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Mining the Unknown: Assigning Function to noncoding Single Nucleotide Polymorphisms

TRENDS IN GENETICS 2017年第1期33卷 34-45页

作者： Nishizaki, Sierra S. Boyle, Alan P. Univ Michigan Dept Human Genet Ann Arbor MI 48109 USA Univ Michigan Dept Computat Med & Bioinformat Ann Arbor MI 48109 USA

One of the formative goals of genetics research is to understand how genetic variation leads to phenotypic differences and human disease. Genome-wide association studies (GWASs) bring us closer to this goal by linking variation with disease faster than ever before. Despite this, GWASs alone are unable to pinpoint disease-causing single nucleotide polymorphisms (SNPs). noncoding SNPs, which represent the majority of GWAS SNPs, present a particular challenge. To address this challenge, an array of computational tools designed to prioritize and predict the function of noncoding GWAS SNPs have been developed. However, fewer than 40% of GWAS publications from 2015 utilized these tools. We discuss several leading methods for annotating noncoding variants and how they can be integrated into research pipelines in hopes that they will be broadly applied in future GWAS analyses.

关键词： NUCLEOTIDES GENETIC polymorphisms non-coding dna COMPUTATIONAL biology HUMAN genetics variation

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The role of long noncoding RNAs in cancer: the dark matter matters

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CURRENT OPINION IN GENETICS & DEVELOPMENT 2018年 48卷 8-15页

作者： Hu, Xiaowen Sood, Anil K. Dang, Chi V. Zhang, Lin Univ Penn Ctr Res Reprod & Womens Hlth Philadelphia PA 19104 USA Univ Penn Dept Obstet & Gynecol Philadelphia PA 19104 USA Univ Texas MD Anderson Canc Ctr Ctr RNA Interference & Noncoding RNA Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr Dept Gynecol Oncol & Reprod Med Houston TX 77030 USA Wistar Inst Anat & Biol Philadelphia PA 19104 USA Ludwig Inst Canc Res New York NY 10017 USA

Sequencing technology has facilitated a new era of cancer research, especially in cancer genomics. Using next-generation sequencing, thousands of long noncoding RNAs (lncRNAs) have been identified as abnormally altered in the cancer genome or differentially expressed in tumor tissues. These lncRNAs are associated with imbalanced gene regulation and aberrant biological processes that contribute to malignant transformation. The functions and therapeutic potential of cancer-related lncRNAs have attracted considerable interest in the past few years. Although few lncRNAs have been well-characterized, researchers have recently made impressive progress in understanding lncRNAs and their novel functions, such as regulation of gene expression, metabolism and dna repair. These latest findings reinforce the crucial roles of lncRNAs in cancer initiation and development, as well as their possible clinical applications.

关键词： non-coding dna CANCER risk factors CANCER genetics dna repair GENE expression

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In silico identification and characterisation of 17 polymorphic anonymous non-coding sequence markers (ANMs) for red grouse (Lagopus lagopus scotica)

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CONSERVATION GENETICS RESOURCES 2015年第2期7卷 319-323页

作者： Wenzel, Marius A. Piertney, Stuart B. Univ Aberdeen Inst Biol & Environm Sci Aberdeen AB24 2TZ Scotland

Anonymous non-coding sequence markers (ANMs) are powerful neutral genetic markers with great utility in phylogeography, population genetics and population genomics. Developing ANMs has previously relied on sequencing random fragments of genomic dna in the target species and then querying bioinformatics databases to identify unannotated, putatively neutral fragments. Here, we describe an alternative in silico approach that is based on identifying large unannotated genomic regions in model species to provide a priori neutral targets for candidate ANMs that are remote from exonic regions. We illustrate this approach by developing a set of 17 polymorphic ANMs for red grouse (Lagopus lagopus scotica) from c. 1 Mbp non-coding chromosome regions of chicken, turkey and zebrafinch genomes. This pipeline presents a powerful and efficient approach when appropriate model genomes are available for the target species of interest.

关键词： Anonymous nuclear markers non-coding dna Neutral evolution Red grouse Lagopus

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Identification of candidate intergenic risk loci in autism spectrum disorder

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BMC GENOMICS 2013年第1期14卷 1-6页

作者： Walker, Susan Scherer, Stephen W. Hosp Sick Children Program Genet & Genome Biol Ctr Appl Genom Toronto ON M5G 1L7 Canada Univ Toronto McLaughlin Ctr Toronto ON M5S 1A1 Canada

Background: Copy number variations (CNVs) and dna sequence alterations affecting specific neuronal genes are established risk factors for Autism Spectrum Disorder (ASD). In what is largely considered a genetic condition, so far, these mutations account for similar to 20% of individuals having an ASD diagnosis. However, non-coding genomic sequence also contains functional elements introducing additional disease risk loci for investigation. Results: We have performed genome-wide analyses and identified rare inherited CNVs affecting non-genic intervals in 41 of 1491 (3%) of ASD cases examined. Examples of such intergenic CNV regions include 16q21 and 2p16.3 near known ASD risk genes CDH8 and NRXN1 respectively, as well as novel loci contiguous with ZHX2, MOCS1, LRRC4C, SEMA3C, and other genes. Conclusions: Rare variants in intergenic regions may implicate new risk loci and genes in ASD and also present useful data for comparison with coming whole genome sequence datasets.

关键词： Autism spectrum disorder Copy number variation non-coding dna

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Why repetitive dna is essential to genome function

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BIOLOGICAL REVIEWS 2005年第2期80卷 227-250页

作者： Shapiro, JA von Sternberg, R Univ Chicago Dept Biochem & Mol Biol Chicago IL 60637 USA NIH Natl Ctr Biotechnol Informat Bethesda MD 20894 USA Natl Museum Nat Hist Smithsonian Inst Dept Syst Biol Washington DC 20013 USA

There are clear theoretical reasons and many well-documented examples which show that repetitive dna is essential for genome function. Generic repeated signals in the dna are necessary to format expression of unique coding sequence files and to organise additional functions essential for genome replication and accurate transmission to progeny cells. Repetitive dna sequence elements are also fundamental to the cooperative molecular interactions forming nucleoprotein complexes. Here, we review the surprising abundance of repetitive dna in many genomes, describe its structural diversity, and discuss dozens of cases where the functional importance of repetitive elements has been studied in molecular detail. In particular, the fact that repeat elements serve either as initiators or boundaries for heterochromatin domains and provide a significant fraction of scaffolding/matrix attachment regions (S/MARs) suggests that the repetitive component of the genome plays a major architectonic role in higher order physical structuring. Employing an information science model, the 'functionalist' perspective on repetitive dna leads to new ways of thinking about the systemic organisation of cellular genomes and provides several novel possibilities involving repeat elements in evolutionarily significant genome reorganisation. These ideas may facilitate the interpretation of comparisons between sequenced genomes, where the repetitive dna component is often greater than the coding sequence component.

关键词： transposable element non-coding dna satellite dna junk dna transcriptional regulation chromatin domains evolution biocomputing systems biology data storage

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Development of multilocus putatively neutral dna markers in the X-chromosome for population genetic studies in humans

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ANNALS OF HUMAN BIOLOGY 2012年第4期39卷 281-289页

作者： Khan, Naazneen Chittoria, Anita Pande, Veena Jaiswal, Yogesh Kumar Das, Aparup Natl Inst Malaria Res Evolutionary Genom & Bioinformat Lab Div Genom & Bioinformat New Delhi 110077 India Kumaun Univ Dept Biotechnol Naini Tal 263001 Uttarakhand India Jiwaji Univ Sch Studies Biotechnol Gwalior 474011 Madhya Pradesh India

Background: It has now been well documented that the type (coding, non-coding) and location (nuclear, mitochondrial etc.) of genetic markers heavily influence evolutionary inferences;realistic assumptions can be drawn if multiple putatively neutral dna fragments spread across the genome are used. Aim: To infer human population history, Single Nucleotide Polymorphisms (SNPs), located in the non-coding regions of different genes in the X-chromosome have been developed as 'putatively neutral markers'. Subjects and methods: A population sample consisting of 16 male individuals from the western part of India was utilized for sequencing eight dna fragments located in introns of three genes (Duchenne muscular dystrophy, Factor IX and Pyruvate dehydrogenase E1 sub-unit) on the human X-chromosome. PCR amplification and dna sequencing confirmed the polymorphic status of all the fragments. Results: Twenty nine SNPs were found to be segregating in the Western Indian population samples. Using these SNPs the nucleotide diversity and demographic parameters of the Western Indian population were estimated. Several tests of neutrality ascertained that all eight fragments evolve putatively neutrally. Further, linkage disequilibrium analyses confirmed this fact. Conclusion: All eight dna fragments seem to bear the characteristics to be considered as 'putatively neutral genetic markers' and thus, could be utilized for inference of human population and demographic histories.

关键词： Multilocus non-coding dna SNPs evolution India

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Reducing GWAS Complexity

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CELL CYCLE 2016年第1期15卷 22-24页

作者： Hazelett, Dennis J. Conti, David V. Han, Ying Al Olama, Ali Amin Easton, Doug Eeles, Rosalind A. Kote-Jarai, Zsofia Haiman, Christopher A. Coetzee, Gerhard A. Cedars Sinai Med Ctr Bioinformat & Computat Biol Res Ctr Biomed Sci Los Angeles CA 90048 USA USC Norris Cotton Canc Ctr Dept Prevent Med Los Angeles CA USA USC Norris Cotton Canc Ctr Dept Urol Los Angeles CA USA Univ Cambridge Ctr Canc Genet Epidemiol Div Genet & Epidemiol Cambridge England Inst Canc Res London SW3 6JB England Royal Marsden NHS Fdn Trust London England USC Norris Cotton Canc Ctr Keck Sch Med Microbiol & Prevent Med NTT 64111441 Eastlake Ave Los Angeles Los Angeles CA 90089 USA

Genome-wide association studies (GWAS) have revealed numerous genomic 'hits' associated with complex phenotypes. In most cases these hits, along with surrogate genetic variation as measure by numerous single nucleotide polymorphisms (SNPs) that are in linkage disequilibrium, are not in coding genes making assignment of functionality or causality intractable. Here we propose that fine-mapping along with the matching of risk SNPs at chromatin biofeatures lessen this complexity by reducing the number of candidate functional/causal SNPs. For example, we show here that only on average 2 SNPs per prostate cancer risk locus are likely candidates for functionality/causality;we further propose that this manageable number should be taken forward in mechanistic studies. The candidate SNPs can be looked up for each prostate cancer risk region in 2 recent publications in 2015(1,2) from our groups.

关键词： GWAS SNP Cancer chromatin non-coding dna enhancer fine-mapping

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Why Do Phylogenomic Data Sets Yield Conflicting Trees? Data Type Influences the Avian Tree of Life more than Taxon Sampling

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SYSTEMATIC BIOLOGY 2017年第5期66卷 857-879页

作者： Reddy, Sushma Kimball, Rebecca T. Pandey, Akanksha Hosner, Peter A. Braun, Michael J. Hackett, Shannon J. Han, Kin-Lan Harshman, John Huddleston, Christopher J. Kingston, Sarah Marks, Ben D. Miglia, Kathleen J. Moore, William S. Sheldon, Frederick H. Witt, Christopher C. Yuri, Tamaki Braun, Edward L. Loyola Univ Chicago Dept Biol 1032 W Sheridan Rd Chicago IL 60660 USA Univ Florida Dept Biol Gainesville FL 32607 USA Univ Florida Florida Museum Nat Hist Gainesville FL 32607 USA Univ Maryland Behav Ecol Evolut & Program College Pk MD 20742 USA Field Museum Nat Hist Chicago IL 60605 USA 74869 Pepperwood Way San Jose CA 95124 USA Smithsonian Inst Collect Program Natl Museum Nat Hist 4210 Silver Hill Rd Suitland MD 20746 USA Dept Biol & Coastal Studies Ctr Bowdoin Coll Coll Stn Brunswick ME 04011 USA Wayne State Univ Dept Biol Sci 5047 Gullen Mall Detroit MI 48202 USA Louisiana State Univ Museum Nat Sci & Dept Biol Sci 119 Foster Hall Baton Rouge LA 70803 USA

Phylogenomics, the use of large-scale data matrices in phylogenetic analyses, has been viewed as the ultimate solution to the problem of resolving difficult nodes in the tree of life. However, it has become clear that analyses of these large genomic data sets can also result in conflicting estimates of phylogeny. Here, we use the early divergences in Neoaves, the largest clade of extant birds, as a "model system" to understand the basis for incongruence among phylogenomic trees. We were motivated by the observation that trees from two recent avian phylogenomic studies exhibit conflicts. Those studies used different strategies: 1) collecting many characters [similar to 42 mega base pairs (Mbp) of sequence data] from 48 birds, sometimes including only one taxon for each major clade;and 2) collecting fewer characters (similar to 0.4 Mbp) from 198 birds, selected to subdivide long branches. However, the studies also used different data types: the taxon-poor data matrix comprised 68% non-coding sequences whereas coding exons dominated the taxon-rich datamatrix. This difference raises the question of whether the primary reason for incongruence is the number of sites, the number of taxa, or the data type. To test among these alternative hypotheses we assembled a novel, large-scale data matrix comprising 90% non-coding sequences from 235 bird species. Although increased taxon sampling appeared to have a positive impact on phylogenetic analyses the most important variable was data type. Indeed, by analyzing different subsets of the taxa in our data matrix we found that increased taxon sampling actually resulted in increased congruence with the tree from the previous taxon-poor study (which had a majority of non-coding data) instead of the taxon-rich study (which largely used coding data). We suggest that the observed differences in the estimates of topology for these studies reflect data-type effects due to violations of the models used in phylogenetic analyses, some of whic

关键词： Birds coding exons GTR model model fit Neoaves non-coding dna phylogenomics taxon sampling

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Regulatory variants: from detection to predicting impact

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BRIEFINGS IN BIOINFORMATICS 2019年第5期20卷 1639-1654页

作者： Rojano, Elena Seoane, Pedro Ranea, Juan A. G. Perkins, James R. Univ Malaga Dept Mol Biol & Biochem Malaga Spain Univ Malaga Supercomp & Bioinnovat Ctr SCBI Malaga Spain Reg Univ Hosp Malaga IBIMA Res Lab Malaga Spain

Variants within non-coding genomic regions can greatly affect disease. In recent years, increasing focus has been given to these variants, and how they can alter regulatory elements, such as enhancers, transcription factor binding sites and dna methylation regions. Such variants can be considered regulatory variants. Concurrently, much effort has been put into establishing international consortia to undertake large projects aimed at discovering regulatory elements in different tissues, cell lines and organisms, and probing the effects of genetic variants on regulation by measuring gene expression. Here, we describe methods and techniques for discovering disease-associated non-coding variants using sequencing technologies. We then explain the computational procedures that can be used for annotating these variants using the information from the aforementioned projects, and prediction of their putative effects, including potential pathogenicity, based on rule-based and machine learning approaches. We provide the details of techniques to validate these predictions, by mapping chromatin-chromatin and chromatin-protein interactions, and introduce Clustered Regularly Interspaced Short Palindromic Repeats-Associated Protein 9 (CRISPR-Cas9) technology, which has already been used in this field and is likely to have a big impact on its future evolution. We also give examples of regulatory variants associated with multiple complex diseases. This review is aimed at bioinformaticians interested in the characterization of regulatory variants, molecular biologists and geneticists interested in understanding more about the nature and potential role of such variants from a functional point of views, and clinicians who may wish to learn about variants in non-coding genomic regions associated with a given disease and find out what to do next to uncover how they impact on the underlying mechanisms.

关键词： variant analysis regulatory variants non-coding dna complex diseases GWAS

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Genomic Alterations of non-coding Regions Underlie Human Cancer: Lessons from T-ALL

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TRENDS IN MOLECULAR MEDICINE 2016年第12期22卷 1035-1046页

作者： Rivera-Reyes, Adrian Hayer, Katharina E. Bassing, Craig H. Childrens Hosp Philadelphia Ctr Childhood Canc Res Dept Pathol & Lab Med Div Canc Pathobiol Philadelphia PA 19104 USA Univ Penn Perelman Sch Med Cell & Mol Biol Grad Grp Dept Pathol & Lab MedAbramson Family Canc Res In Philadelphia PA 19104 USA

It has been appreciated for decades that somatic genomic alterations that change coding sequences of proto-oncogenes, translocate enhancers/promoters near proto-oncogenes, or create fusion oncogenes can drive cancer by inducing oncogenic activities. An explosion of genome-wide technologies over the past decade has fueled discoveries of the roles of three-dimensional chromosome structure and powerful cis-acting elements (super-enhancers) in regulating gene transcription. In recent years, studies of human T cell acute lymphoblastic leukemia (T-ALL) using genome-wide technologies have provided paradigms for how non-coding genomic region alterations can disrupt 3D chromosome architecture or establish super-enhancers to activate oncogenic transcription of proto-oncogenes. These studies raise important issues to consider with the objective of leveraging basic knowledge into new diagnostic and therapeutic opportunities for cancer patients.

关键词： GENOMICS non-coding RNA non-coding dna ONCOGENES ADULT T-cell leukemia GENETIC transcription regulation TREATMENT

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