RESUMEN
Assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) generates genome-wide chromatin accessibility profiles, providing valuable insights into epigenetic gene regulation at both pooled-cell and single-cell population levels. Comprehensive analysis of ATAC-seq data involves the use of various interdependent programs. Learning the correct sequence of steps needed to process the data can represent a major hurdle. Selecting appropriate parameters at each stage, including pre-analysis, core analysis, and advanced downstream analysis, is important to ensure accurate analysis and interpretation of ATAC-seq data. Additionally, obtaining and working within a limited computational environment presents a significant challenge to non-bioinformatic researchers. Therefore, we present Cloud ATAC, an open-source, cloud-based interactive framework with a scalable, flexible, and streamlined analysis framework based on the best practices approach for pooled-cell and single-cell ATAC-seq data. These frameworks use on-demand computational power and memory, scalability, and a secure and compliant environment provided by the Google Cloud. Additionally, we leverage Jupyter Notebook's interactive computing platform that combines live code, tutorials, narrative text, flashcards, quizzes, and custom visualizations to enhance learning and analysis. Further, leveraging GPU instances has significantly improved the run-time of the single-cell framework. The source codes and data are publicly available through NIH Cloud lab https://github.com/NIGMS/ATAC-Seq-and-Single-Cell-ATAC-Seq-Analysis. This manuscript describes the development of a resource module that is part of a learning platform named ``NIGMS Sandbox for Cloud-based Learning'' https://github.com/NIGMS/NIGMS-Sandbox. The overall genesis of the Sandbox is described in the editorial NIGMS Sandbox [1] at the beginning of this Supplement. This module delivers learning materials on the analysis of bulk and single-cell ATAC-seq data in an interactive format that uses appropriate cloud resources for data access and analyses.
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Nube Computacional , Secuenciación de Nucleótidos de Alto Rendimiento , Programas Informáticos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Biología Computacional/métodos , Secuenciación de Inmunoprecipitación de Cromatina/métodos , Análisis de la Célula Individual/métodos , Cromatina/genética , Cromatina/metabolismoRESUMEN
BACKGROUND & OBJECTIVES: Aneuploids are the most common chromosomal abnormality in liveborns and are usually the result of non-disjunction (NDJ) in meiosis. Copy number variations (CNVs) are large structural variations affecting the human genome. CNVs influence critical genes involved in causing NDJ by altering their copy number which affects the clinical outcome. In this study influence of CNVs on critical meiotic recombination was examined using new computational technologies to assess their role in causing aneuploidy. METHODS: This investigation was based on the analysis of 12 random normal populations consisting of 1714 individuals for aneuploid causing genes under CNV effect. To examine the effect of CNVs on genes causing aneuploidy, meiotic recombination genes were analyzed using EnrichR, WebGestalt and Ingenuity Pathway Analysis (IPA). RESULTS: Forty three NDJ genes were found under CNV burden; IPA (Ingenuity Pathway Analysis) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis of CNV in meiotic recombination genes revealed a significant role of breast cancer gene 1, amyloid protein precursor, mitogen-activated protein kinase and nerve growth factor as key molecular players involved in causing aneuploidy. Interaction between these genes with other CNV-overlapping genes involved in cell cycle, recombination and meiosis might lead to increased incidences of aneuploidy. INTERPRETATION & CONCLUSIONS: The findings of this study implied that the effect of CNVs on normal genome contributed in amplifying the occurrences of chromosomal aneuploidies. The normal individuals consisting of variations in the susceptible genes causing aneuploids in the population remain undetected until the disorder genes express in the succeeding generations.
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Biomarcadores , Variaciones en el Número de Copia de ADN/genética , Meiosis/genética , Recombinación Genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Aneuploidia , Femenino , Genoma Humano , Humanos , India , Masculino , Persona de Mediana EdadRESUMEN
Global patterns of copy number variations (CNVs) in chromosomes are required to understand the dynamics of genome organization and complexity. For this study, analysis was performed using the Affymetrix Genome-Wide Human SNP Array 6.0 chip and CytoScan High-Density arrays. We identified a total of 44 109 CNVs from 1715 genomes with a mean of 25 CNVs in an individual, which established the first drafts of population-specific CNV maps providing a rationale for prioritizing chromosomal regions. About 19 905 ancient CNVs were identified across all chromosomes and populations at varying frequencies. CNV count, and sometimes CNV size, contributed to the bulk CNV size of the chromosome. Population specific lengthening and shortening of chromosomal length was observed. Sex bias for CNV presence was largely dependent on ethnicity. Lower CNV inheritance rate was observed for India, compared to YRI and CEU. A total of 33 candidate CNV hotspots from 5382 copy number (CN) variable region (CNVR) clusters were identified. Population specific CNV distribution patterns in p and q arms disturbed the assumption that CNV counts in the p arm are less common compared to long arms, and the CNV occurrence and distribution in chromosomes is length independent. This study unraveled the force of independent evolutionary dynamics on genome organization and complexity across chromosomes and populations.
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Variaciones en el Número de Copia de ADN , Genoma Humano/genética , Estudio de Asociación del Genoma Completo/métodos , Polimorfismo de Nucleótido Simple , Adolescente , Adulto , Anciano , Algoritmos , Mapeo Cromosómico/métodos , Biología Computacional/métodos , Femenino , Frecuencia de los Genes , Genética de Población/métodos , Técnicas de Genotipaje/métodos , Salud Global , Humanos , Patrón de Herencia , Masculino , Persona de Mediana Edad , Mutación , Reacción en Cadena de la Polimerasa , Adulto JovenRESUMEN
Summary Van der Woude syndrome (VWS) is an autosomal dominant developmental malformation presenting with bilateral lower lip pits related to cleft lip, cleft palate and other malformations. We performed a whole-genome copy number variations (CNVs) scan in an Indian family with members suffering from VWS using 2·6 million combined SNP and CNV markers. We found CNVs affecting IRF6, a known candidate gene for VWS, in all three cases, while none of the non-VWS members showed any CNVs in the IRF6 region. The duplications and deletions of the chromosomal critical region in 1q32-q41 confirm the involvement of CNVs in IRF6 in South Indian VWS patients. Molecular network analysis of these and other cleft lip/palate related module genes suggests that they are associated with cytokine-mediated signalling pathways and response to interferon-gamma mediated signalling pathways. This is a maiden study indicating the involvement of CNVs in IRF6 in causing VWS in the Indian population.
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Anomalías Múltiples/genética , Aberraciones Cromosómicas , Cromosomas Humanos Par 1/genética , Labio Leporino/genética , Fisura del Paladar/genética , Quistes/genética , Dosificación de Gen/genética , Factores Reguladores del Interferón/genética , Labio/anomalías , Citocinas/metabolismo , Genotipo , Humanos , India , Polimorfismo de Nucleótido Simple/genética , Transducción de Señal/genéticaRESUMEN
Copy number variations (CNVs) alter the transcriptional and translational levels of genes by disrupting the coding structure and this burden of CNVs seems to be a significant contributor to phenotypic variations. Therefore it was necessary to assess the complexities of CNV burden on the coding genome. A total of 1715 individuals from 12 populations were used for CNV analysis in the present investigation. Analysis was performed using Affymetrix Genome-Wide Human SNP Array 6·0 chip and CytoScan High-Density arrays. CNVs were more frequently observed in the coding region than in the non-coding region. CNVs were observed vastly more frequently in the coding region than the non-coding region. CNVs were found to be enriched in the regions containing functional genes (83-96%) compared with the regions containing pseudogenes (4-17%). CNVs across the genome of an individual showed multiple hits across many genes, whose proteins interact physically and function under the same pathway. We identified varying numbers of proteins and degrees of interactions within protein complexes of single individual genomes. This study represents the first draft of a population-specific CNV genes map as well as a cross-populational map. The complex relationship of CNVs on genes and their physically interacting partners unravels many complexities involved in phenotype expression. This study identifies four mechanisms contributing to the complexities caused by the presence of multiple CNVs across many genes in the coding part of the genome.
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Variaciones en el Número de Copia de ADN/genética , Genes/genética , Genoma Humano/genética , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Fenotipo , Mapeo Cromosómico/métodos , Humanos , Polimorfismo de Nucleótido Simple/genética , Mapeo de Interacción de ProteínasRESUMEN
BACKGROUND: Asthma is a complex disease caused by gene-gene, gene-protein, and protein-protein interactions and the influence of environment, which plays a significant role in causing asthma pathogenesis. ADAM33 is known to be an important gene involved in asthma pathogenesis. No one single gene is a causal factor of asthma; rather, asthma is caused by a complex interaction of multiple genes having pathogenetic and protective effects. OBJECTIVE: To identify and understand the interacting genes and proteins of ADAM33. METHODS: The Ingenuity Pathway Analysis and GeneMANIA tools and a literature survey were used to identify the interacting candidates of ADAM33 and the WEB-based GEne SeT AnaLysis Toolkit was used to perform enrichment analysis of the proteins identified. RESULTS: Keeping ADAM33 as a major hub, the authors identified some proteins whose interaction with ADAM33 had been associated with asthma and they recognized some proteins, such as amyloid ß (A4) precursor protein, ataxin-7, α4-integrin, α5-integrin, α9-integrin, tissue inhibitor of metalloproteinase-4, and ubiquilin-4, that had not been previously associated with asthma. CONCLUSION: The proteins identified in this study were enriched for various mechanisms that are involved in airway hyperresponsiveness, and through the interaction with ADAM33, they may have potential relevance in asthma.
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Proteínas ADAM/metabolismo , Asma/metabolismo , Hiperreactividad Bronquial/patología , Matriz Extracelular/metabolismo , Redes y Vías Metabólicas , Proteínas ADAM/genética , Asma/genética , Hiperreactividad Bronquial/genética , Células Epiteliales/metabolismo , Fibroblastos/metabolismo , Humanos , Interleucina-13/genética , Interleucina-4/genética , MicroARNs/genética , Miocitos del Músculo Liso/metabolismo , Estructura Terciaria de Proteína , Inhibidores Tisulares de Metaloproteinasas/genéticaRESUMEN
BACKGROUND: Many studies have been conducted to identify either insertions-deletions (inDels) or copy number variations (CNVs) in humans, but few studies have been conducted to identify both of these forms coexisting in the same region. AIMS AND OBJECTIVES: To map the functionally significant sites within human genes that are likely to influence human traits and diseases. MATERIALS AND METHODS: In this report, we describe an inDel map in the 1051 Tibetan CNV regions obtained through CNV genotyping using Affymetrix Genome-wide single nucleotide polymorphism 6.0 chip. InDel polymorphisms in these copy number polymorphism regions were identified with a computational approach using the 2500 deoxyribonucleic acid sequences obtained from the 1000 Genome Project. RESULTS: The study identified a total of 95935 inDels that range from 1 bp to several bps in length which were found scattered across regulatory regions, exons and in introns of genes underlying the CNVs. A study on the distribution of inDels revealed that the majority of inDels were found in coding regions of the genome than the noncoding, while within the genes, inDels in intron regions were more followed by exonic regions and finally the regulatory regions. CONCLUSION: Study of inDels in CNV regions contribute to the enhanced understanding of the role played by the two variations and their collective influence on the genome. Further, a collection of these inDel genetic markers will aid in genetic mapping, further understanding of the phenotypic variability, identification of disease genes and in detecting novel CNVs.
RESUMEN
Developmental dyslexia (DD) is a complex heritable disorder with unexpected difficulty in learning to read and spell despite adequate intelligence, education, environment, and normal senses. We performed genome-wide screening for copy number variations (CNVs) in 10 large Indian dyslexic families using Affymetrix Genome-Wide Human SNP Array 6.0. Results revealed the complex genomic rearrangements due to one non-contiguous deletion and five contiguous micro duplications and micro deletions at 17q21.31 region in three dyslexic families. CNVs in this region harbor the genes KIAA1267, LRRC37A, ARL17A/B, NSFP1, and NSF. The CNVs in case 1 and case 2 at this locus were found to be in homozygous state and case 3 was a de novo CNV. These CNVs were found with at least one CNV having a common break and end points in the parents. This cluster of genes containing NSF is implicated in learning, cognition, and memory, though not formally associated with dyslexia. Molecular network analysis of these and other dyslexia related module genes suggests NSF and other genes to be associated with cellular/vesicular membrane fusion and synaptic transmission. Thus, we suggest that NSF in this cluster would be the nearest gene responsible for the learning disability phenotype.
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Cromosomas Humanos Par 17/genética , Variaciones en el Número de Copia de ADN/genética , Dislexia/genética , Reordenamiento Génico , Predisposición Genética a la Enfermedad , Genoma Humano , Adolescente , Adulto , Estudios de Casos y Controles , Niño , Hibridación Genómica Comparativa , Familia , Femenino , Estudios de Seguimiento , Humanos , Masculino , Fenotipo , Pronóstico , Adulto JovenRESUMEN
A 3.5-Mb region of the X chromosome underwent duplication and transposition to the Y chromosome ~5-6 Mya. This X-transposed-region (XTR) originated at Xq21.3 and was inserted at Yp11.2. The two locations have 98.78 % homology and a high concentration of tandem repeats. In whole-genome scans of ten large families with dyslexic members, we identified transposed blocks comprising >102 kb of the Yp11.2 region in its homologous region at Xq21.3 in three females from three different families. Although recombination is known to be limited only to the pseudoautosomal regions (PARs) of the X and Y chromosomes, we report allelic unequal recombination between the XTR region Yp11.2 and Xq21.3, indicating the presence of a new PAR, which we named PAR3. This PAR3 region was also found in 2 % of the general population. An additional layer of justification could be provided from six other dyslexic cases which harbored duplications and deletions in the same Xq21.3 and Yp11.2 regions through allelic unequal recombination.
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Cromosomas Humanos X/genética , Cromosomas Humanos Y/genética , Variaciones en el Número de Copia de ADN/genética , Evolución Molecular , Dislexia/genética , Dislexia/fisiopatología , Femenino , Genes Ligados a X , Humanos , LinajeRESUMEN
Genome-wide screening for copy number variations (CNVs) in ten Indian dyslexic families revealed the presence of five de novo CNVs in regions harboring GABARAP, NEGR1, ACCN1, DCDC5, and one in already known candidate gene CNTNAP2. These genes are located on regions of chromosomes 17p13.1, 1p31.1, 17q11.21, 11p14.1 and 7q35, respectively, and are implicated in learning, cognition and memory processes through dendritic spinal plasticity, though not formally associated with dyslexia. Molecular network analysis of these and other dyslexia-related module genes suggests them to be associated with synaptic transmission, axon guidance and cell adhesion. Thus, we suggest that dyslexia may also be caused by neuronal disconnection in addition to the earlier view that it is due to neuronal migrational disorder.
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Variaciones en el Número de Copia de ADN/genética , Espinas Dendríticas/metabolismo , Dislexia/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Plasticidad Neuronal/genética , Adolescente , Niño , Rotura Cromosómica , Familia , Femenino , Ontología de Genes , Humanos , Masculino , Pruebas Neuropsicológicas , Fenotipo , Polimorfismo Genético , Mapas de Interacción de Proteínas/genética , Reproducibilidad de los Resultados , Transducción de Señal/genética , Adulto JovenRESUMEN
PURPOSE: Congenital hereditary endothelial dystrophy 2 (CHED2) is an autosomal recessive disorder caused by mutations in the solute carrier family 4, sodium borate transporter, member 11 (SLC4A11) gene. The purpose of this study was to identify the genetic cause of CHED2 in six Indian families and catalog all known mutations in the SLC4A11 gene. METHODS: Peripheral blood samples were collected from individuals of the families with CHED2 and used in genomic DNA isolation. PCR primers were used to amplify the entire coding region including intron-exon junctions of SLC4A11. Amplicons were subsequently sequenced to identify the mutations. RESULTS: DNA sequence analysis of the six families identified four novel (viz., p.Thr262Ile, p.Gly417Arg, p.Cys611Arg, and p.His724Asp) mutations and one known p.Arg869His homozygous mutation in the SLC4A11 gene. The mutation p.Gly417Arg was identified in two families. CONCLUSIONS: This study increases the mutation spectrum of the SLC4A11 gene. A review of the literature showed that the total number of mutations in the SLC4A11 gene described to date is 78. Most of the mutations are missense, followed by insertions-deletions. The present study will be helpful in genetic diagnosis of the families reported here.
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Proteínas de Transporte de Anión/genética , Antiportadores/genética , Distrofias Hereditarias de la Córnea/genética , Secuencia de Aminoácidos , Secuencia de Bases , Niño , Preescolar , Simulación por Computador , Secuencia Conservada/genética , Análisis Mutacional de ADN , Familia , Femenino , Humanos , India , Masculino , Datos de Secuencia Molecular , MutaciónRESUMEN
Developmental dyslexia (DD) is a complex heritable disorder with unexpected difficulty in learning to read and spell despite adequate intelligence, education, environment, and normal senses. We performed a whole genome copy number variations (CNV) scan on 11 dyslexic families consisting of 14 dyslexic subjects and 24 non dyslexic members using 1.8 million combined SNP and CNV markers. We found CNVs affecting protocadherin genes in six dyslexics from three families, while none among the non-dyslexic control members showed any CNV in protocadherins. We identified duplications in five cases and a deletion in one case in Xq21.3 region bearing PCDH11X. Unequal recombination between the X-transposed region (XTR) of Yp11.2 and the X chromosome might be causing these structural changes. PCDH11X, expressed in brain is implicated in cell-cell communication, verbal ability, cerebral asymmetry, and dendritic synaptic plasticity, may be regarded as a new candidate gene for dyslexia.
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Cadherinas/genética , Variaciones en el Número de Copia de ADN/genética , Dislexia/genética , Predisposición Genética a la Enfermedad , Genoma Humano/genética , Mutación/genética , Regiones no Traducidas 3'/genética , Regiones no Traducidas 5'/genética , Adolescente , Anciano , Rotura Cromosómica , Deleción Cromosómica , Duplicación Cromosómica/genética , Familia , Femenino , Humanos , India , Masculino , Modelos Genéticos , Linaje , Protocadherinas , Reproducibilidad de los Resultados , Adulto JovenRESUMEN
Keratoconus is a progressive thinning, steepening and distortion of the cornea which can lead to loss of vision if left untreated. Keratoconus has a complex multifactorial etiology, with genetic and environmental components contributing to the disease pathophysiology. Studies have observed high concordance between monozygotic twins, discordance between dizygotic twins, and high familial segregation indicating the presence of a very strong genetic component in the pathogenesis of keratoconus. The use of genome-wide linkage studies on families and twins, genome-wide association studies (GWAS) on case-controls, next-generation sequencing (NGS)-based genomic screens on both familial and non-familial cohorts have led to the identification of keratoconus candidate genes with much greater success and increased resproducibility of genetic findings. This review focuses on candidate genes identified till date and attempts to understand their role in biological processes underlying keratoconus pathogenesis. In addition, using these genes I propose molecular pathways that could contribute to keratoconus pathogenesis. The pathways identified the presence of direct cross-talk between known candidate genes of keratoconus and remarkably, 28 known candidate genes have a direct relationship among themselves that involves direct protein-protein binding, regulatory activities such as activation and inhibition, chaperone, transcriptional activation/co-activation, and enzyme catalysis. This review attempts to describe these relationships and cross-talks in the context of keratoconus pathogenesis.
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Marcadores Genéticos , Genómica/métodos , Queratocono/genética , Queratocono/patología , Secuenciación de Nucleótidos de Alto Rendimiento , HumanosRESUMEN
Ventricular Septal Defect (VSD), the most common congenital heart defect, is characterized by a hole in the septum between the right and left ventricles. The pathogenesis of VSD is unknown in most clinical cases. There is a paucity of data relevant to epigenetic changes in VSD. The placenta is a fetal tissue crucial in cardiac development and a potentially useful surrogate for evaluating the development of heart tissue. To understand epigenetic mechanisms that may play a role in the development of VSD, genome-wide DNA methylation assay on placentas of 8 term subjects with isolated VSD and no known or suspected genetic syndromes and 10 unaffected controls was performed using the Illumina HumanMethylation450 BeadChip assay. We identified a total of 80 highly accurate potential CpGs in 80 genes for detection of VSD; area under the receiver operating characteristic curve (AUC ROC) 1.0 with significant 95% CI (FDR) p-values < 0.05 for each individual locus. The biological processes and functions for many of these differentially methylated genes are previously known to be associated with heart development or disease, including cardiac ventricle development (HEY2, ISL1), heart looping (SRF), cardiac muscle cell differentiation (ACTC1, HEY2), cardiac septum development (ISL1), heart morphogenesis (SRF, HEY2, ISL1, HEYL), Notch signaling pathway (HEY2, HEYL), cardiac chamber development (ISL1), and cardiac muscle tissue development (ACTC1, ISL1). In addition, we identified 8 microRNAs that have the potential to be biomarkers for the detection of VSD including: miR-191, miR-548F1, miR-148A, miR-423, miR-92B, miR-611, miR-2110, and miR-548H4. To our knowledge this is the first report in which placental analysis has been used for determining the pathogenesis of and predicting VSD.
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Epigénesis Genética , Defectos del Tabique Interventricular/genética , Placenta/metabolismo , Estudios de Casos y Controles , Islas de CpG , Metilación de ADN/genética , Femenino , Corazón Fetal/anomalías , Corazón Fetal/embriología , Corazón Fetal/metabolismo , Marcadores Genéticos , Defectos del Tabique Interventricular/embriología , Defectos del Tabique Interventricular/etiología , Humanos , Recién Nacido , Masculino , MicroARNs/genética , EmbarazoRESUMEN
Multiple sclerosis (MS) is a demyelinating disease of the central nervous system causing axonal injury, neuronal loss, and atrophy of the central nervous system leading to permanent neurological and clinical disability. Presence of mutations in M9 domain of HNRNPA1 and detection of autoantibodies against this domain in HNRNPA1 qualifies it as a strong candidate for causing MS. These two aspects indicate the presence of a facilitator in associating them. Varicella zoster virus (VZV), known to cause chicken pox infection in humans, is a significant contender in sensitizing the infected people towards MS. Reactivation of latent herpes viruses by other infectious agents and cross-recognition of common viral antigens with antigens found in the myelin sheath induces molecular mimicry or superantigens. Mutations in HNRNPA1 cause mislocalization to the cytoplasm, and co-localize with stress granules (SG) causing cellular apoptosis, this creates the first step toward MS pathogenesis. Mutant HNRNPA1 accumulates in SG allowing the cells to display peptides of HNRNPA1 on surfaces of major histocompatibility complex (MHC) I triggering a cascade of immune reactions. Since glycoprotein E (gE) of VZV shares >62% amino acids sequence similarity with Prion-like domain (PrLD) of HNRNPA1, signifying the reason behind autoantibodies against M9 and PrLD of HNRNPA1. This review attempts to delineate the interactions of VZV, gE of VZV, with M9 domain and PrLD of HNRNPA1 in a step-by-step process. This supports the tripartite model that an environmental trigger in genetically susceptible individuals causes an autoimmune response to self-CNS antigens that result in the pathology observed in the brain and spinal cord of MS patients.
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Sistema Nervioso Central/inmunología , Varicela/inmunología , Varicela/virología , Herpesvirus Humano 3/inmunología , Ribonucleoproteína Nuclear Heterogénea A1/inmunología , Esclerosis Múltiple , Mutación , Proteínas del Envoltorio Viral/inmunología , Animales , Antígenos Virales/inmunología , Apoptosis/genética , Apoptosis/inmunología , Autoanticuerpos/genética , Autoanticuerpos/inmunología , Axones/inmunología , Axones/patología , Sistema Nervioso Central/patología , Sistema Nervioso Central/virología , Varicela/patología , Herpesvirus Humano 3/patogenicidad , Ribonucleoproteína Nuclear Heterogénea A1/genética , Antígenos de Histocompatibilidad Clase I/inmunología , Humanos , Modelos Inmunológicos , Imitación Molecular/genética , Imitación Molecular/inmunología , Esclerosis Múltiple/genética , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/patología , Esclerosis Múltiple/virología , Vaina de Mielina/inmunología , Vaina de Mielina/patología , Vaina de Mielina/virología , Dominios Proteicos , Superantígenos/genética , Superantígenos/inmunologíaRESUMEN
OBJECTIVES: To identify Damaging mutations in microRNAs (miRNAs) and 3' untranslated regions (UTRs) of target genes to establish Multiple sclerosis (MS) disease pathway. METHODS: Female aged 16, with Relapsing Remitting Multiple sclerosis (RRMS) was reported with initial symptoms of blurred vision, severe immobility, upper and lower limb numbness and backache. Whole Exome Sequencing (WES) and disease pathway analysis was performed to identify mutations in miRNAs and UTRs. RESULTS: We identified Deleterious/Damaging multibase mutations in MIR8485 and NRXN1. miR-8485 was found carrying frameshift homozygous deletion of bases CA, while NRXN1 was found carrying nonframeshift homozygous substitution of bases CT to TC in exon 8 replacing Serine with Leucine. CONCLUSIONS: Mutations in miR-8485 and NRXN1 was found to alter calcium homeostasis and NRXN1/NLGN1 cell adhesion molecule binding affinities. The miR-8485 mutation leads to overexpression of NRXN1 altering pre-synaptic Ca2+ homeostasis, inducing neurodegeneration.
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Moléculas de Adhesión Celular Neuronal/genética , MicroARNs/genética , Esclerosis Múltiple Recurrente-Remitente/genética , Degeneración Nerviosa/genética , Proteínas del Tejido Nervioso/genética , Adolescente , Calcio/metabolismo , Proteínas de Unión al Calcio , Moléculas de Adhesión Celular Neuronal/metabolismo , Femenino , Homeostasis/genética , Homeostasis/fisiología , Humanos , MicroARNs/metabolismo , Esclerosis Múltiple Recurrente-Remitente/metabolismo , Esclerosis Múltiple Recurrente-Remitente/patología , Mutación , Degeneración Nerviosa/metabolismo , Degeneración Nerviosa/patología , Proteínas del Tejido Nervioso/metabolismo , Moléculas de Adhesión de Célula Nerviosa , Sinapsis/genética , Sinapsis/metabolismo , Sinapsis/patologíaRESUMEN
Tetralogy of Fallot (TOF) is the most common Critical Congenital Heart Defect (CCHD). The etiology of TOF is unknown in most cases. Preliminary data from our group and others suggest that epigenetic changes may play an important role in CHD. Epidemiologically, a significant percentage of CHD including TOF fail to be diagnosed in the prenatal and early newborn period which can negatively affect health outcomes. We performed genome-wide methylation assay in newborn blood in 24 non-syndromic TOF cases and 24 unaffected matched controls using Illumina Infinium HumanMethylation450 BeadChips. We identified 64 significantly differentially methylated CpG sites in TOF cases, of which 25 CpG sites had high predictive accuracy for TOF, based on the area under the receiver operating characteristics curve (AUC ROC) ≥ 0.90). The CpG methylation difference between TOF and controls was ≥10% in 51 CpG targets suggesting biological significance. Gene ontology analysis identified significant biological processes and functions related to these differentially methylated genes, including: CHD development, cardiomyopathy, diabetes, immunological, inflammation and other plausible pathways in CHD development. Multiple genes known or plausibly linked to heart development and post-natal heart disease were found to be differentially methylated in the blood DNA of newborns with TOF including: ABCB1, PPP2R5C, TLR1, SELL, SCN3A, CREM, RUNX and LHX9. We generated novel and highly accurate putative molecular markers for TOF detection using leucocyte DNA and thus provided information on pathogenesis of TOF.
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Epigénesis Genética , Tetralogía de Fallot/sangre , Tetralogía de Fallot/genética , Área Bajo la Curva , Biología Computacional , Islas de CpG , Metilación de ADN , Estudio de Asociación del Genoma Completo , Humanos , Recién Nacido , Curva ROC , Transducción de SeñalRESUMEN
Background and Objectives. Uridine diphospho-glucuronosyltransferase 2B (UGT2B) is a family of genes involved in metabolizing steroid hormones and several other xenobiotics. These UGT2B genes are highly polymorphic in nature and have distinct polymorphisms associated with specific regions around the globe. Copy number variations (CNVs) status of UGT2B17 in Indian population is not known and their disease associations have been inconclusive. It was therefore of interest to investigate the CNV profile of UGT2B genes. Methods. We investigated the presence of CNVs in UGT2B genes in 31 members from eight Indian families using Affymetrix Genome-Wide Human SNP Array 6.0 chip. Results. Our data revealed >50% of the study members carried CNVs in UGT2B genes, of which 76% showed deletion polymorphism. CNVs were observed more in UGT2B17 (76.4%) than in UGT2B15 (17.6%). Molecular network and pathway analysis found enrichment related to steroid metabolic process, carboxylesterase activity, and sequence specific DNA binding. Interpretation and Conclusion. We report the presence of UGT2B gene deletion and duplication polymorphisms in Indian families. Network analysis indicates the substitutive role of other possible genes in the UGT activity. The CNVs of UGT2B genes are very common in individuals indicating that the effect is neutral in causing any suspected diseases.
RESUMEN
BACKGROUND: Parkinson disease (PD) is a neurological disease responsible for a considerable rate of mortality and morbidity in the society. Since the symptoms of the disease appear much later than the actual onset of neuron degeneration, a majority of cases remain undiagnosed until the manifestation of the symptoms. OBJECTIVES: In order to investigate the existence of such susceptibility in the population, we analyzed Copy Number Variation (CNV) influences on PD genes in 1715 individuals from 12 different populations. RESULTS: Overall, 16 CNV-PD genes, 3 known to be causal and 13 associated, were found to be significantly enriched. PARK2, was under heavy burden with ~1% of the population containing CNV in the exonic region. The impact of these genes on the genome and disease pathway was analyzed using several genome analysis tools. Protein interaction network of CNV-PD genes revealed a complex interaction of molecules forming a major hub by the α-Synuclein, whose direct interactors, LRRK2, PARK2 and ATP13A2 are under CNV influence. CONCLUSIONS: We hypothesize that CNVs may not be the initiating event in the pathogenesis of PD and remain latent until additional secondary hits are acquired and also propose novel genes that may fall under the PD pathway which contribute in pathogenesis.
Asunto(s)
Variaciones en el Número de Copia de ADN/genética , Predisposición Genética a la Enfermedad/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Enfermedad de Parkinson/etnología , Enfermedad de Parkinson/genética , Algoritmos , Estudios de Cohortes , Bases de Datos Genéticas , Femenino , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Masculino , Fenotipo , ATPasas de Translocación de Protón/genética , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
PURPOSE: Asthma is a complex disease caused by interplay of genes and environment on the genome of an individual. Copy number variations (CNVs) are more common compared to the other variations that disrupt genome organization. The effect of CNVs on asthma subgenome has been less studied compared to studies on the other variations. We report the assessments of CNV burden in asthma genes of normal cohorts carried out in different geographical areas of the world and discuss the relevance of the observation with respect to asthma pathogenesis. METHODS: CNV analysis was performed using Affymerix high-resolution arrays, and various bioinformatics tools were used to understand the influence of genes on asthma pathogenesis. RESULTS: This study identified 61 genes associated with asthma and provided various mechanisms and pathways underlying asthma pathogenesis. CCL3L1, ADAM8, and MUC5B were the most prevalent asthma genes. Among them, CCL3L1 was found across all 12 populations in varying copy number states. This study also identified the inheritance of asthma-CNVs from parents to offspring creating the latent period for manifestation of asthma. CONCLUSIONS: This study revealed CNV burden with varying copy number states and identified susceptibility towards the disease manifestation. It can be hypothesized that primary CNVs may not be the initiating event in the pathogenesis of asthma and additional preceding mutations or CNVs may be required. The initiator or primary CNVs sensitize normal cohorts leading to an increased probability of accumulating mutations or exposure to allergic stimulating agents that can augment the development of asthma.