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[PMID]:29389989
[Au] Autor:Almutairy M; Torng E
[Ad] Endereço:Department of Computer Science and Engineering, Michigan State University, East Lansing, Michigan, United States of America.
[Ti] Título:Comparing fixed sampling with minimizer sampling when using k-mer indexes to find maximal exact matches.
[So] Source:PLoS One;13(2):e0189960, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Bioinformatics applications and pipelines increasingly use k-mer indexes to search for similar sequences. The major problem with k-mer indexes is that they require lots of memory. Sampling is often used to reduce index size and query time. Most applications use one of two major types of sampling: fixed sampling and minimizer sampling. It is well known that fixed sampling will produce a smaller index, typically by roughly a factor of two, whereas it is generally assumed that minimizer sampling will produce faster query times since query k-mers can also be sampled. However, no direct comparison of fixed and minimizer sampling has been performed to verify these assumptions. We systematically compare fixed and minimizer sampling using the human genome as our database. We use the resulting k-mer indexes for fixed sampling and minimizer sampling to find all maximal exact matches between our database, the human genome, and three separate query sets, the mouse genome, the chimp genome, and an NGS data set. We reach the following conclusions. First, using larger k-mers reduces query time for both fixed sampling and minimizer sampling at a cost of requiring more space. If we use the same k-mer size for both methods, fixed sampling requires typically half as much space whereas minimizer sampling processes queries only slightly faster. If we are allowed to use any k-mer size for each method, then we can choose a k-mer size such that fixed sampling both uses less space and processes queries faster than minimizer sampling. The reason is that although minimizer sampling is able to sample query k-mers, the number of shared k-mer occurrences that must be processed is much larger for minimizer sampling than fixed sampling. In conclusion, we argue that for any application where each shared k-mer occurrence must be processed, fixed sampling is the right sampling method.
[Mh] Termos MeSH primário: Biologia Computacional
[Mh] Termos MeSH secundário: Animais
Genoma Humano
Sequenciamento de Nucleotídeos em Larga Escala
Seres Humanos
Camundongos
Modelos Teóricos
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180202
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0189960


  2 / 24233 MEDLINE  
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[PMID]:28465312
[Au] Autor:Noorani A; Bornschein J; Lynch AG; Secrier M; Achilleos A; Eldridge M; Bower L; Weaver JMJ; Crawte J; Ong CA; Shannon N; MacRae S; Grehan N; Nutzinger B; O'Donovan M; Hardwick R; Tavaré S; Fitzgerald RC; Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium
[Ad] Endereço:Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge CB2 0XZ, United Kingdom.
[Ti] Título:A comparative analysis of whole genome sequencing of esophageal adenocarcinoma pre- and post-chemotherapy.
[So] Source:Genome Res;27(6):902-912, 2017 06.
[Is] ISSN:1549-5469
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The scientific community has avoided using tissue samples from patients that have been exposed to systemic chemotherapy to infer the genomic landscape of a given cancer. Esophageal adenocarcinoma is a heterogeneous, chemoresistant tumor for which the availability and size of pretreatment endoscopic samples are limiting. This study compares whole-genome sequencing data obtained from chemo-naive and chemo-treated samples. The quality of whole-genomic sequencing data is comparable across all samples regardless of chemotherapy status. Inclusion of samples collected post-chemotherapy increased the proportion of late-stage tumors. When comparing matched pre- and post-chemotherapy samples from 10 cases, the mutational signatures, copy number, and SNV mutational profiles reflect the expected heterogeneity in this disease. Analysis of SNVs in relation to allele-specific copy-number changes pinpoints the common ancestor to a point prior to chemotherapy. For cases in which pre- and post-chemotherapy samples do show substantial differences, the timing of the divergence is near-synchronous with endoreduplication. Comparison across a large prospective cohort (62 treatment-naive, 58 chemotherapy-treated samples) reveals no significant differences in the overall mutation rate, mutation signatures, specific recurrent point mutations, or copy-number events in respect to chemotherapy status. In conclusion, whole-genome sequencing of samples obtained following neoadjuvant chemotherapy is representative of the genomic landscape of esophageal adenocarcinoma. Excluding these samples reduces the material available for cataloging and introduces a bias toward the earlier stages of cancer.
[Mh] Termos MeSH primário: Adenocarcinoma/genética
Antineoplásicos/uso terapêutico
Neoplasias Esofágicas/genética
Regulação Neoplásica da Expressão Gênica
Genoma Humano
Taxa de Mutação
Proteínas de Neoplasias/genética
[Mh] Termos MeSH secundário: Adenocarcinoma/tratamento farmacológico
Adenocarcinoma/metabolismo
Adenocarcinoma/patologia
Idoso
Transformação Celular Neoplásica/genética
Transformação Celular Neoplásica/metabolismo
Transformação Celular Neoplásica/patologia
Biologia Computacional
Variações do Número de Cópias de DNA
Neoplasias Esofágicas/tratamento farmacológico
Neoplasias Esofágicas/metabolismo
Neoplasias Esofágicas/patologia
Esôfago/metabolismo
Esôfago/patologia
Feminino
Perfilação da Expressão Gênica
Sequenciamento de Nucleotídeos em Larga Escala
Seres Humanos
Masculino
Meia-Idade
Terapia Neoadjuvante/métodos
Proteínas de Neoplasias/metabolismo
Mutação Puntual
Polimorfismo de Nucleotídeo Único
Estudos Prospectivos
Fatores de Tempo
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Neoplasm Proteins)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE
[do] DOI:10.1101/gr.214296.116


  3 / 24233 MEDLINE  
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[PMID]:29382830
[Au] Autor:Aramillo Irizar P; Schäuble S; Esser D; Groth M; Frahm C; Priebe S; Baumgart M; Hartmann N; Marthandan S; Menzel U; Müller J; Schmidt S; Ast V; Caliebe A; König R; Krawczak M; Ristow M; Schuster S; Cellerino A; Diekmann S; Englert C; Hemmerich P; Sühnel J; Guthke R; Witte OW; Platzer M; Ruppin E; Kaleta C
[Ad] Endereço:Research Group Medical Systems Biology, Institute of Experimental Medicine, Christian-Albrechts-University Kiel, D-24105, Kiel, Germany.
[Ti] Título:Transcriptomic alterations during ageing reflect the shift from cancer to degenerative diseases in the elderly.
[So] Source:Nat Commun;9(1):327, 2018 01 30.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Disease epidemiology during ageing shows a transition from cancer to degenerative chronic disorders as dominant contributors to mortality in the old. Nevertheless, it has remained unclear to what extent molecular signatures of ageing reflect this phenomenon. Here we report on the identification of a conserved transcriptomic signature of ageing based on gene expression data from four vertebrate species across four tissues. We find that ageing-associated transcriptomic changes follow trajectories similar to the transcriptional alterations observed in degenerative ageing diseases but are in opposite direction to the transcriptomic alterations observed in cancer. We confirm the existence of a similar antagonism on the genomic level, where a majority of shared risk alleles which increase the risk of cancer decrease the risk of chronic degenerative disorders and vice versa. These results reveal a fundamental trade-off between cancer and degenerative ageing diseases that sheds light on the pronounced shift in their epidemiology during ageing.
[Mh] Termos MeSH primário: Envelhecimento/genética
Doenças Cardiovasculares/genética
Diabetes Mellitus/genética
Neoplasias/genética
Doenças Neurodegenerativas/genética
Transcriptoma
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idoso
Idoso de 80 Anos ou mais
Envelhecimento/metabolismo
Envelhecimento/patologia
Animais
Encéfalo/crescimento & desenvolvimento
Encéfalo/metabolismo
Doenças Cardiovasculares/sangue
Doenças Cardiovasculares/patologia
Criança
Pré-Escolar
Doença Crônica
Diabetes Mellitus/sangue
Diabetes Mellitus/patologia
Fundulidae/genética
Fundulidae/crescimento & desenvolvimento
Fundulidae/metabolismo
Ontologia Genética
Genoma Humano
Seres Humanos
Lactente
Fígado/crescimento & desenvolvimento
Fígado/metabolismo
Camundongos
Meia-Idade
Anotação de Sequência Molecular
Neoplasias/metabolismo
Neoplasias/patologia
Doenças Neurodegenerativas/sangue
Doenças Neurodegenerativas/patologia
Pele/crescimento & desenvolvimento
Pele/metabolismo
Peixe-Zebra/genética
Peixe-Zebra/crescimento & desenvolvimento
Peixe-Zebra/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180307
[Lr] Data última revisão:
180307
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180201
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02395-2


  4 / 24233 MEDLINE  
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[PMID]:28453704
[Au] Autor:Lesurf R; Griffith OL; Griffith M; Hundal J; Trani L; Watson MA; Aft R; Ellis MJ; Ota D; Suman VJ; Meric-Bernstam F; Leitch AM; Boughey JC; Unzeitig G; Buzdar AU; Hunt KK; Mardis ER
[Ad] Endereço:McDonnell Genome Institute at Washington University School of Medicine, St Louis, USA
[Ti] Título:Genomic characterization of HER2-positive breast cancer and response to neoadjuvant trastuzumab and chemotherapy-results from the ACOSOG Z1041 (Alliance) trial.
[So] Source:Ann Oncol;28(5):1070-1077, 2017 05 01.
[Is] ISSN:1569-8041
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Background: HER2 (ERBB2) gene amplification and its corresponding overexpression are present in 15-30% of invasive breast cancers. While HER2-targeted agents are effective treatments, resistance remains a major cause of death. The American College of Surgeons Oncology Group Z1041 trial (NCT00513292) was designed to compare the pathologic complete response (pCR) rate of distinct regimens of neoadjuvant chemotherapy and trastuzumab, but ultimately identified no difference. Patients and methods: In supplement to tissues from 37 Z1041 cases, 11 similarly treated cases were obtained from a single institution study (NCT00353483). We have extracted genomic DNA from both pre-treatment tumor biopsies and blood of these 48 cases, and performed whole genome (WGS) and exome sequencing. Coincident with these efforts, we have generated RNA-seq profiles from 42 of the tumor biopsies. Among patients in this cohort, 24 (50%) achieved a pCR. Results: We have characterized the genomic landscape of HER2-positive breast cancer and investigated associations between genomic features and pCR. Cases assigned to the HER2-enriched subtype by RNA-seq analysis were more likely to achieve a pCR compared to the luminal, basal-like, or normal-like subtypes (19/27 versus 3/15; P = 0.0032). Mutational events led to the generation of putatively active neoantigens, but were overall not associated with pCR. ERBB2 and GRB7 were the genes most commonly observed in fusion events, and genomic copy number analysis of the ERBB2 locus indicated that cases with either no observable or low-level ERBB2 amplification were less likely to achieve a pCR (7/8 versus 17/40; P = 0.048). Moreover, among cases that achieved a pCR, tumors consistently expressed immune signatures that may contribute to therapeutic response. Conclusion: The identification of these features suggests that it may be possible to predict, at the time of diagnosis, those HER2-positive breast cancer patients who will not respond to treatment with chemotherapy and trastuzumab. ClinicalTrials.gov identifiers: NCT00513292, NCT00353483.
[Mh] Termos MeSH primário: Antineoplásicos Imunológicos/uso terapêutico
Neoplasias da Mama/tratamento farmacológico
Trastuzumab/uso terapêutico
[Mh] Termos MeSH secundário: Idoso
Neoplasias da Mama/genética
Quimioterapia Adjuvante
Variações do Número de Cópias de DNA
Feminino
Estudos de Associação Genética
Genoma Humano
Mutação em Linhagem Germinativa
Seres Humanos
Mutação INDEL
Meia-Idade
Terapia Neoadjuvante
Polimorfismo de Nucleotídeo Único
Receptor ErbB-2/metabolismo
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents, Immunological); EC 2.7.10.1 (ERBB2 protein, human); EC 2.7.10.1 (Receptor, ErbB-2); P188ANX8CK (Trastuzumab)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE
[do] DOI:10.1093/annonc/mdx048


  5 / 24233 MEDLINE  
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[PMID]:28453708
[Au] Autor:Vis DJ; Lewin J; Liao RG; Mao M; Andre F; Ward RL; Calvo F; Teh BT; Camargo AA; Knoppers BM; Sawyers CL; Wessels LFA; Lawler M; Siu LL; Voest E; Clinical Working Group of the Global Alliance for Genomics and Health
[Ad] Endereço:Netherlands Cancer Institute, Amsterdam, The Netherlands.
[Ti] Título:Towards a global cancer knowledge network: dissecting the current international cancer genomic sequencing landscape.
[So] Source:Ann Oncol;28(5):1145-1151, 2017 May 01.
[Is] ISSN:1569-8041
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Background: While next generation sequencing has enhanced our understanding of the biological basis of malignancy, current knowledge on global practices for sequencing cancer samples is limited. To address this deficiency, we developed a survey to provide a snapshot of current sequencing activities globally, identify barriers to data sharing and use this information to develop sustainable solutions for the cancer research community. Methods: A multi-item survey was conducted assessing demographics, clinical data collection, genomic platforms, privacy/ethics concerns, funding sources and data sharing barriers for sequencing initiatives globally. Additionally, respondents were asked as to provide the primary intent of their initiative (clinical diagnostic, research or combination). Results: Of 107 initiatives invited to participate, 59 responded (response rate = 55%). Whole exome sequencing (P = 0.03) and whole genome sequencing (P = 0.01) were utilized less frequently in clinical diagnostic than in research initiatives. Procedures to identify cancer-specific variants were heterogeneous, with bioinformatics pipelines employing different mutation calling/variant annotation algorithms. Measurement of treatment efficacy varied amongst initiatives, with time on treatment (57%) and RECIST (53%) being the most common; however, other parameters were also employed. Whilst 72% of initiatives indicated data sharing, its scope varied, with a number of restrictions in place (e.g. transfer of raw data). The largest perceived barriers to data harmonization were the lack of financial support (P < 0.01) and bioinformatics concerns (e.g. lack of interoperability) (P = 0.02). Capturing clinical data was more likely to be perceived as a barrier to data sharing by larger initiatives than by smaller initiatives (P = 0.01). Conclusions: These results identify the main barriers, as perceived by the cancer sequencing community, to effective sharing of cancer genomic and clinical data. They highlight the need for greater harmonization of technical, ethical and data capture processes in cancer sample sequencing worldwide, in order to support effective and responsible data sharing for the benefit of patients.
[Mh] Termos MeSH primário: Estudos de Associação Genética
Neoplasias/genética
[Mh] Termos MeSH secundário: Análise Mutacional de DNA
Bases de Dados Genéticas
Predisposição Genética para Doença
Genoma Humano
Seres Humanos
Anotação de Sequência Molecular
Inquéritos e Questionários
Sequenciamento Completo do Exoma
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE
[do] DOI:10.1093/annonc/mdx037


  6 / 24233 MEDLINE  
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[PMID]:28453676
[Au] Autor:Qian Y; Butler TJ; Opsahl-Ong K; Giroux NS; Sidore C; Nagaraja R; Cucca F; Ferrucci L; Abecasis GR; Schlessinger D; Ding J
[Ad] Endereço:Laboratory of Genetics and Genomics, National Institute on Aging, NIH, Baltimore, MD, USA.
[Ti] Título:fastMitoCalc: an ultra-fast program to estimate mitochondrial DNA copy number from whole-genome sequences.
[So] Source:Bioinformatics;33(9):1399-1401, 2017 May 01.
[Is] ISSN:1367-4811
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Availability and Implementation: fastMitoCalc is available at https://lgsun.irp.nia.nih.gov/hsgu/software/mitoAnalyzer/index.html. Contact: jun.ding@nih.gov. Supplementary information: Supplementary data are available at Bioinformatics online.
[Mh] Termos MeSH primário: Dosagem de Genes
Genoma Mitocondrial
Genômica/métodos
Análise de Sequência de DNA/métodos
Software
[Mh] Termos MeSH secundário: Genoma Humano
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE
[do] DOI:10.1093/bioinformatics/btw835


  7 / 24233 MEDLINE  
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[PMID]:28453674
[Au] Autor:Mohamadi H; Khan H; Birol I
[Ad] Endereço:Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC, V5Z 4S6, Canada.
[Ti] Título:ntCard: a streaming algorithm for cardinality estimation in genomics data.
[So] Source:Bioinformatics;33(9):1324-1330, 2017 05 01.
[Is] ISSN:1367-4811
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Motivation: Many bioinformatics algorithms are designed for the analysis of sequences of some uniform length, conventionally referred to as k -mers. These include de Bruijn graph assembly methods and sequence alignment tools. An efficient algorithm to enumerate the number of unique k -mers, or even better, to build a histogram of k -mer frequencies would be desirable for these tools and their downstream analysis pipelines. Among other applications, estimated frequencies can be used to predict genome sizes, measure sequencing error rates, and tune runtime parameters for analysis tools. However, calculating a k -mer histogram from large volumes of sequencing data is a challenging task. Results: Here, we present ntCard, a streaming algorithm for estimating the frequencies of k -mers in genomics datasets. At its core, ntCard uses the ntHash algorithm to efficiently compute hash values for streamed sequences. It then samples the calculated hash values to build a reduced representation multiplicity table describing the sample distribution. Finally, it uses a statistical model to reconstruct the population distribution from the sample distribution. We have compared the performance of ntCard and other cardinality estimation algorithms. We used three datasets of 480 GB, 500 GB and 2.4 TB in size, where the first two representing whole genome shotgun sequencing experiments on the human genome and the last one on the white spruce genome. Results show ntCard estimates k -mer coverage frequencies >15× faster than the state-of-the-art algorithms, using similar amount of memory, and with higher accuracy rates. Thus, our benchmarks demonstrate ntCard as a potentially enabling technology for large-scale genomics applications. Availability and Implementation: ntCard is written in C ++ and is released under the GPL license. It is freely available at https://github.com/bcgsc/ntCard. Contact: hmohamadi@bcgsc.ca or ibirol@bcgsc.ca. Supplementary information: Supplementary data are available at Bioinformatics online.
[Mh] Termos MeSH primário: Genômica/métodos
Análise de Sequência de DNA/métodos
Software
[Mh] Termos MeSH secundário: Algoritmos
Tamanho do Genoma
Genoma Humano
Genoma de Planta
Seres Humanos
Modelos Estatísticos
Picea/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE
[do] DOI:10.1093/bioinformatics/btw832


  8 / 24233 MEDLINE  
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[PMID]:28453673
[Au] Autor:Lemaçon A; Joly Beauparlant C; Soucy P; Allen J; Easton D; Kraft P; Simard J; Droit A
[Ad] Endereço:Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Quebec, Canada.
[Ti] Título:VEXOR: an integrative environment for prioritization of functional variants in fine-mapping analysis.
[So] Source:Bioinformatics;33(9):1389-1391, 2017 05 01.
[Is] ISSN:1367-4811
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Motivation: The identification of the functional variants responsible for observed genome-wide association studies (GWAS) signals is one of the most challenging tasks of the post-GWAS research era. Several tools have been developed to annotate genetic variants by their genomic location and potential functional implications. Each of these tools has its own requirements and internal logic, which forces the user to become acquainted with each interface. Results: From an awareness of the amount of work needed to analyze a single locus, we have built a flexible, versatile and easy-to-use web interface designed to help in prioritizing variants and predicting their potential functional implications. This interface acts as a single-point of entry linking association results with reference tools and relevant experiments. Availability and Implementation: VEXOR is an integrative web application implemented through the Shiny framework and available at: http://romix.genome.ulaval.ca/vexor. Contact: arnaud.droit@crchuq.ulaval.ca. Supplementary information: Supplementary data are available at Bioinformatics online.
[Mh] Termos MeSH primário: Estudo de Associação Genômica Ampla/métodos
Polimorfismo Genético
Análise de Sequência de DNA/métodos
Software
[Mh] Termos MeSH secundário: Genoma Humano
Genômica/métodos
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE
[do] DOI:10.1093/bioinformatics/btw826


  9 / 24233 MEDLINE  
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[PMID]:29295990
[Au] Autor:Bell CG; Gao F; Yuan W; Roos L; Acton RJ; Xia Y; Bell J; Ward K; Mangino M; Hysi PG; Wang J; Spector TD
[Ad] Endereço:Department of Twin Research & Genetic Epidemiology, King's College London, London, SE1 7EH, UK. cgb@mrc.soton.ac.uk.
[Ti] Título:Obligatory and facilitative allelic variation in the DNA methylome within common disease-associated loci.
[So] Source:Nat Commun;9(1):8, 2018 01 02.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Integrating epigenetic data with genome-wide association study (GWAS) results can reveal disease mechanisms. The genome sequence itself also shapes the epigenome, with CpG density and transcription factor binding sites (TFBSs) strongly encoding the DNA methylome. Therefore, genetic polymorphism impacts on the observed epigenome. Furthermore, large genetic variants alter epigenetic signal dosage. Here, we identify DNA methylation variability between GWAS-SNP risk and non-risk haplotypes. In three subsets comprising 3128 MeDIP-seq peripheral-blood DNA methylomes, we find 7173 consistent and functionally enriched Differentially Methylated Regions. 36.8% can be attributed to common non-SNP genetic variants. CpG-SNPs, as well as facilitative TFBS-motifs, are also enriched. Highlighting their functional potential, CpG-SNPs strongly associate with allele-specific DNase-I hypersensitivity sites. Our results demonstrate strong DNA methylation allelic differences driven by obligatory or facilitative genetic effects, with potential direct or regional disease-related repercussions. These allelic variations require disentangling from pure tissue-specific modifications, may influence array studies, and imply underestimated population variability in current reference epigenomes.
[Mh] Termos MeSH primário: Metilação de DNA
Doença/genética
Variação Genética
Estudo de Associação Genômica Ampla/métodos
[Mh] Termos MeSH secundário: Alelos
Ilhas de CpG/genética
Epigênese Genética
Predisposição Genética para Doença/genética
Genoma Humano/genética
Haplótipos
Sequenciamento de Nucleotídeos em Larga Escala/métodos
Seres Humanos
Polimorfismo de Nucleotídeo Único
Fatores de Risco
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180306
[Lr] Data última revisão:
180306
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180104
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-01586-1


  10 / 24233 MEDLINE  
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[PMID]:28465412
[Au] Autor:Severson E; Arnett KL; Wang H; Zang C; Taing L; Liu H; Pear WS; Shirley Liu X; Blacklow SC; Aster JC
[Ad] Endereço:Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
[Ti] Título:Genome-wide identification and characterization of Notch transcription complex-binding sequence-paired sites in leukemia cells.
[So] Source:Sci Signal;10(477), 2017 May 02.
[Is] ISSN:1937-9145
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Notch transcription complexes (NTCs) drive target gene expression by binding to two distinct types of genomic response elements, NTC monomer-binding sites and sequence-paired sites (SPSs) that bind NTC dimers. SPSs are conserved and have been linked to the Notch responsiveness of a few genes. To assess the overall contribution of SPSs to Notch-dependent gene regulation, we determined the DNA sequence requirements for NTC dimerization using a fluorescence resonance energy transfer (FRET) assay and applied insights from these in vitro studies to Notch-"addicted" T cell acute lymphoblastic leukemia (T-ALL) cells. We found that SPSs contributed to the regulation of about a third of direct Notch target genes. Although originally described in promoters, SPSs are present mainly in long-range enhancers, including an enhancer containing a newly described SPS that regulates expression. Our work provides a general method for identifying SPSs in genome-wide data sets and highlights the widespread role of NTC dimerization in Notch-transformed leukemia cells.
[Mh] Termos MeSH primário: Elementos Facilitadores Genéticos
Regulação Leucêmica da Expressão Gênica
Genoma Humano
Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética
Receptores Notch/metabolismo
Fatores de Transcrição/metabolismo
[Mh] Termos MeSH secundário: Animais
Perfilação da Expressão Gênica
Seres Humanos
Camundongos
Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo
Regiões Promotoras Genéticas
Ligação Proteica
Receptores Notch/genética
Transdução de Sinais
Fatores de Transcrição/genética
Células Tumorais Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, Notch); 0 (Transcription Factors)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180303
[Lr] Data última revisão:
180303
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE



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