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1.
Genome Biol ; 20(1): 230, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31684996

RESUMO

BACKGROUND: Molecular and cellular changes are intrinsic to aging and age-related diseases. Prior cross-sectional studies have investigated the combined effects of age and genetics on gene expression and alternative splicing; however, there has been no long-term, longitudinal characterization of these molecular changes, especially in older age. RESULTS: We perform RNA sequencing in whole blood from the same individuals at ages 70 and 80 to quantify how gene expression, alternative splicing, and their genetic regulation are altered during this 10-year period of advanced aging at a population and individual level. We observe that individuals are more similar to their own expression profiles later in life than profiles of other individuals their own age. We identify 1291 and 294 genes differentially expressed and alternatively spliced with age, as well as 529 genes with outlying individual trajectories. Further, we observe a strong correlation of genetic effects on expression and splicing between the two ages, with a small subset of tested genes showing a reduction in genetic associations with expression and splicing in older age. CONCLUSIONS: These findings demonstrate that, although the transcriptome and its genetic regulation is mostly stable late in life, a small subset of genes is dynamic and is characterized by a reduction in genetic regulation, most likely due to increasing environmental variance with age.

2.
Nat Med ; 25(6): 911-919, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31160820

RESUMO

It is estimated that 350 million individuals worldwide suffer from rare diseases, which are predominantly caused by mutation in a single gene1. The current molecular diagnostic rate is estimated at 50%, with whole-exome sequencing (WES) among the most successful approaches2-5. For patients in whom WES is uninformative, RNA sequencing (RNA-seq) has shown diagnostic utility in specific tissues and diseases6-8. This includes muscle biopsies from patients with undiagnosed rare muscle disorders6,9, and cultured fibroblasts from patients with mitochondrial disorders7. However, for many individuals, biopsies are not performed for clinical care, and tissues are difficult to access. We sought to assess the utility of RNA-seq from blood as a diagnostic tool for rare diseases of different pathophysiologies. We generated whole-blood RNA-seq from 94 individuals with undiagnosed rare diseases spanning 16 diverse disease categories. We developed a robust approach to compare data from these individuals with large sets of RNA-seq data for controls (n = 1,594 unrelated controls and n = 49 family members) and demonstrated the impacts of expression, splicing, gene and variant filtering strategies on disease gene identification. Across our cohort, we observed that RNA-seq yields a 7.5% diagnostic rate, and an additional 16.7% with improved candidate gene resolution.


Assuntos
Doenças Raras/genética , Ceramidase Ácida/genética , Estudos de Casos e Controles , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Variação Genética , Humanos , Masculino , Modelos Genéticos , Mutação , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/genética , Canais de Potássio/genética , RNA/sangue , RNA/genética , Processamento de RNA/genética , Doenças Raras/sangue , Análise de Sequência de RNA , Sequenciamento Completo do Exoma
3.
Nat Commun ; 10(1): 2760, 2019 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-31235787

RESUMO

Heart failure is a leading cause of mortality, yet our understanding of the genetic interactions underlying this disease remains incomplete. Here, we harvest 1352 healthy and failing human hearts directly from transplant center operating rooms, and obtain genome-wide genotyping and gene expression measurements for a subset of 313. We build failing and non-failing cardiac regulatory gene networks, revealing important regulators and cardiac expression quantitative trait loci (eQTLs). PPP1R3A emerges as a regulator whose network connectivity changes significantly between health and disease. RNA sequencing after PPP1R3A knockdown validates network-based predictions, and highlights metabolic pathway regulation associated with increased cardiomyocyte size and perturbed respiratory metabolism. Mice lacking PPP1R3A are protected against pressure-overload heart failure. We present a global gene interaction map of the human heart failure transition, identify previously unreported cardiac eQTLs, and demonstrate the discovery potential of disease-specific networks through the description of PPP1R3A as a central regulator in heart failure.


Assuntos
Redes Reguladoras de Genes/genética , Insuficiência Cardíaca/genética , Miócitos Cardíacos/patologia , Fosfoproteínas Fosfatases/metabolismo , Animais , Benzenoacetamidas , Células Cultivadas , Conjuntos de Dados como Assunto , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Estudo de Associação Genômica Ampla , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Humanos , Masculino , Redes e Vias Metabólicas/genética , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Fosfoproteínas Fosfatases/genética , Cultura Primária de Células , Piridinas , Locos de Características Quantitativas/genética , Ratos , Ratos Sprague-Dawley , Análise de Sequência de RNA/métodos
4.
J Oral Maxillofac Surg ; 76(9): 1991-1997, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29654774

RESUMO

PURPOSE: To compare the volumetric changes in successfully treated clefts with secondary alveolar grafting using recombinant human bone morphogenic protein-2 (rhBMP-2) delivered in ß-tricalcium phosphate (ßTCP) scaffold versus autogenous grafts obtained from the iliac crest and mandibular symphysis. PATIENTS AND METHODS: We performed a retrospective cohort study of cone-beam computed tomography scans of 25 subjects with unilateral or bilateral clefts. Of the 25 patients, 7 received an iliac crest bone graft, 9 received a mandibular symphyseal bone graft, and 9 subjects received the rhBMP-2/ßTCP bone substitute. Volumetric rendering software was used to calculate the amount of new bone formation and residual bone defect present in the cleft area. The data were analyzed using Wilcoxon and Kruskal-Wallis tests and Pearson's correlation coefficient. RESULTS: The mean percentage of new bone formation for the iliac crest, symphysis, and rhBMP-2/ßTCP was 85.47, 80.56, and 81.22%, respectively (P = .0854). The initial cleft volume had a weak positive correlation with the percentage of new bone formation (r = 0.18), but the postoperative residual cleft volume had a strong negative correlation (r = 0.71). CONCLUSIONS: rhBMP2 delivered in a ßTCP scaffold in alveolar cleft patients can be a viable alternative to autogenous iliac crest and symphysis grafts, eliminating donor site morbidity.

5.
J Neurochem ; 144(3): 302-317, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28869759

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deposition of amyloid beta (Aß) and dysregulation of neurotrophic signaling, causing synaptic dysfunction, loss of memory, and cell death. The expression of p75 neurotrophin receptor is elevated in the brain of AD patients, suggesting its involvement in this disease. However, the exact mechanism of its action is not yet clear. Here, we show that p75 interacts with beta-site amyloid precursor protein cleaving enzyme-1 (BACE1), and this interaction is enhanced in the presence of Aß. Our results suggest that the colocalization of BACE1 and amyloid precursor protein (APP) is increased in the presence of both Aß and p75 in cortical neurons. In addition, the localization of APP and BACE1 in early endosomes is increased in the presence of Aß and p75. An increased phosphorylation of APP-Thr668 and BACE1-Ser498 by c-Jun N-terminal kinase (JNK) in the presence of Aß and p75 could be responsible for this localization. In conclusion, our study proposes a potential involvement in amyloidogenesis for p75, which may represent a future therapeutic target for AD. Cover Image for this Issue: doi. 10.1111/jnc.14163.

6.
Genet Med ; 20(1): 159-163, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28640241

RESUMO

PurposeCurrent clinical genomics assays primarily utilize short-read sequencing (SRS), but SRS has limited ability to evaluate repetitive regions and structural variants. Long-read sequencing (LRS) has complementary strengths, and we aimed to determine whether LRS could offer a means to identify overlooked genetic variation in patients undiagnosed by SRS.MethodsWe performed low-coverage genome LRS to identify structural variants in a patient who presented with multiple neoplasia and cardiac myxomata, in whom the results of targeted clinical testing and genome SRS were negative.ResultsThis LRS approach yielded 6,971 deletions and 6,821 insertions > 50 bp. Filtering for variants that are absent in an unrelated control and overlap a disease gene coding exon identified three deletions and three insertions. One of these, a heterozygous 2,184 bp deletion, overlaps the first coding exon of PRKAR1A, which is implicated in autosomal dominant Carney complex. RNA sequencing demonstrated decreased PRKAR1A expression. The deletion was classified as pathogenic based on guidelines for interpretation of sequence variants.ConclusionThis first successful application of genome LRS to identify a pathogenic variant in a patient suggests that LRS has significant potential for the identification of disease-causing structural variation. Larger studies will ultimately be required to evaluate the potential clinical utility of LRS.


Assuntos
Estudos de Associação Genética , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Predisposição Genética para Doença , Variação Genética , Genoma Humano , Genômica , Análise de Sequência de DNA , Criança , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/genética , Ecocardiografia , Genômica/métodos , Humanos , Masculino , Fenótipo , Análise de Sequência de DNA/métodos , Deleção de Sequência
7.
Nat Genet ; 49(5): 700-707, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28394350

RESUMO

Genetic studies of complex traits have mainly identified associations with noncoding variants. To further determine the contribution of regulatory variation, we combined whole-genome and transcriptome data for 624 individuals from Sardinia to identify common and rare variants that influence gene expression and splicing. We identified 21,183 expression quantitative trait loci (eQTLs) and 6,768 splicing quantitative trait loci (sQTLs), including 619 new QTLs. We identified high-frequency QTLs and found evidence of selection near genes involved in malarial resistance and increased multiple sclerosis risk, reflecting the epidemiological history of Sardinia. Using family relationships, we identified 809 segregating expression outliers (median z score of 2.97), averaging 13.3 genes per individual. Outlier genes were enriched for proximal rare variants, providing a new approach to study large-effect regulatory variants and their relevance to traits. Our results provide insight into the effects of regulatory variants and their relationship to population history and individual genetic risk.


Assuntos
Perfilação da Expressão Gênica/métodos , Variação Genética , Estudo de Associação Genômica Ampla/métodos , Locos de Características Quantitativas/genética , Processamento Alternativo , Mapeamento Cromossômico , Saúde da Família , Feminino , Predisposição Genética para Doença/genética , Genética Populacional , Genótipo , Humanos , Itália , Masculino , Polimorfismo de Nucleotídeo Único , Sítio de Iniciação de Transcrição
8.
Sci Rep ; 7: 45038, 2017 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-28332630

RESUMO

The promyelocytic leukemia (PML) protein is an essential component of PML nuclear bodies (PML NBs) frequently lost in cancer. PML NBs coordinate chromosomal regions via modification of nuclear proteins that in turn may regulate genes in the vicinity of these bodies. However, few PML NB-associated genes have been identified. PML and PML NBs can also regulate mTOR and cell fate decisions in response to cellular stresses. We now demonstrate that PML depletion in U2OS cells or TERT-immortalized normal human diploid fibroblasts results in decreased expression of the mTOR inhibitor DDIT4 (REDD1). DNA and RNA immuno-FISH reveal that PML NBs are closely associated with actively transcribed DDIT4 loci, implicating these bodies in regulation of basal DDIT4 expression. Although PML silencing did reduce the sensitivity of U2OS cells to metabolic stress induced by metformin, PML loss did not inhibit the upregulation of DDIT4 in response to metformin, hypoxia-like (CoCl2) or genotoxic stress. Analysis of publicly available cancer data also revealed a significant correlation between PML and DDIT4 expression in several cancer types (e.g. lung, breast, prostate). Thus, these findings uncover a novel mechanism by which PML loss may contribute to mTOR activation and cancer progression via dysregulation of basal DDIT4 gene expression.


Assuntos
Regulação da Expressão Gênica , Proteína da Leucemia Promielocítica/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Fatores de Transcrição/genética , Linhagem Celular Tumoral , Cobalto/farmacologia , Fibroblastos/metabolismo , Técnicas de Inativação de Genes , Inativação Gênica , Loci Gênicos , Humanos , Hipóxia/genética , Hipóxia/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Ligação Proteica , Biossíntese de Proteínas , Radiação Ionizante , Fatores de Transcrição/metabolismo , Transcrição Genética
9.
Hum Mutat ; 38(6): 611-614, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28251733

RESUMO

At least 15% of the disease-causing mutations affect mRNA splicing. Many splicing mutations are missed in a clinical setting due to limitations of in silico prediction algorithms or their location in noncoding regions. Whole-transcriptome sequencing is a promising new tool to identify these mutations; however, it will be a challenge to obtain disease-relevant tissue for RNA. Here, we describe an individual with a sporadic atypical spinal muscular atrophy, in whom clinical DNA sequencing reported one pathogenic ASAH1 mutation (c.458A>G;p.Tyr153Cys). Transcriptome sequencing on patient leukocytes identified a highly significant and atypical ASAH1 isoform not explained by c.458A>G(p<10-16 ). Subsequent Sanger-sequencing identified the splice mutation responsible for the isoform (c.504A>C;p.Lys168Asn) and provided a molecular diagnosis of autosomal-recessive spinal muscular atrophy with progressive myoclonic epilepsy. Our findings demonstrate the utility of RNA sequencing from blood to identify splice-impacting disease mutations for nonhematological conditions, providing a diagnosis for these otherwise unsolved patients.


Assuntos
Ceramidase Ácida/genética , Atrofia Muscular Espinal/sangue , Epilepsias Mioclônicas Progressivas/sangue , Processamento de RNA/genética , Ceramidase Ácida/sangue , Pré-Escolar , Humanos , Masculino , Atrofia Muscular Espinal/complicações , Atrofia Muscular Espinal/genética , Mutação , Epilepsias Mioclônicas Progressivas/complicações , Epilepsias Mioclônicas Progressivas/genética , Patologia Molecular , Análise de Sequência de DNA , Transcriptoma/genética
10.
G3 (Bethesda) ; 7(1): 31-39, 2017 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-27799337

RESUMO

Exosomes are small extracellular vesicles that carry heterogeneous cargo, including RNA, between cells. Increasing evidence suggests that exosomes are important mediators of intercellular communication and biomarkers of disease. Despite this, the variability of exosomal RNA between individuals has not been well quantified. To assess this variability, we sequenced the small RNA of cells and exosomes from a 17-member family. Across individuals, we show that selective export of miRNAs occurs not only at the level of specific transcripts, but that a cluster of 74 mature miRNAs on chromosome 14q32 is massively exported in exosomes while mostly absent from cells. We also observe more interindividual variability between exosomal samples than between cellular ones and identify four miRNA expression quantitative trait loci shared between cells and exosomes. Our findings indicate that genomically colocated miRNAs can be exported together and highlight the variability in exosomal miRNA levels between individuals as relevant for exosome use as diagnostics.


Assuntos
Exossomos/genética , MicroRNAs/genética , Locos de Características Quantitativas/genética , Linhagem Celular , Cromossomos Humanos Par 14/genética , Regulação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Ativação Linfocitária/genética , RNA Interferente Pequeno/genética , Análise de Sequência de RNA
11.
Genome Res ; 26(6): 768-77, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27197214

RESUMO

The X Chromosome, with its unique mode of inheritance, contributes to differences between the sexes at a molecular level, including sex-specific gene expression and sex-specific impact of genetic variation. Improving our understanding of these differences offers to elucidate the molecular mechanisms underlying sex-specific traits and diseases. However, to date, most studies have either ignored the X Chromosome or had insufficient power to test for the sex-specific impact of genetic variation. By analyzing whole blood transcriptomes of 922 individuals, we have conducted the first large-scale, genome-wide analysis of the impact of both sex and genetic variation on patterns of gene expression, including comparison between the X Chromosome and autosomes. We identified a depletion of expression quantitative trait loci (eQTL) on the X Chromosome, especially among genes under high selective constraint. In contrast, we discovered an enrichment of sex-specific regulatory variants on the X Chromosome. To resolve the molecular mechanisms underlying such effects, we generated chromatin accessibility data through ATAC-sequencing to connect sex-specific chromatin accessibility to sex-specific patterns of expression and regulatory variation. As sex-specific regulatory variants discovered in our study can inform sex differences in heritable disease prevalence, we integrated our data with genome-wide association study data for multiple immune traits identifying several traits with significant sex biases in genetic susceptibilities. Together, our study provides genome-wide insight into how genetic variation, the X Chromosome, and sex shape human gene regulation and disease.


Assuntos
Cromossomos Humanos X/genética , Transcriptoma , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Predisposição Genética para Doença , Genoma Humano , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Caracteres Sexuais
12.
Oral Maxillofac Surg Clin North Am ; 28(2): 169-76, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27150304

RESUMO

Over the last decade, presurgical orthopedic molding for the patient with cleft lip and palate has become much more common; it is even reasonable to assume it may be the standard of care for those wide unilateral and bilateral clefts with substantial dentofacial deformities. In 2013, there was a comparative study of nasoalveolar molding methods, comparing the Grayson-NAM device and DynaCleft. The results showed the 2 to be equivocal with both methods significantly reducing the cleft width and improving the nasal asymmetry.


Assuntos
Fenda Labial/terapia , Fissura Palatina/terapia , Dispositivos de Fixação Ortopédica , Cuidados Pré-Operatórios , Processo Alveolar/anormalidades , Fita Atlética , Fenda Labial/cirurgia , Fissura Palatina/cirurgia , Modelos Dentários , Gengivoplastia/métodos , Humanos , Recém-Nascido , Nariz/anormalidades , Rinoplastia/métodos , Stents
13.
Oral Maxillofac Surg Clin North Am ; 28(2): 221-8, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27150307

RESUMO

This article relates to the use of 501c3 foundations in the care of patients with cleft and craniofacial disorders. Both authors are medical directors and founders of foundations that serve these children: A Smile for a Child Foundation was set up to help children locally; Free to Smile was set up as an international missions foundation. This article explores the advantages and disadvantages of each type of foundation as well as the struggles and successes foundations face to help children locally and internationally.


Assuntos
Fenda Labial/cirurgia , Fissura Palatina/cirurgia , Fundações , Missões Médicas/organização & administração , Humanos , Lactente , Recém-Nascido
16.
PLoS One ; 10(11): e0143216, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26588248

RESUMO

Chromosomal translocations are driver mutations of human cancers, particularly leukemias. They define disease subtypes and are used as prognostic markers, for minimal residual disease monitoring and therapeutic targets. Due to their low incidence, several translocations and their biological consequences remain poorly characterized. To address this, we engineered mouse strains that conditionally express E2A-HLF, a fusion oncogene from the translocation t(17;19) associated with 1% of pediatric B-cell precursor ALL. Conditional oncogene activation and expression were directed to the B-cell compartment by the Cre driver promoters CD19 or Mb1 (Igα, CD79a), or to the hematopoietic stem cell compartment by the Mx1 promoter. E2A-HLF expression in B-cell progenitors induced hyposplenia and lymphopenia, whereas expression in hematopoietic stem/progenitor cells was embryonic lethal. Increased cell death was detected in E2A-HLF expressing cells, suggesting the need for cooperating genetic events that suppress cell death for B-cell oncogenic transformation. E2A-HLF/Mb1.Cre aged mice developed a fatal myeloproliferative-like disorder with low frequency characterized by leukocytosis, anemia, hepatosplenomegaly and organ-infiltration by mature myelocytes. In conclusion, we have developed conditional E2A-HLF knock-in mice, which provide an experimental platform to study cooperating genetic events and further elucidate translational biology in cross-species comparative studies.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/genética , Transformação Celular Neoplásica/genética , Hepatomegalia/genética , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Células Precursoras de Linfócitos B/metabolismo , Esplenomegalia/genética , Animais , Antígenos CD19/genética , Antígenos CD19/metabolismo , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Antígenos CD79/genética , Antígenos CD79/metabolismo , Morte Celular/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Modelos Animais de Doenças , Expressão Gênica , Técnicas de Introdução de Genes , Engenharia Genética , Hepatomegalia/metabolismo , Hepatomegalia/patologia , Humanos , Integrases/genética , Integrases/metabolismo , Camundongos , Camundongos Transgênicos , Proteínas de Resistência a Myxovirus/genética , Proteínas de Resistência a Myxovirus/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Células Precursoras de Linfócitos B/patologia , Regiões Promotoras Genéticas , Esplenomegalia/metabolismo , Esplenomegalia/patologia , Translocação Genética
18.
Blood ; 126(14): 1683-94, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26311362

RESUMO

Chromosomal rearrangements involving the mixed-lineage leukemia (MLL) gene occur in primary and treatment-related leukemias and confer a poor prognosis. Studies based primarily on mouse models have substantially advanced our understanding of MLL leukemia pathogenesis, but often use supraphysiological oncogene expression with uncertain implications for human leukemia. Genome editing using site-specific nucleases provides a powerful new technology for gene modification to potentially model human disease, however, this approach has not been used to re-create acute leukemia in human cells of origin comparable to disease observed in patients. We applied transcription activator-like effector nuclease-mediated genome editing to generate endogenous MLL-AF9 and MLL-ENL oncogenes through insertional mutagenesis in primary human hematopoietic stem and progenitor cells (HSPCs) derived from human umbilical cord blood. Engineered HSPCs displayed altered in vitro growth potentials and induced acute leukemias following transplantation in immunocompromised mice at a mean latency of 16 weeks. The leukemias displayed phenotypic and morphologic similarities with patient leukemia blasts including a subset with mixed phenotype, a distinctive feature seen in clinical disease. The leukemic blasts expressed an MLL-associated transcriptional program with elevated levels of crucial MLL target genes, displayed heightened sensitivity to DOT1L inhibition, and demonstrated increased oncogenic potential ex vivo and in secondary transplant assays. Thus, genome editing to create endogenous MLL oncogenes in primary human HSPCs faithfully models acute MLL-rearranged leukemia and provides an experimental platform for prospective studies of leukemia initiation and stem cell biology in a genetic subtype of poor prognosis leukemia.


Assuntos
Transformação Celular Neoplásica/genética , Modelos Animais de Doenças , Células-Tronco Hematopoéticas , Histona-Lisina N-Metiltransferase/genética , Leucemia Aguda Bifenotípica/genética , Proteína de Leucina Linfoide-Mieloide/genética , Animais , Antígenos CD34/imunologia , Separação Celular , Técnicas de Introdução de Genes , Genoma Humano , Humanos , Camundongos , Microscopia Confocal , Mutagênese Sítio-Dirigida , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase , Transdução Genética , Transfecção
19.
Genome Res ; 25(7): 927-36, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25953952

RESUMO

Genomic imprinting is an important regulatory mechanism that silences one of the parental copies of a gene. To systematically characterize this phenomenon, we analyze tissue specificity of imprinting from allelic expression data in 1582 primary tissue samples from 178 individuals from the Genotype-Tissue Expression (GTEx) project. We characterize imprinting in 42 genes, including both novel and previously identified genes. Tissue specificity of imprinting is widespread, and gender-specific effects are revealed in a small number of genes in muscle with stronger imprinting in males. IGF2 shows maternal expression in the brain instead of the canonical paternal expression elsewhere. Imprinting appears to have only a subtle impact on tissue-specific expression levels, with genes lacking a systematic expression difference between tissues with imprinted and biallelic expression. In summary, our systematic characterization of imprinting in adult tissues highlights variation in imprinting between genes, individuals, and tissues.


Assuntos
Impressão Genômica , Genômica , Adulto , Alelos , Análise por Conglomerados , Metilação de DNA , Bases de Dados de Ácidos Nucleicos , Feminino , Regulação da Expressão Gênica , Variação Genética , Genótipo , Humanos , Masculino , Especificidade de Órgãos/genética , Polimorfismo de Nucleotídeo Único , Reprodutibilidade dos Testes , Fatores Sexuais
20.
Science ; 348(6235): 666-9, 2015 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-25954003

RESUMO

Accurate prediction of the functional effect of genetic variation is critical for clinical genome interpretation. We systematically characterized the transcriptome effects of protein-truncating variants, a class of variants expected to have profound effects on gene function, using data from the Genotype-Tissue Expression (GTEx) and Geuvadis projects. We quantitated tissue-specific and positional effects on nonsense-mediated transcript decay and present an improved predictive model for this decay. We directly measured the effect of variants both proximal and distal to splice junctions. Furthermore, we found that robustness to heterozygous gene inactivation is not due to dosage compensation. Our results illustrate the value of transcriptome data in the functional interpretation of genetic variants.


Assuntos
Regulação da Expressão Gênica , Variação Genética , Genoma Humano/genética , Proteínas/genética , Transcriptoma , Processamento Alternativo , Perfilação da Expressão Gênica , Inativação Gênica , Heterozigoto , Humanos , Degradação do RNAm Mediada por Códon sem Sentido , Fenótipo
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