Masculino , Femenino , Peso Corporal/genética , Genes/genética , Obesidad/genética , Ejercicio Físico , Índice de Masa Corporal , Expresión Génica/genética , Leptina/genética , Polimorfismo de Nucleótido Simple/genética , Receptor de Melanocortina Tipo 4/genética , Dieta/métodos , Melanocortinas/genética , Receptores de Leptina/genética , Epigenómica , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/metabolismo , Hipotálamo
3.
Genes (Basel) ; 13(1)2022 01 09.
Artículo en Inglés | MEDLINE | ID: mdl-35052457

RESUMEN

Monogenic diabetes is a genetic disorder caused by one or more variations in a single gene. It encompasses a broad spectrum of heterogeneous conditions, including neonatal diabetes, maturity onset diabetes of the young (MODY) and syndromic diabetes, affecting 1-5% of patients with diabetes. Some of these variants are harbored by genes whose altered function can be tackled by specific actions ("actionable genes"). In suspected patients, molecular diagnosis allows the implementation of effective approaches of precision medicine so as to allow individual interventions aimed to prevent, mitigate or delay clinical outcomes. This review will almost exclusively concentrate on the clinical strategy that can be specifically pursued in carriers of mutations in "actionable genes", including ABCC8, KCNJ11, GCK, HNF1A, HNF4A, HNF1B, PPARG, GATA4 and GATA6. For each of them we will provide a short background on what is known about gene function and dysfunction. Then, we will discuss how the identification of their mutations in individuals with this form of diabetes, can be used in daily clinical practice to implement specific monitoring and treatments. We hope this article will help clinical diabetologists carefully consider who of their patients deserves timely genetic testing for monogenic diabetes.


Asunto(s)
Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/genética , Genes , Mutación , Medicina de Precisión , Pruebas Genéticas , Humanos
4.
Reprod Sci ; 29(2): 480-496, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34697776

RESUMEN

Polycystic ovary syndrome (PCOS) is a multifactorial endocrinopathy of indistinguishable etiopathogenesis that is liable to entail genetic and environmental machinery synergistically interacting with its phenotypic expression. It has been hypothesized that the environment secondarily interacts with genes to define the quantifiable phenotype in a primary, genetically determined, hyper-androgenic ovarian defect. The severity and prevalence of the disease are escalating due to uncontrolled diet and lifestyle, the influence of multiple environmental factors as well as genetic disorders. Many candidate genes have been identified to be one of the causes of PCOS. Different studies have been carried out to find the genetic correlation of PCOS. The mutational landscape analysis scans the entire genes for SNPs which usually occurs more frequently in patients and not in healthy individuals. In this study, an extensive computational analysis of all reported nsSNPs of the 27 selected PCOS-related genes was performed to infer the most pathogenic forms associated with PCOS. As a result, 28 genetic variants from 11 genes were predicted to be most harmful. Results of the present study can be useful for building an integrative genotype-phenotype database for further studies.


Asunto(s)
Predisposición Genética a la Enfermedad/genética , Síndrome del Ovario Poliquístico/genética , Simulación por Computador , Femenino , Genes/genética , Pruebas Genéticas , Humanos , Mutación/genética , Polimorfismo de Nucleótido Simple/genética
5.
Reprod Sci ; 29(2): 475-479, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34231177

RESUMEN

Kallmann syndrome (KS) is a rare genetic disorder that is characterized by idiopathic hypogonadotropic hypogonadism associated with anosmia. Genetic variants in ANOS1 gene are the most common mutations associated with X-linked recessive form of KS. Canonical ± 1 or 2 splice site variants in ANOS1 have been described to be responsible for KS. Here, we identified a novel noncanonical splice site variant (c.1062+4T>C) in ANOS1 gene in two siblings with KS by whole-exome sequencing (WES). Sanger sequencing showed this mutation was inherited from their mother, whose brother was a KS patient as well. Through the functional assay in vitro, we found that this mutation resulted in a 50-bp deletion of exon 7, which caused frameshift mutation leading to a premature termination of translation and a truncated anosmin-1 protein. Our results revealed that this noncanonical splice site variant is involved in KS. Thus, it is suggested that we should pay attention to the noncanonical splice site variants when using molecular genetic diagnostics of KS.


Asunto(s)
Proteínas de la Matriz Extracelular/genética , Genes/genética , Síndrome de Kallmann/genética , Proteínas del Tejido Nervioso/genética , Isoformas de Proteínas/genética , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Linaje , Hermanos , Secuenciación del Exoma Completo , Adulto Joven
6.
PLoS Comput Biol ; 17(12): e1009669, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34871311

RESUMEN

There is a growing realization that multi-way chromatin contacts formed in chromosome structures are fundamental units of gene regulation. However, due to the paucity and complexity of such contacts, it is challenging to detect and identify them using experiments. Based on an assumption that chromosome structures can be mapped onto a network of Gaussian polymer, here we derive analytic expressions for n-body contact probabilities (n > 2) among chromatin loci based on pairwise genomic contact frequencies available in Hi-C, and show that multi-way contact probability maps can in principle be extracted from Hi-C. The three-body (triplet) contact probabilities, calculated from our theory, are in good correlation with those from measurements including Tri-C, MC-4C and SPRITE. Maps of multi-way chromatin contacts calculated from our analytic expressions can not only complement experimental measurements, but also can offer better understanding of the related issues, such as cell-line dependent assemblies of multiple genes and enhancers to chromatin hubs, competition between long-range and short-range multi-way contacts, and condensates of multiple CTCF anchors.


Asunto(s)
Cromatina , Mapeo Cromosómico/métodos , Regulación de la Expresión Génica/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Cromatina/química , Cromatina/genética , Cromatina/metabolismo , ADN/química , ADN/metabolismo , Elementos de Facilitación Genéticos/genética , Genes/genética , Genómica , Humanos
7.
Rev. Ciênc. Méd. Biol. (Impr.) ; 20(3): 375-386, dez 20, 2021. tab, fig
Artículo en Portugués | LILACS | ID: biblio-1354189

RESUMEN

Introdução: o sistema RANKL (receptor-ativador do fator nuclear-ligante κB)/RANK (receptor ativador do NF-kB)/OPG (osteoprotegrina) Introdução: o sistema OPG (osteoprotegrina)/RANK (receptor ativador do NF-kB)/RANKL (receptor-ativador do fator nuclear-ligante κB) regula os processos fisiológicos e patológicos da remodelação óssea. Polimorfismos genéticos nos genes OPG, RANK e RANKL têm sido associados a doenças, em diferentes populações. Objetivo: Descrever a frequência e o potencial regulatório dos polimorfismos do sistema OPG, RANK e RANKL em uma população brasileira; avaliar o seu potencial como marcadores genéticos informativos de ancestralidade; comparar com patologias associadas em outras populações. Metodologia: neste estudo, 506 indivíduos adultos, participantes de uma coorte acometidos de asma e periodontite, tiveram o DNA genômico extraído e genotipado, utilizando-se a plataforma Illumina. As plataformas NCBI, RegulomeDB, Haploview 4.2 e rSNPBase foram consultadas e utilizadas para análises. Resultados e Discussão: os polimorfismos mais frequentes na população estudada foram o rs3102724 no gene OPG, com frequência de menor alelo (MAF) de 46%; o rs4941129 em RANK, MAF 50%; e o rs9525641 em RANKL, MAF 46%. Os rs3134063 (1f) em OPG, rs17069898 (1f) em RANK e rs2200287 (1d) em RANKL apresentaram maior impacto funcional. Em OPG e RANK, nove polimorfismos se caracterizaram como marcadores genéticos informativos de ancestralidade, com predomínio nas populações YRI (africanos) e CEU (europeus). Os nove polimorfismos, com função intrônica, apresentaram MAF entre 2 a 46% na população-alvo e foram associados a patologias do metabolismo ósseo em outras populações. Conclusão: polimorfismos dos genes estudados se mostraram frequentes na população estudada e tiveram seus alelos mais frequentes associados a doenças em populações ancestrais. Sugere-se que sejam realizados mais estudos.


Introduction: The OPG (osteoprotegerin)/ RANK (NF-kB activating receptor)/ RANKL (nuclear-binding factor κB receptor-activating system regulates the physiological and pathological processes of bone remodeling. Genetic polymorphisms (SNPs) in OPG, RANK and RANKL genes have been associated with diseases in different populations. Objective: Describe the regulatory frequency and potential of SNPs in OPG, RANK and RANKL in a Brazilian population; assess their potential as informative genetic markers of ancestry; compare with pathologies associated with these polymorphisms in other populations. Methods: in this study, 506 adult individuals, participating in a cohort involving asthma and periodontitis, had genomic DNA extracted and genotyped using the Illumina platform. The NCBI, RegulomeDB, Haploview 4.2 and rSNPBase platforms were consulted and used for analysis. Results and discussion: the most frequent polymorphisms in the studied population were the rs3102724 in the OPG gene, with the lowest allele frequency (MAF) of 46%; rs4941129 in RANK, MAF 50% and rs9525641 in RANKL, MAF 46%. The rs3134063 (1f) in OPG, rs17069898 (1f) in RANK and rs2200287 (1d) in RANKL, had greater functional impact. In OPG and RANK, 9 SNPs were characterized as informative genetic markers of ancestry, predominantly in YRI (African) and CEU (European) populations. These 9 SNPs, with intronic function, presented MAF between 2 and 46% in our population, and were associated with pathologies in bone metabolism in other populations. Conclusion: SNPs of the studied genes were found to be frequent in the studied population and had their most frequent alleles associated with diseases in ancestral populations. It is suggested that further studies be carried out


Asunto(s)
Humanos , Masculino , Femenino , Adulto , Polimorfismo Genético , Ligando RANK , Genes , Periodontitis , Asma , Simulación por Computador
8.
An. Fac. Cienc. Méd. (Asunción) ; 54(3): 33-40, Dec. 2021.
Artículo en Español | LILACS | ID: biblio-1352903

RESUMEN

El estado mutacional del KRAS ha sido considerado como biomarcador para tratamientos biológicos tras varios ensayos clínicos realizados en pacientes con cáncer colorrectal metastásico. Reportes recientes indican que las frecuencias de mutación del gen KRAS en pacientes con CCR de Asia, Europa y Latinoamérica están entre el 24%, 36% y 40%, respectivamente. Paraguay no cuenta con este tipo de informes, a pesar de registrar anualmente en promedio 75 nuevos casos de pacientes diagnosticados con CCR sólo en el Servicio de Cirugía General del Hospital Central del Instituto de Previsión Social (IPS). El presente trabajo ha implementado este análisis de rutina, prerrequisito obligatorio para la administración de fármacos basados en anticuerpos terapéuticos, y revelado una frecuencia de mutación del gen KRAS del 34% en pacientes paraguayos con CCR que acuden a los Servicios del Hospital Central del IPS


The mutational status of the KRAS has been consider as a biomarker for biological treatments after several clinical trials carried out in patient with metastatic colorectal cancer. Recent reports indicate that the KRAS gene mutation frequencies in CRC patients from Asia, Europe, and Latin America are between 24%, 36%, and 40%, respectively. Paraguay does not have this kind of reports, despite registering an average of 75 new cases of patients diagnosed with CRC per year only in the General Surgery Service of the "Central Hospital - Instituto de Prevision Social (IPS)". The present work has implemented this routine analysis, a mandatory prerequisite for the administration of drugs based on therapeutic antibodies and revealed a KRAS gene mutation frequency of 34% in Paraguayan patients with CRC who attend the IPS Central Hospital Services


Asunto(s)
Neoplasias Colorrectales , Mutación , Estudios Transversales , Diagnóstico , Genes
9.
Genome Biol ; 22(1): 338, 2021 12 14.
Artículo en Inglés | MEDLINE | ID: mdl-34906207

RESUMEN

Aggregating transcriptomics data across hospitals can increase sensitivity and robustness of differential expression analyses, yielding deeper clinical insights. As data exchange is often restricted by privacy legislation, meta-analyses are frequently employed to pool local results. However, the accuracy might drop if class labels are inhomogeneously distributed among cohorts. Flimma ( https://exbio.wzw.tum.de/flimma/ ) addresses this issue by implementing the state-of-the-art workflow limma voom in a federated manner, i.e., patient data never leaves its source site. Flimma results are identical to those generated by limma voom on aggregated datasets even in imbalanced scenarios where meta-analysis approaches fail.


Asunto(s)
Expresión Génica , Privacidad , Investigación Biomédica , Redes de Comunicación de Computadores , Seguridad Computacional/legislación & jurisprudencia , Seguridad Computacional/normas , Bases de Datos Factuales/legislación & jurisprudencia , Bases de Datos Factuales/normas , Expresión Génica/ética , Genes , Regulación Gubernamental , Humanos , Aprendizaje Automático
10.
Med Sci Monit ; 27: e933425, 2021 Dec 20.
Artículo en Inglés | MEDLINE | ID: mdl-34928926

RESUMEN

BACKGROUND The aim of this study was to identify feature autophagy-related genes (ARGs) in systemic lupus erythematosus (SLE), evaluate their diagnostic value, and further explore DNA methylation and expression levels in the pathogenesis of SLE. MATERIAL AND METHODS WGCNA was used to construct network and selected hub genes based on gene expression dataset GSE81622. ARGS were overlapped with hub genes, and feature ARGs were identified. A diagnostic model was established by these feature ARGs using LASSO. GSE96879 was used to analyze the methylation levels of feature ARGs. The expression and methylation levels of feature ARGs were verified using RT-PCR and methylation-specific PCR. RESULTS We found that 55 hub genes were highly connected to the red module of WGCNA, and ARGs were extracted from the Human Autophagy Database and the GO_AUTOPHAGY gene set. Overlapping of 55 hub gene with ARGs resulted in 18 feature ARGs. S100A8, MyD88, and NCR3 from the 18 feature ARGs showed higher good diagnostic value for SLE. Five differentially methylated positions locating to S100A8, MyD88, and NCR3 genes were identified from GSE96879. After validation tests, RT-PCR showed that gene expressions of MyD88 and S100A8 were increased in the PBMCs samples of SLE patients compared with healthy controls, whereas NCR3 was the opposite. MSP found that cg24898863 (S100A8) was hypomethylated, while cg27490128 (NCR3) was hypermethylated in the SLE group, and S100A8 and NCR3 methylation were positively correlated with their expressions. CONCLUSIONS Our present study identified the potential roles of feature ARGs in SLE diagnosis, and shows correlation among DNA methylation and gene expressions of these feature ARGs in SLE.


Asunto(s)
Autofagia/genética , Metilación de ADN/genética , Lupus Eritematoso Sistémico/genética , Adulto , Femenino , Genes/genética , Marcadores Genéticos/genética , Predisposición Genética a la Enfermedad/genética , Humanos , Lupus Eritematoso Sistémico/diagnóstico , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos , Reacción en Cadena de la Polimerasa , Factores de Riesgo
11.
Rev. ecuat. pediatr ; 22(3): 1-7, 30 de diciembre del 2021.
Artículo en Español | LILACS | ID: biblio-1352458

RESUMEN

Introducción: El síndrome de Noonan es un trastorno genético de herencia autosómica dominante con una expresión fenotípica variable. Se encuentra dentro de las enfermedades conocidas como rasopatías, producidas por las mutaciones en los genes RAS. Los pacientes se caracterizan por dismorfismo facial, talla baja, enfermedad cardíaca congénita, alteraciones músculos esqueléticas y en algunos casos discapacidad intelectual. Caso clínico: En el presente reporte se describe el caso de un paciente masculino de un mes de edad que acude a consulta externa, presentando dismorfismo facial y estenosis pulmonar, por lo que se realiza un seguimiento multidisciplinario por sospecha de Síndrome de Noonan. A partir del cuarto mes desarrolló linfedema en la zona del deltoides. Evolución: A los 7 meses de vida se realiza secuenciación de exoma, encontrando una variante patogénica en el gen SOS1, confirmando el diagnóstico de dicho síndrome. Conclusión: Este caso documenta la presencia de síndrome de Noonan con mutación del gen SOS1 con dismorfología facial típica, estenosis de la válvula pulmonar, criptorquidia y displasia linfática con linfedema del deltoides, hallazgo no descrito en casos previos.


Introduction: Noonan syndrome is a dominant autosomal inherited ge-netic disorder with variable phenotypic expression. It is found within diseases known as rasopathies and is pro-duced by mutations in RAS genes. Patients are character-ized by facial dysmorphism, short stature, congenital heart disease, musculoskeletal disorders, and, in some cases, intellectual disability. Clinical case: This report describes the case of a one-month-old male patient who comes to the outpatient clinic, presenting with facial dysmorphism and pulmonary steno-sis, for which a multidisciplinary follow-up is carried out due to suspicion of Noonan syndrome. From the fourth month, the patient developed lymphedema in the deltoid area. Evolution: At 7 months of age, exome sequencing was per-formed, finding a pathogenic vari-ant in the SOS1 gene and confirming the diagnosis of this syndrome. Conclusion: This case documents the presence of Noonan syndrome with a mutation of the SOS1 gene with typical facial dysmorphology, pulmonary valve stenosis, cryptor-chidism and lymphatic dysplasia with deltoid.


Asunto(s)
Humanos , Preescolar , Anomalías Craneofaciales , Cardiopatías Congénitas , Síndrome de Noonan , Anomalías Congénitas , Genes
12.
Rev. Ciênc. Méd. Biol. (Impr.) ; 20(3): 480-484, dez 20, 2021. fig
Artículo en Portugués | LILACS | ID: biblio-1354354

RESUMEN

Introdução: o gene TERT codifica a subunidade catalítica da telomerase responsável pelo alongamento dos telômeros no final dos cromossomos. Mutações na região promotora do gene TERT resultam em superexpressão da subunidade catalítica e promovem aumento da atividade da telomerase, fatos que levam ao aumento da incidência do câncer. No carcinoma anaplásico da tireoide, essas mutações são preditores de pior prognóstico e estão associadas a comportamento clínico agressivo, incluindo alta frequência de recidivas, metástases a distância e morte específica pela doença. Objetivo: relatar o caso de uma paciente idosa portadora de carcinoma anaplásico da tireoide, cujo teste de sequenciamento genético revelou a mutação do promotor TERT C228T. Caso clínico: mulher idosa, 66 anos, diagnosticada inicialmente com nódulo tireoidiano, o qual cresceu rapidamente em um curto período de tempo. Diante da suspeita de neoplasia maligna, a paciente foi submetida a tireoidectomia total, com realização de esvaziamento cervical. Os estudos anatomopatológico e imuno-histoquímico do tumor confirmaram o carcinoma. Estudos moleculares realizados a partir da tecnologia do sequenciamento de nova geração negaram a presença de fusões gênicas, porém detectaram a mutação TERT C228T. Discussão: a identificação da mutação no promotor TERT C288T reforça a hipótese de que mutações TERT são frequentes em tumores tireoidianos mais agressivos, como é o caso do carcinoma anaplásico da tireoide. Conclusão: os dados apresentados neste estudo reforçam a premissa de que mutações no promotor TERT são preditores de pior prognóstico e de comportamento clínico mais agressivo.


Introduction: the TERT gene encodes the catalytic telomerase subunit responsible for elongating telomeres at the end of chromosomes. Mutations in the promoter region of the TERT gene result in overexpression of the catalytic subunit and promote increased telomerase activity, facts that lead to an increased incidence of cancer. In anaplastic thyroid carcinoma, these mutations are predictors of worse prognosis and are associated with aggressive clinical behavior, including a high frequency of relapses, distant metastases, and diseasespecific death. Objective: to report the case of an elderly patient with anaplastic thyroid carcinoma, whose gene sequencing test revealed a TERT C228T promoter mutation. Case report: Elderly woman, 66 years old, initially diagnosed with a thyroid nodule, which grew rapidly in a short period of time. Given the suspicion of malignant neoplasm, the patient underwent total thyroidectomy, with neck dissection. The anatomopathological and immunohistochemical studies of the tumor confirmed the carcinoma. Molecular studies performed using next-generation sequencing technology denied the presence of gene fusions, but detected the TERT C228T mutation. Discussion: identification of the mutation in the TERT C288T promoter reinforces the hypothesis that TERT mutations are frequent in more aggressive thyroid tumors, such as anaplastic thyroid carcinoma. Conclusion: data presented in this study reinforce the premise that mutations in the TERT promoter are predictors of worse prognosis and more aggressive clinical behavior.


Asunto(s)
Humanos , Femenino , Anciano , Tiroidectomía , Telomerasa , Carcinoma Anaplásico de Tiroides , Mutación , Genes
13.
Nature ; 599(7886): 684-691, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34789882

RESUMEN

The three-dimensional (3D) structure of chromatin is intrinsically associated with gene regulation and cell function1-3. Methods based on chromatin conformation capture have mapped chromatin structures in neuronal systems such as in vitro differentiated neurons, neurons isolated through fluorescence-activated cell sorting from cortical tissues pooled from different animals and from dissociated whole hippocampi4-6. However, changes in chromatin organization captured by imaging, such as the relocation of Bdnf away from the nuclear periphery after activation7, are invisible with such approaches8. Here we developed immunoGAM, an extension of genome architecture mapping (GAM)2,9, to map 3D chromatin topology genome-wide in specific brain cell types, without tissue disruption, from single animals. GAM is a ligation-free technology that maps genome topology by sequencing the DNA content from thin (about 220 nm) nuclear cryosections. Chromatin interactions are identified from the increased probability of co-segregation of contacting loci across a collection of nuclear slices. ImmunoGAM expands the scope of GAM to enable the selection of specific cell types using low cell numbers (approximately 1,000 cells) within a complex tissue and avoids tissue dissociation2,10. We report cell-type specialized 3D chromatin structures at multiple genomic scales that relate to patterns of gene expression. We discover extensive 'melting' of long genes when they are highly expressed and/or have high chromatin accessibility. The contacts most specific of neuron subtypes contain genes associated with specialized processes, such as addiction and synaptic plasticity, which harbour putative binding sites for neuronal transcription factors within accessible chromatin regions. Moreover, sensory receptor genes are preferentially found in heterochromatic compartments in brain cells, which establish strong contacts across tens of megabases. Our results demonstrate that highly specific chromatin conformations in brain cells are tightly related to gene regulation mechanisms and specialized functions.


Asunto(s)
Encéfalo/citología , Células/clasificación , Ensamble y Desensamble de Cromatina , Cromatina/química , Cromatina/genética , Genes , Conformación Molecular , Animales , Sitios de Unión , Células/metabolismo , Cromatina/metabolismo , Regulación de la Expresión Génica , Masculino , Ratones , Familia de Multigenes/genética , Neuronas/clasificación , Neuronas/metabolismo , Desnaturalización de Ácido Nucleico , Factores de Transcripción/metabolismo
14.
Invest Ophthalmol Vis Sci ; 62(14): 22, 2021 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-34797904

RESUMEN

Purpose: This study interrogated the transcriptional features and immune cellular landscape of the retinae of rats subjected to oxygen-induced retinopathy (OIR). Methods: Bulk RNA sequencing was performed with retinal RNA isolated from control and OIR rats. Gene set enrichment analysis (GSEA) was undertaken to identify gene sets associated with immune responses in retinal neovascularization. Bulk gene expression deconvolution analysis by CIBERSORTx was performed to identify immune cell types involved in retinal neovascularization, followed by functional enrichment analysis of differentially expressed genes (DEGs). Protein-protein interaction analysis was performed to predict the hub genes relevant to identified immune cell types. CIBERSORTx was applied to profile immune cell types in the macula of patients with both proliferative diabetic retinopathy (PDR) and diabetic macular edema using a public RNA-seq dataset. Results: Transcriptome analysis by GSEA revealed that the retina of OIR rats and patients with PDR is characterized by increased immunoregulatory interactions and complement cascade. Deconvolution analysis demonstrated that M2 macrophages infiltrate the retinae of OIR rats and patients with PDR. Functional enrichment analysis of DEGs in OIR rats showed that the dysregulated genes are related to leukocyte-mediated immunity and myeloid leukocyte activation. Downstream protein-protein interaction analysis revealed that several potential hub genes, including Ccl2, Itgam, and Tlr2, contribute to M2 macrophage infiltration in the ischemic retina. Conclusions: This study highlights application of the gene expression deconvolution tool to identify immune cell types in inflammatory ocular diseases with transcriptomes, providing a new approach to assess changes in immune cell types in diseased ocular tissues.


Asunto(s)
Retinopatía Diabética/inmunología , Regulación de la Expresión Génica/fisiología , Macrófagos/inmunología , Edema Macular/inmunología , Neovascularización Retiniana/inmunología , Animales , Retinopatía Diabética/genética , Modelos Animales de Enfermedad , Femenino , Perfilación de la Expresión Génica , Genes , Edema Macular/genética , Oxígeno/toxicidad , Embarazo , Mapas de Interacción de Proteínas , Ratas , Ratas Sprague-Dawley , Neovascularización Retiniana/genética , Transcriptoma
15.
Nat Methods ; 18(11): 1322-1332, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34725481

RESUMEN

Long-read sequencing has the potential to transform variant detection by reaching currently difficult-to-map regions and routinely linking together adjacent variations to enable read-based phasing. Third-generation nanopore sequence data have demonstrated a long read length, but current interpretation methods for their novel pore-based signal have unique error profiles, making accurate analysis challenging. Here, we introduce a haplotype-aware variant calling pipeline, PEPPER-Margin-DeepVariant, that produces state-of-the-art variant calling results with nanopore data. We show that our nanopore-based method outperforms the short-read-based single-nucleotide-variant identification method at the whole-genome scale and produces high-quality single-nucleotide variants in segmental duplications and low-mappability regions where short-read-based genotyping fails. We show that our pipeline can provide highly contiguous phase blocks across the genome with nanopore reads, contiguously spanning between 85% and 92% of annotated genes across six samples. We also extend PEPPER-Margin-DeepVariant to PacBio HiFi data, providing an efficient solution with superior performance over the current WhatsHap-DeepVariant standard. Finally, we demonstrate de novo assembly polishing methods that use nanopore and PacBio HiFi reads to produce diploid assemblies with high accuracy (Q35+ nanopore-polished and Q40+ PacBio HiFi-polished).


Asunto(s)
Genes , Haplotipos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Nanoporos , Polimorfismo de Nucleótido Simple , Análisis de Secuencia de ADN/métodos , Programas Informáticos , Genoma Humano , Humanos , Anotación de Secuencia Molecular
16.
Clin Appl Thromb Hemost ; 27: 10760296211059813, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34786962

RESUMEN

The pathogenesis of chronic refractory immune thrombocytopenia (C/RITP) is mechanistically complex and considerably varies across patients. Few studies have focused on the genetic characteristics of C/RITP in children. The aim of this study was to analyze and summarize the clinical manifestations and genetic characteristics of C/RITP children with mutations in immune-related genes. In the study, 51 children with variants in immune-related genes (mutation group) and 103 children with no abnormal mutations (control group) were enrolled. Children in the mutation group showed severity of hemorrhage, a higher incidence of abnormal immunological indices, and an increased expression of SLE biomarkers. The number of peripheral T and B lymphocytes in the mutation group significantly increased. Nine patients (17.6%) had probable pathogenic variant genes associated with primary immunodeficiencies (TNFRSF13B, CARD11, CBL, and RAG2), and 42 patients (82.4%) had variants of uncertain significance in 23 genes. C/RITP patients with variants in immune-related genes had more severe bleeding, abnormal immunological indices, and an increased expression of SLE biomarker. Next-generation sequenciong (NGS) might be a useful way to differentiate those patients from C/RITP.


Asunto(s)
Genes/inmunología , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Púrpura Trombocitopénica Idiopática/inmunología , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Estudios Retrospectivos
17.
Arq. bras. cardiol ; 117(5 supl. 1): 96-96, nov., 2021. ilus.
Artículo en Portugués | Sec. Est. Saúde SP, CONASS, SESSP-IDPCPROD, Sec. Est. Saúde SP | ID: biblio-1348628

RESUMEN

INTRODUÇÃO: Doença de Fabry (DF) é uma patologia rara de depósito lisossomal causada por mutação do gene GALA na região Xq22.1 do cromossomo X que codifica a enzima α-galactosidase A (α-GAL). Trata-se de um erro inato do metabolismo que causa acúmulo progressivo de glicoesfingolipídeos não clivados principalmente em locais como pele, rins, coração, sistema nervoso, endotélio vascular e olhos. Descrevemos o caso de um paciente com a forma clássica da doença com investigação genética da família negativa. RELATO DE CASO: masculino, 22 anos, aos 8 anos de idade apresentou quadro de dores em queimação e pontada em região de metatarso bilateral, com intensidade 6/10 pela escala visual analógica (EVA), associado a acroparestesia, que surgia ao praticar exercícios físicos, e hipoidrose generalizada. Aos 10 anos de idade, as dores também acometiam as mãos, com intensidade maior (EVA 8/10), desencadeadas por febre, ansiedade e exposição ao calor. Nesse mesmo período, passaram a ocorrer crises episódicas de dores excruciantes, intensidade EVA 10/10, juntamente com acroparestesia intensificada, fadiga extrema, sensação de hipertermia em região abdominal, torácica e cervical, e extremidades frias, com duração de horas a dias. Aos 15 anos, apresentou alterações do hábito intestinal e angioqueratomas difusos na cintura pélvica, com progressão lenta para mãos, braços, tronco, costas, joelhos e mucosa oral. Seu diagnóstico só foi confirmado aos 22 anos de idade, com a atividade de α-GAL de 0 mcmol/L/h e presença de variante patogênica no gene GLA, c.334C>T. Mãe e única irmã do paciente não apresentaram esta variante. ECG, ECOTT e RNM de coração não evidenciaram alterações. CONCLUSÃO: Em todas as doenças raras, o diagnóstico tardio é a regra, pelo desconhecimento da doença. No caso relatado, apesar do diagnóstico ter sido feito após 14 anos do início dos sintomas, ainda não estavam presentes complicações bem estabelecidas, como comprometimento cardíaco e renal, favorecendo o sucesso do tratamento de reposição enzimática. A ausência da mesma variante patogênica em sua mãe faz o diagnóstico de uma mutação primária "de novo".


Asunto(s)
Glicoesfingolípidos , Enfermedad de Fabry , Genes , Mutación
18.
Am J Hum Genet ; 108(10): 1813-1816, 2021 10 07.
Artículo en Inglés | MEDLINE | ID: mdl-34626580

RESUMEN

The use of approved nomenclature in publications is vital to enable effective scientific communication and is particularly crucial when discussing genes of clinical relevance. Here, we discuss several examples of cases where the failure of researchers to use a HUGO Gene Nomenclature Committee (HGNC)-approved symbol in publications has led to confusion between unrelated human genes in the literature. We also inform authors of the steps they can take to ensure that they use approved nomenclature in their manuscripts and discuss how referencing HGNC IDs can remove ambiguity when referring to genes that have previously been published with confusing alias symbols.


Asunto(s)
Bases de Datos Genéticas/normas , Genes/genética , Genoma Humano , Investigadores/normas , Terminología como Asunto , Genómica , Humanos
19.
Neurotoxicology ; 87: 182-187, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34624384

RESUMEN

Multiple sclerosis (MS) is a chronic inflammatory disease with demyelinated lesions in the central nervous system caused by genetic and environmental factors. DNA methylation as an epigenetic change influenced by environmental factors, including heavy metals has been implemented in MS disease. We investigated the correlation of DNA methylation changes in APOE and ACKR3 genes in MS patients and the possible association with blood concentration of arsenic (As), cadmium (Cd) and lead (Pb) as major heavy metal pollutants. This study included 69 relapsing-remitting multiple sclerosis (RR-MS) patients and 69 age/gender-matched healthy subjects. The HRM real-time PCR method was used to investigate the changes in DNA methylation and heavy metal concentrations were measured by electrothermal atomic absorption spectrometry. Our results showed that the methylation pattern in the ACKR3 gene of the patient group was more hypomethylated, while in the case of the APOE gene, this pattern was more towards hypermethylation compared to healthy subjects. Moreover, the blood levels of As and Cd metals, but not Pb, were significantly higher in the patient group compare to the control group (p ≤ 0.05). The data indicate that the increase in expression of ACKR3 gene by hypomethylation and the decrease in expression of APOE gene via hypermethylation are possibly involved in the onset and progression of inflammatory processes in MS patients. The level of As can also lead to hypomethylation by disrupting the methylation patterns of the ACKR3 gene, resulting in increased expression in MS patients. Finally, we have shown that epigenetic changes can be an important factor in increasing and decreasing the expression of genes involved in the onset and/or progression of inflammatory processes in MS. Furthermore, exposure to heavy metals, especially As, by changing the natural patterns of DNA methylation can be effective in this disease.


Asunto(s)
Apolipoproteínas E/genética , Metilación de ADN/efectos de los fármacos , Metales Pesados/toxicidad , Esclerosis Múltiple Recurrente-Remitente/genética , Receptores CXCR/genética , Adulto , Arsénico/sangre , Arsénico/toxicidad , Cadmio/sangre , Cadmio/toxicidad , Estudios de Casos y Controles , Femenino , Genes/genética , Humanos , Masculino , Metales Pesados/sangre , Esclerosis Múltiple Recurrente-Remitente/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa
20.
Infect Genet Evol ; 96: 105098, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34610433

RESUMEN

INTRODUCTION: Growing evidence documented the critical impacts of vitamin D (VD) in the prognosis of COVID-19 patients. The functions of VD are dependent on the vitamin D receptor (VDR) in the VD/VDR signaling pathway. Therefore, we aimed to assess the association of VDR gene polymorphisms with COVID-19 outcomes. METHODS: In the present study, eight VDR single nucleotide polymorphisms (SNPs) were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 500 COVID-19 patients in Iran, including 160 asymptomatic, 250 mild/moderate, and 90 severe/critical cases. The association of these polymorphisms with severity, clinical outcomes, and comorbidities were evaluated through the calculation of the Odds ratio (OR). RESULTS: Interestingly, significant associations were disclosed for some of the SNP-related alleles and/or genotypes in one or more genetic models with different clinical data in COVID-19 patients. Significant association of VDR-SNPs with signs, symptoms, and comorbidities was as follows: ApaI with shortness of breath (P ˂ 0.001) and asthma (P = 0.034) in severe/critical patients (group III); BsmI with chronic renal disease (P = 0.010) in mild/moderate patients (group II); Tru9I with vomiting (P = 0.031), shortness of breath (P = 0.04), and hypertension (P = 0.030); FokI with fever and hypertension (P = 0.027) in severe/critical patients (group III); CDX2 with shortness of breath (P = 0.022), hypertension (P = 0.036), and diabetes (P = 0.042) in severe/critical patients (group III); EcoRV with diabetes (P ˂ 0.001 and P = 0.045 in mild/moderate patients (group II) and severe/critical patients (group III), respectively). However, the association of VDR TaqI and BglI polymorphisms with clinical symptoms and comorbidities in COVID-19 patients was not significant. CONCLUSION: VDR gene polymorphisms might play critical roles in the vulnerability to infection and severity of COVID-19, probably by altering the risk of comorbidities. However, these results require further validation in larger studies with different ethnicities and geographical regions.


Asunto(s)
COVID-19/etiología , Polimorfismo de Longitud del Fragmento de Restricción , Polimorfismo de Nucleótido Simple , Receptores de Calcitriol/genética , Adulto , Anciano , COVID-19/epidemiología , Comorbilidad , Diabetes Mellitus/epidemiología , Femenino , Genes , Predisposición Genética a la Enfermedad , Humanos , Hipertensión/epidemiología , Irán/epidemiología , Masculino , Persona de Mediana Edad , Insuficiencia Renal Crónica/epidemiología , Índice de Severidad de la Enfermedad
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