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Pesquisa : G05.365.590.029 [Categoria DeCS]
Referências encontradas : 626 [refinar]
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[PMID]:29220678
[Au] Autor:Falkenberg KD; Braverman NE; Moser AB; Steinberg SJ; Klouwer FCC; Schlüter A; Ruiz M; Pujol A; Engvall M; Naess K; van Spronsen F; Körver-Keularts I; Rubio-Gozalbo ME; Ferdinandusse S; Wanders RJA; Waterham HR
[Ad] Endereço:Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands.
[Ti] Título:Allelic Expression Imbalance Promoting a Mutant PEX6 Allele Causes Zellweger Spectrum Disorder.
[So] Source:Am J Hum Genet;101(6):965-976, 2017 Dec 07.
[Is] ISSN:1537-6605
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Zellweger spectrum disorders (ZSDs) are autosomal-recessive disorders that are caused by defects in peroxisome biogenesis due to bi-allelic mutations in any of 13 different PEX genes. Here, we identified seven unrelated individuals affected with an apparent dominant ZSD in whom a heterozygous mutant PEX6 allele (c.2578C>T [p.Arg860Trp]) was overrepresented due to allelic expression imbalance (AEI). We demonstrated that AEI of PEX6 is a common phenomenon and is correlated with heterozygosity for a frequent variant in the 3' untranslated region (UTR) of the mutant allele, which disrupts the most distal of two polyadenylation sites. Asymptomatic parents, who were heterozygous for PEX c.2578C>T, did not show AEI and were homozygous for the 3' UTR variant. Overexpression models confirmed that the overrepresentation of the pathogenic PEX6 c.2578T variant compared to wild-type PEX6 c.2578C results in a peroxisome biogenesis defect and thus constitutes the cause of disease in the affected individuals. AEI promoting the overrepresentation of a mutant allele might also play a role in other autosomal-recessive disorders, in which only one heterozygous pathogenic variant is identified.
[Mh] Termos MeSH primário: Regiões 3´ não Traduzidas/genética
ATPases Associadas a Diversas Atividades Celulares/genética
Desequilíbrio Alélico/genética
Síndrome de Zellweger/genética
[Mh] Termos MeSH secundário: Alelos
Células Cultivadas
Feminino
Regulação da Expressão Gênica/genética
Predisposição Genética para Doença
Seres Humanos
Masculino
Peroxissomos/genética
Peroxissomos/patologia
Sequenciamento Completo do Exoma
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (3' Untranslated Regions); EC 3.6.4.- (ATPases Associated with Diverse Cellular Activities); EC 3.6.4.- (PEX6 protein, human)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171209
[St] Status:MEDLINE


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[PMID]:28825726
[Au] Autor:Polak P; Kim J; Braunstein LZ; Karlic R; Haradhavala NJ; Tiao G; Rosebrock D; Livitz D; Kübler K; Mouw KW; Kamburov A; Maruvka YE; Leshchiner I; Lander ES; Golub TR; Zick A; Orthwein A; Lawrence MS; Batra RN; Caldas C; Haber DA; Laird PW; Shen H; Ellisen LW; D'Andrea AD; Chanock SJ; Foulkes WD; Getz G
[Ad] Endereço:Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
[Ti] Título:A mutational signature reveals alterations underlying deficient homologous recombination repair in breast cancer.
[So] Source:Nat Genet;49(10):1476-1486, 2017 Oct.
[Is] ISSN:1546-1718
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Biallelic inactivation of BRCA1 or BRCA2 is associated with a pattern of genome-wide mutations known as signature 3. By analyzing ∼1,000 breast cancer samples, we confirmed this association and established that germline nonsense and frameshift variants in PALB2, but not in ATM or CHEK2, can also give rise to the same signature. We were able to accurately classify missense BRCA1 or BRCA2 variants known to impair homologous recombination (HR) on the basis of this signature. Finally, we show that epigenetic silencing of RAD51C and BRCA1 by promoter methylation is strongly associated with signature 3 and, in our data set, was highly enriched in basal-like breast cancers in young individuals of African descent.
[Mh] Termos MeSH primário: Neoplasias da Mama/genética
Genes Neoplásicos
Mutação
Reparo de DNA por Recombinação/genética
Transcriptoma/genética
[Mh] Termos MeSH secundário: Desequilíbrio Alélico
Metilação de DNA
Feminino
Regulação Neoplásica da Expressão Gênica/genética
Redes Reguladoras de Genes/genética
Inativação Gênica
Genes BRCA1
Genes BRCA2
Predisposição Genética para Doença
Mutação em Linhagem Germinativa
Seres Humanos
Proteínas de Neoplasias/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Neoplasm Proteins)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170822
[St] Status:MEDLINE
[do] DOI:10.1038/ng.3934


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[PMID]:28796844
[Au] Autor:Savol AJ; Wang PI; Jeon Y; Colognori D; Yildirim E; Pinter SF; Payer B; Lee JT; Sadreyev RI
[Ad] Endereço:Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, United States of America.
[Ti] Título:Genome-wide identification of autosomal genes with allelic imbalance of chromatin state.
[So] Source:PLoS One;12(8):e0182568, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In mammals, monoallelic gene expression can result from X-chromosome inactivation, genomic imprinting, and random monoallelic expression (RMAE). Epigenetic regulation of RMAE is not fully understood. Here we analyze allelic imbalance in chromatin state of autosomal genes using ChIP-seq in a clonal cell line. We identify approximately 3.7% of autosomal genes that show significant differences between chromatin states of two alleles. Allelic regulation is represented among several functional gene categories including histones, chromatin modifiers, and multiple early developmental regulators. Most cases of allelic skew are produced by quantitative differences between two allelic chromatic states that belong to the same gross type (active, silent, or bivalent). Combinations of allelic states of different types are possible but less frequent. When different chromatin marks are skewed on the same gene, their skew is coordinated as a result of quantitative relationships between these marks on each individual allele. Finally, combination of allele-specific densities of chromatin marks is a quantitative predictor of allelic skew in gene expression.
[Mh] Termos MeSH primário: Desequilíbrio Alélico
Cromatina/genética
[Mh] Termos MeSH secundário: Alelos
Animais
Linhagem Celular
Epigênese Genética
Feminino
Fibroblastos/metabolismo
Expressão Gênica
Genoma
Impressão Genômica
Masculino
Camundongos
Camundongos da Linhagem 129
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Chromatin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171017
[Lr] Data última revisão:
171017
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170811
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0182568


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[PMID]:28665992
[Au] Autor:Ghazanfar S; Vuocolo T; Morrison JL; Nicholas LM; McMillen IC; Yang JYH; Buckley MJ; Tellam RL
[Ad] Endereço:Data61, CSIRO, North Ryde, NSW, Australia.
[Ti] Título:Gene expression allelic imbalance in ovine brown adipose tissue impacts energy homeostasis.
[So] Source:PLoS One;12(6):e0180378, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Heritable trait variation within a population of organisms is largely governed by DNA variations that impact gene transcription and protein function. Identifying genetic variants that affect complex functional traits is a primary aim of population genetics studies, especially in the context of human disease and agricultural production traits. The identification of alleles directly altering mRNA expression and thereby biological function is challenging due to difficulty in isolating direct effects of cis-acting genetic variations from indirect trans-acting genetic effects. Allele specific gene expression or allelic imbalance in gene expression (AI) occurring at heterozygous loci provides an opportunity to identify genes directly impacted by cis-acting genetic variants as indirect trans-acting effects equally impact the expression of both alleles. However, the identification of genes showing AI in the context of the expression of all genes remains a challenge due to a variety of technical and statistical issues. The current study focuses on the discovery of genes showing AI using single nucleotide polymorphisms as allelic reporters. By developing a computational and statistical process that addressed multiple analytical challenges, we ranked 5,809 genes for evidence of AI using RNA-Seq data derived from brown adipose tissue samples from a cohort of late gestation fetal lambs and then identified a conservative subgroup of 1,293 genes. Thus, AI was extensive, representing approximately 25% of the tested genes. Genes associated with AI were enriched for multiple Gene Ontology (GO) terms relating to lipid metabolism, mitochondrial function and the extracellular matrix. These functions suggest that cis-acting genetic variations causing AI in the population are preferentially impacting genes involved in energy homeostasis and tissue remodelling. These functions may contribute to production traits likely to be under genetic selection in the population.
[Mh] Termos MeSH primário: Tecido Adiposo Marrom/metabolismo
Desequilíbrio Alélico
Homeostase
[Mh] Termos MeSH secundário: Animais
Feminino
Seres Humanos
Polimorfismo de Nucleotídeo Único
Gravidez
Ovinos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171006
[Lr] Data última revisão:
171006
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170701
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0180378


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[PMID]:28235418
[Au] Autor:de Santiago I; Liu W; Yuan K; O'Reilly M; Chilamakuri CS; Ponder BA; Meyer KB; Markowetz F
[Ad] Endereço:Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge, UK.
[Ti] Título:BaalChIP: Bayesian analysis of allele-specific transcription factor binding in cancer genomes.
[So] Source:Genome Biol;18(1):39, 2017 Feb 24.
[Is] ISSN:1474-760X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Allele-specific measurements of transcription factor binding from ChIP-seq data are key to dissecting the allelic effects of non-coding variants and their contribution to phenotypic diversity. However, most methods of detecting an allelic imbalance assume diploid genomes. This assumption severely limits their applicability to cancer samples with frequent DNA copy-number changes. Here we present a Bayesian statistical approach called BaalChIP to correct for the effect of background allele frequency on the observed ChIP-seq read counts. BaalChIP allows the joint analysis of multiple ChIP-seq samples across a single variant and outperforms competing approaches in simulations. Using 548 ENCODE ChIP-seq and six targeted FAIRE-seq samples, we show that BaalChIP effectively corrects allele-specific analysis for copy-number variation and increases the power to detect putative cis-acting regulatory variants in cancer genomes.
[Mh] Termos MeSH primário: Alelos
Teorema de Bayes
Sítios de Ligação
Biologia Computacional/métodos
Neoplasias/genética
Neoplasias/metabolismo
Fatores de Transcrição/metabolismo
[Mh] Termos MeSH secundário: Desequilíbrio Alélico
Linhagem Celular Tumoral
Imunoprecipitação da Cromatina
Variações do Número de Cópias de DNA
Amplificação de Genes
Genótipo
Sequenciamento de Nucleotídeos em Larga Escala
Seres Humanos
Controle de Qualidade
Reprodutibilidade dos Testes
Fluxo de Trabalho
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Transcription Factors)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170707
[Lr] Data última revisão:
170707
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170226
[St] Status:MEDLINE
[do] DOI:10.1186/s13059-017-1165-7


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[PMID]:27783335
[Au] Autor:Jamard E; Volard B; Dugué AE; Legros A; Leconte A; Clarisse B; Davy G; Polycarpe F; Dugast C; Abadie C; Frebourg T; Tinat J; Tennevet I; Layet V; Joly F; Castéra L; Berthet P; Vaur D; Krieger S
[Ad] Endereço:Laboratoire de Biologie et Génétique du Cancer - Centre Normand de Génomique Médicale et Médecine Personnalisée, Centre François Baclesse, 3 avenue du général Harris, 14076, Caen Cedex 05, France.
[Ti] Título:BRCA1 allele-specific expression in genetic predisposed breast/ovarian cancer.
[So] Source:Fam Cancer;16(2):167-171, 2017 Apr.
[Is] ISSN:1573-7292
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Germline allele specific expression (ASE), resulting in a lowered expression of one of the BRCA1 alleles, has been described as a possible predisposition marker in Hereditary Breast or Ovarian Cancer (HBOC), usable for molecular diagnosis in HBOC. The main objective of this prospective case-control study was to compare the proportion of ASE between controls without familial history of breast or ovarian cancer, and HBOC cases without BRCA1 or BRCA2 deleterious mutation. BRCA1 ASE evaluated on three SNPs among controls and HBOC patients without deleterious mutation were assessed by pyrosequencing. The allelic ratios and the proportion of ASE were compared between controls and cases using a Student's t test and a Fisher exact test, respectively. The linearity and reproducibility of the ASE dosage was demonstrated with R > 0.99 and a coefficient of variation below 10 %, and ASE was detected in two positive controls harbouring BRCA1 truncated mutations. In the heterozygote population, composed of 99/264 controls (37.5 %) and 96/227 patients (42.3 %), we detected a 5 % ASE without truncated mutations, in each population. We failed to detect any significant difference of ASE between controls and patients. So far, BRCA1 Allelic specific expression is not usable in routine diagnosis as a possible predisposition marker in HBOC patients except for the detection of truncated mutations.
[Mh] Termos MeSH primário: Desequilíbrio Alélico/genética
Proteína BRCA1/genética
Genes BRCA1
Predisposição Genética para Doença/genética
Mutação em Linhagem Germinativa/genética
Síndrome Hereditária de Câncer de Mama e Ovário/genética
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Biomarcadores Tumorais/genética
Estudos de Casos e Controles
Feminino
Heterozigoto
Seres Humanos
Meia-Idade
Polimorfismo de Nucleotídeo Único
Estudos Prospectivos
Adulto Jovem
[Pt] Tipo de publicação:CLINICAL TRIAL; COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (BRCA1 Protein); 0 (BRCA1 protein, human); 0 (Biomarkers, Tumor)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171020
[Lr] Data última revisão:
171020
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161027
[St] Status:MEDLINE
[do] DOI:10.1007/s10689-016-9940-2


  7 / 626 MEDLINE  
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[PMID]:27725226
[Au] Autor:Yu CC; Qiu W; Juang CS; Mansukhani MM; Halmos B; Su GH
[Ad] Endereço:Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA.
[Ti] Título:Mutant allele specific imbalance in oncogenes with copy number alterations: Occurrence, mechanisms, and potential clinical implications.
[So] Source:Cancer Lett;384:86-93, 2017 01 01.
[Is] ISSN:1872-7980
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Mutant allele specific imbalance (MASI) was initially coined to describe copy number alterations associated with the mutant allele of an oncogene. The copy number gain (CNG) specific to the mutant allele can be readily observed in electropherograms. With the development of genome-wide analyses at base-pair resolution with copy number counts, we can now further differentiate MASI into those with CNG, with copy neutral alteration (also termed acquired uniparental disomy; UPD), or with loss of heterozygosity (LOH) due to the loss of the wild-type (WT) allele. Here we summarize the occurrence of MASI with CNG, aUPD, or MASI with LOH in some major oncogenes (such as EGFR, KRAS, PIK3CA, and BRAF). We also discuss how these various classifications of MASI have been demonstrated to impact tumorigenesis, progression, metastasis, prognosis, and potentially therapeutic responses in cancer, notably in lung, colorectal, and pancreatic cancers.
[Mh] Termos MeSH primário: Desequilíbrio Alélico
Biomarcadores Tumorais/genética
Variações do Número de Cópias de DNA
Dosagem de Genes
Mutação
Neoplasias/genética
Oncogenes
[Mh] Termos MeSH secundário: Animais
Regulação Neoplásica da Expressão Gênica
Predisposição Genética para Doença
Seres Humanos
Perda de Heterozigosidade
Neoplasias/metabolismo
Neoplasias/patologia
Fenótipo
Proteínas Proto-Oncogênicas p21(ras)/genética
Receptor do Fator de Crescimento Epidérmico/genética
Dissomia Uniparental
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Biomarkers, Tumor); 0 (KRAS protein, human); EC 2.7.10.1 (EGFR protein, human); EC 2.7.10.1 (Receptor, Epidermal Growth Factor); EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171029
[Lr] Data última revisão:
171029
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161012
[St] Status:MEDLINE


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[PMID]:27836965
[Au] Autor:Shih YH; Dvornikov AV; Zhu P; Ma X; Kim M; Ding Y; Xu X
[Ad] Endereço:Department of Biochemistry and Molecular Biology, Division of Cardiovascular Diseases, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA.
[Ti] Título:Exon- and contraction-dependent functions of titin in sarcomere assembly.
[So] Source:Development;143(24):4713-4722, 2016 12 15.
[Is] ISSN:1477-9129
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Titin-truncating variants (TTNtvs) are the major cause of dilated cardiomyopathy (DCM); however, allelic heterogeneity (TTNtvs in different exons) results in variable phenotypes, and remains a major hurdle for disease diagnosis and therapy. Here, we generated a panel of ttn mutants in zebrafish. Four single deletion mutants in ttn.2 or ttn.1 resulted in four phenotypes and three double ttn.2/ttn.1 mutants exhibited more severe phenotypes in somites. Protein analysis identified ttn as a near-null mutant and the other six mutants as hypomorphic alleles. Studies of ttn uncovered a function of titin in guiding the assembly of nascent myofibrils from premyofibrils. By contrast, sarcomeres were assembled in the hypomorphic ttn mutants but either became susceptible to biomechanical stresses such as contraction or degenerated during development. Further genetic studies indicated that the exon usage hypothesis, but not the toxic peptide or the Cronos hypothesis, could account for these exon-dependent effects. In conclusion, we modeled TTNtv allelic heterogeneity during development and paved the way for future studies to decipher allelic heterogeneity in adult DCM.
[Mh] Termos MeSH primário: Conectina/genética
Miofibrilas/metabolismo
Sarcômeros/metabolismo
Peixe-Zebra/crescimento & desenvolvimento
[Mh] Termos MeSH secundário: Alelos
Desequilíbrio Alélico/genética
Animais
Animais Geneticamente Modificados
Cardiomiopatia Dilatada/genética
Conectina/metabolismo
Sarcômeros/genética
Deleção de Sequência/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Connectin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171125
[Lr] Data última revisão:
171125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161113
[St] Status:MEDLINE


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[PMID]:27539784
[Au] Autor:Jeffries AR; Uwanogho DA; Cocks G; Perfect LW; Dempster E; Mill J; Price J
[Ad] Endereço:University of Exeter Medical School, University of Exeter, Exeter EX2 5DW, United Kingdom Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, United Kingdom.
[Ti] Título:Erasure and reestablishment of random allelic expression imbalance after epigenetic reprogramming.
[So] Source:RNA;22(10):1620-30, 2016 Oct.
[Is] ISSN:1469-9001
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Clonal level random allelic expression imbalance and random monoallelic expression provides cellular heterogeneity within tissues by modulating allelic dosage. Although such expression patterns have been observed in multiple cell types, little is known about when in development these stochastic allelic choices are made. We examine allelic expression patterns in human neural progenitor cells before and after epigenetic reprogramming to induced pluripotency, observing that loci previously characterized by random allelic expression imbalance (0.63% of expressed genes) are generally reset to a biallelic state in induced pluripotent stem cells (iPSCs). We subsequently neuralized the iPSCs and profiled isolated clonal neural stem cells, observing that significant random allelic expression imbalance is reestablished at 0.65% of expressed genes, including novel loci not found to show allelic expression imbalance in the original parental neural progenitor cells. Allelic expression imbalance was associated with altered DNA methylation across promoter regulatory regions, with clones characterized by skewed allelic expression being hypermethylated compared to their biallelic sister clones. Our results suggest that random allelic expression imbalance is established during lineage commitment and is associated with increased DNA methylation at the gene promoter.
[Mh] Termos MeSH primário: Desequilíbrio Alélico
Reprogramação Celular
Epigênese Genética
[Mh] Termos MeSH secundário: Células Cultivadas
Metilação de DNA
Seres Humanos
Células-Tronco Pluripotentes Induzidas/citologia
Células-Tronco Pluripotentes Induzidas/metabolismo
Células-Tronco Neurais/citologia
Células-Tronco Neurais/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160820
[St] Status:MEDLINE
[do] DOI:10.1261/rna.058347.116


  10 / 626 MEDLINE  
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[PMID]:27468897
[Au] Autor:Sung MK; Jang J; Lee KS; Ghim CM; Choi JK
[Ad] Endereço:Department of Bio and Brain Engineering, KAIST, Daejeon, 34141, Republic of Korea.
[Ti] Título:Selected heterozygosity at cis-regulatory sequences increases the expression homogeneity of a cell population in humans.
[So] Source:Genome Biol;17(1):164, 2016 Jul 28.
[Is] ISSN:1474-760X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Examples of heterozygote advantage in humans are scarce and limited to protein-coding sequences. Here, we attempt a genome-wide functional inference of advantageous heterozygosity at cis-regulatory regions. RESULTS: The single-nucleotide polymorphisms bearing the signatures of balancing selection are enriched in active cis-regulatory regions of immune cells and epithelial cells, the latter of which provide barrier function and innate immunity. Examples associated with ancient trans-specific balancing selection are also discovered. Allelic imbalance in chromatin accessibility and divergence in transcription factor motif sequences indicate that these balanced polymorphisms cause distinct regulatory variation. However, a majority of these variants show no association with the expression level of the target gene. Instead, single-cell experimental data for gene expression and chromatin accessibility demonstrate that heterozygous sequences can lower cell-to-cell variability in proportion to selection strengths. This negative correlation is more pronounced for highly expressed genes and consistently observed when using different data and methods. Based on mathematical modeling, we hypothesize that extrinsic noise from fluctuations in transcription factor activity may be amplified in homozygotes, whereas it is buffered in heterozygotes. While high expression levels are coupled with intrinsic noise reduction, regulatory heterozygosity can contribute to the suppression of extrinsic noise. CONCLUSIONS: This mechanism may confer a selective advantage by increasing cell population homogeneity and thereby enhancing the collective action of the cells, especially of those involved in the defense systems in humans.
[Mh] Termos MeSH primário: Regulação da Expressão Gênica
Variação Genética
Heterozigoto
Sequências Reguladoras de Ácido Nucleico
[Mh] Termos MeSH secundário: Algoritmos
Alelos
Desequilíbrio Alélico
Sítios de Ligação
Cromatina/genética
Cromatina/metabolismo
Montagem e Desmontagem da Cromatina
Seres Humanos
Modelos Biológicos
Motivos de Nucleotídeos
Especificidade de Órgãos/genética
Polimorfismo de Nucleotídeo Único
Ligação Proteica
Fatores de Transcrição/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Chromatin); 0 (Transcription Factors)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170713
[Lr] Data última revisão:
170713
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160730
[St] Status:MEDLINE
[do] DOI:10.1186/s13059-016-1027-8



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