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The chromatin accessibility landscape of primary human cancers

SCIENCE 2018年第6413期362卷 420-+页

作者： Corces, M. Ryan Granja, Jeffrey M. Shams, Shadi Louie, Bryan H. Seoane, Jose A. Zhou, Wanding Silva, Tiago C. Groeneveld, Clarice Wong, Christopher K. Cho, Seung Woo Satpathy, Ansuman T. Mumbach, Maxwell R. Hoadley, Katherine A. Robertson, A. Gordon Sheffield, Nathan C. Felau, Ina Castro, Mauro A. A. Berman, Benjamin P. Staudt, Louis M. Zenklusen, Jean C. Laird, Peter W. Curtis, Christina Greenleaf, William J. Chang, Howard Y. Stanford Univ Ctr Personal Dynam Regulomes Stanford CA 94305 USA Stanford Univ Sch Med Dept Genet Stanford CA 94305 USA Stanford Univ Sch Med Program Biophys Stanford CA 94305 USA Stanford Univ Sch Med Dept Med Stanford CA 94305 USA Stanford Univ Sch Med Stanford Canc Inst Stanford CA 94305 USA Van Andel Res Inst Ctr Epigenet Grand Rapids MI 49503 USA Cedars Sinai Med Ctr Ctr Bioinformat & Funct Genom Los Angeles CA 90048 USA Univ Sao Paulo Ribeirao Preto Med Sch Dept Genet BR-14040905 Ribeirao Preto SP Brazil Univ Fed Parana Polytech Ctr Bioinformat & Syst Biol Lab BR-80060000 Curitiba PR Brazil Univ Calif Santa Cruz Ctr Biomol Sci & Engn Dept Biomol Engn Santa Cruz CA 95064 USA Univ N Carolina Lineberger Comprehens Canc Ctr Dept Genet Chapel Hill NC 27599 USA BC Canc Agcy Canadas Michael Smith Genome Sci Ctr Vancouver BC V5Z 4S6 Canada Univ Virginia Ctr Publ Hlth Genom Charlottesville VA 22908 USA NCI NIH Bethesda MD 20892 USA Stanford Univ Dept Appl Sci Menlo Pk CA 94025 USA Chan Zuckerberg Biohub San Francisco CA 94158 USA Stanford Univ Program Epithelial Biol Stanford CA 94305 USA Stanford Univ Howard Hughes Med Inst Stanford CA 94305 USA

We present the genome-wide chromatin accessibility profiles of 410 tumor samples spanning 23 cancer types from The Cancer Genome Atlas (TCGA). We identify 562,709 transposase-accessible dna elements that substantially extend the compendium of known cis-regulatory elements. Integration of ATAC-seq (the assay for transposase-accessible chromatin using sequencing) with TCGA multi-omic data identifies a large number of putative distal enhancers that distinguish molecular subtypes of cancers, uncovers specific driving transcription factors via protein-dna footprints, and nominates long-range gene-regulatory interactions in cancer. These data reveal genetic risk loci of cancer predisposition as active dna regulatory elements in cancer, identify gene-regulatory interactions underlying cancer immune evasion, and pinpoint noncoding mutations that drive enhancer activation and may affect patient survival. These results suggest a systematic approach to understanding the noncoding genome in cancer to advance diagnosis and therapy.

关键词： CHROMATIN GENETIC regulation CANCER genetics TRANSPOSASE genetics TRANSCRIPTION factors non-coding dna dna sequencing

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The Retrotransposon storm and the dangers of a Collyer's genome

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CURRENT OPINION IN GENETICS & DEVELOPMENT 2018年 49卷 95-105页

作者： Dubnau, Josh SUNY Stony Brook Dept Anesthesiol Stony Brook NY 11794 USA SUNY Stony Brook Dept Neurobiol & Behav Stony Brook NY 11794 USA Stony Brook Sch Med Stony Brook NY 11794 USA

Like the famous Collyer's mansion in NY, our genomes have accumulated vast quantities of sequences that have been referred to as 'junk dna,' much of which consists of retrotransposons (RTEs). A recent literature establishes the phenomenology that many RTEs become expressed at progressively higher levels during the course of normal aging. This seems to reflect gradual loss of heterochromatin in old age. In addition, RTEs appear to be precociously expressed in brains of younger animals that are experiencing neurodegenerative decline. Although it is difficult to distinguish cause from consequence, several recent studies support the contention that RTE expression, and even perhaps transposition, causally contribute to both the normal deterioration seen with age and to the precipitous decline in some neurodegenerative disorders. This may reflect a two hit model in which normal age-dependent loss of heterochromatin synergizes with a disruption to posttranscriptional silencing of RTEs caused by genetic and environmental stress.

关键词： RETROTRANSPOSONS HETEROCHROMATIN NEURODEGENERATION non-coding dna TRANSLOCATION (Genetics)

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Structural families of genomic microsatellites

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GENE 2008年第1-2期408卷 124-132页

作者： Subirana, Juan A. Messeguer, Xavier Univ Politecn Cataluna Dept Engn Quim E-08028 Barcelona Spain Univ Politecn Cataluna Dept Llenguatges & Sist Informat E-08034 Barcelona Spain

We present an analysis of tandem repeats of short sequence motifs (microsatellites) in twelve eukaryotes for which a large part of the genome has been sequenced and assembled. The pattern of motif abundance varies significantly in different species, but it is very similar in different chromosomes of the same species. The most abundant repeats can be classified in two main families. The first family has a rigid conformation, with purines in one strand and pyrimidines in the complementary strand, mainly A(n)/T(n) and (AG)(n)/(CT)(n). The second family has alternating, flexible sequences, such as (AT)(n), (AC)(n) and related sequences. In the pluricellular organisms the relative frequency of both families is rather constant. These observations indicate that microsatellites have structural information and may be involved in the organization of chromatin fibers and in chromosome architecture in general. An additional intriguing finding is the absence of microsatellites with sequences which appear to be forbidden, such as (AATT)(n). Additional tables and references are given as supplementary material. (c) 2007 Elsevier B.V. All rights reserved.

关键词： dna structure chromatin fibers non-coding dna dna repeats

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Variable locus length in the human genome leads to ascertainment bias in functional inference for non-coding elements

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BIOINFORMATICS 2009年第5期25卷 578-584页

作者： Taher, Leila Ovcharenko, Ivan Natl Lib Med Computat Biol Branch Natl Ctr Biotechnol Informat NIH Bethesda MD 20894 USA

Motivation: Several functional gene annotation databases have been developed in the recent years, and are widely used to infer the biological function of gene sets, by scrutinizing the attributes that appear over- and underrepresented. However, this strategy is not directly applicable to the study of non-coding dna, as the non-coding sequence span varies greatly among different gene loci in the human genome and longer loci have a higher likelihood of being selected purely by chance. Therefore, conclusions involving the function of non-coding elements that are drawn based on the annotation of neighboring genes are often biased. We assessed the systematic bias in several particular Gene Ontology (GO) categories using the standard hypergeometric test, by randomly sampling non-coding elements from the human genome and inferring their function based on the functional annotation of the closest genes. While no category is expected to occur significantly over- or underrepresented for a random selection of elements, categories such as 'cell adhesion', 'nervous system development' and 'transcription factor activities' appeared to be systematically overrepresented, while others such as 'olfactory receptor activity'-underrepresented. Results: Our results suggest that functional inference for non-coding elements using gene annotation databases requires a special correction. We introduce a set of correction coefficients for the probabilities of the GO categories that accounts for the variability in the length of the non-coding dna across different loci and effectively eliminates the ascertainment bias from the functional characterization of non-coding elements. Our approach can be easily generalized to any other gene annotation database.

关键词： .Databases GO categories functional inference gene annotation non-coding dna

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Predicting regulatory variants with composite statistic

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BIOINFORMATICS 2016年第18期32卷 2729-2736页

作者： Li, Mulin Jun Pan, Zhicheng Liu, Zipeng Wu, Jiexing Wang, Panwen Zhu, Yun Xu, Feng Xia, Zhengyuan Sham, Pak Chung Kocher, Jean-Pierre A. Li, Miaoxin Liu, Jun S. Wang, Junwen Harvard Univ Dept Stat Boston MA 02138 USA Univ Hong Kong Ctr Genom Sci Hong Kong Hong Kong Peoples R China Univ Hong Kong Sch Biomed Sci Hong Kong Hong Kong Peoples R China Univ Hong Kong Dept Anaesthesiol Hong Kong Hong Kong Peoples R China Univ Hong Kong Dept Psychiat Hong Kong Hong Kong Peoples R China Univ Hong Kong Ctr Reprod Dev & Growth LKS Fac Med Hong Kong Hong Kong Peoples R China Tsinghua Univ Ctr Stat Sci Beijing 100084 Peoples R China Mayo Clin Ctr Individualized Med Dept Hlth Sci Res Scottsdale AZ 85259 USA Arizona State Univ Dept Biomed Informat Scottsdale AZ 85259 USA

Motivation: Prediction and prioritization of human non-coding regulatory variants is critical for understanding the regulatory mechanisms of disease pathogenesis and promoting personalized medicine. Existing tools utilize functional genomics data and evolutionary information to evaluate the pathogenicity or regulatory functions of non-coding variants. However, different algorithms lead to inconsistent and even conflicting predictions. Combining multiple methods may increase accuracy in regulatory variant prediction. Results: Here, we compiled an integrative resource for predictions from eight different tools on functional annotation of non-coding variants. We further developed a composite strategy to integrate multiple predictions and computed the composite likelihood of a given variant being regulatory variant. Benchmarked by multiple independent causal variants datasets, we demonstrated that our composite model significantly improves the prediction performance. Availability and Implementation: We implemented our model and scoring procedure as a tool, named PRVCS, which is freely available to academic and non-profit usage at http://***/PRVCS. Contact: ***@***, jliu@***, or limx54@*** Supplementary information: Supplementary data are available at Bioinformatics online.

关键词： PREDICTION (Logic) GENOMICS non-coding dna VIRULENCE (Microbiology) MEDICINE

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Phylogenetic utility of the trnH-psbA IGR and stem-loop diversity of the 3' UTR in Cactaceae (Caryophyllales)

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PLANT SYSTEMATICS AND EVOLUTION 2017年第3期303卷 299-315页

作者： Hernandez-Ledesma, Patricia Barcenas, Rolando T. Univ Autonoma Queretaro Fac Ciencias Nat Lab Genet Mol & Ecol Evolut Campus Aeropuerto Queretaro 76140 Queretaro Mexico

The ultrastructure of the psbA-trnH intergenic region (hereafter IGR) of the Cactaceae was characterised based on 642 sequences identifying a conserved region and a mutational hot spot with different evolutionary rates. The first section of the IGR includes a highly conserved 3' UTR of the psbA containing a TATA-box and a stem-loop. The second section of the IGR is a highly variable intergenic spacer (hereafter IGS) with a mutational hot spot. The phylogenetic utility of this IGR was tested by applying four different partitioned schemes to the same data set and searching for trees under different evolutionary models. The IGR showed 90 different stem-loop conformations with the highest diversity found in the Cactoideae with 78 architectures, the Opuntioideae with nine and the Pereskioideae with seven different architectures. The shortest stem-loop was recovered for Rhipsalis paradoxa with 47 nt, while the longest stem-loop was found in five species of Echinocereus. The organisation of the IGR in the Cactaceae follows the overall general organisation analysed for other angiosperms, and it seems that within the family, there is a general tendency to the reduction in length of the IGR in Maihuenia + Opuntioideae + Cacteae compared with Pereskia. The over-partition of the data set reduces resolution and support, while the un-partitioned analysis, disregarding primary homology assessment, shows good support and resolution but builds a phylogeny on ambiguous grounds. The best proposal scheme for this IGR is a partitioned analysis including three different regions that shows high support and resolution and considers primary homology assessment as a fundamental step in phylogeny reconstruction.

关键词： Cactineae Hairpin architecture non-coding dna Phylogenetic reconstruction RNA secondary structure TATA-box

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Phylogeny of the eudicot order Malpighiales: analysis of a recalcitrant clade with sequences of the petD group II intron

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PLANT SYSTEMATICS AND EVOLUTION 2009年第3-4期282卷 201-228页

作者： Korotkova, Nadja Schneider, Julio V. Quandt, Dietmar Worberg, Andreas Zizka, Georg Borsch, Thomas Univ Bonn Nees Inst Biodivers Plants D-5300 Bonn Germany Univ Leipzig Dept Systemat Bot Leipzig Germany Tech Univ Dresden Inst Bot Plant Phylogenet & Phylogenom Grp D-8027 Dresden Germany Res Inst Senckenberg Dept Bot & Mol Evolut Frankfurt Germany Goethe Univ Frankfurt Frankfurt Germany

Malpighiales are one of the most diverse orders of angiosperms. Molecular phylogenetic studies based on combined sequences of coding genes allowed to identify major lineages but hitherto were unable to resolve relationships among most families. Spacers and introns of the chloroplast genome have recently been shown to provide strong signal for inferring relationships among major angiosperm lineages and within difficult clades. In this study, we employed sequence data of the petD group II intron and the petB-petD spacer for a set of 64 Malpighiales taxa, representing all major lineages. Celastrales and Oxalidales served as outgroups. Sequence alignment was straightforward due to frequent microstructural changes with easily recognizable motifs (e. g., simple sequence repeats), and well defined mutational hotspots. The secondary structure of the complete petD intron was calculated for Idesia polycarpa as an example. Domains I and IV are the most length variable parts of the intron. They contain terminal A/T-rich stem-loop elements that are suggested to elongate independently in different lineages with a slippage mechanism earlier reported from the P8 stem-loop of the trnL intron. Parsimony and Bayesian analyses of the petD dataset yielded trees largely congruent with results from earlier multigene studies but statistical support of nodes was generally higher. For the first time a deep node of the Malpighiales backbone, a clade comprising Achariaceae, Violaceae, Malesherbiaceae, Turneraceae, Passifloraceae, and a Lacistemataceae-Salicaceae lineage received significant statistical support (83% JK, 1.00 PP) from plastid dna sequences.

关键词： Malpighiales Angiosperms Molecular evolution Group II introns non-coding dna

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Genome-wide ultraconserved elements exhibit higher phylogenetic informativeness than traditional gene markers in percomorph fishes

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MOLECULAR PHYLOGENETICS AND EVOLUTION 2015年 92卷 140-146页

作者： Gilbert, Princess S. Chang, Jonathan Pan, Calvin Sobel, Eric M. Sinsheimer, Janet S. Faircloth, Brant C. Alfaro, Michael E. Univ Calif Los Angeles Dept Ecol & Evolutionary Biol Los Angeles CA 90095 USA Univ Calif Los Angeles Dept Med Los Angeles CA 90095 USA Univ Calif Los Angeles Dept Biomath Los Angeles CA 90095 USA Univ Calif Los Angeles Dept Human Genet Los Angeles CA 90095 USA Univ Calif Los Angeles Dept Biostat Los Angeles CA 90095 USA Louisiana State Univ Dept Biol Sci Baton Rouge LA 70803 USA Louisiana State Univ Museum Nat Sci Baton Rouge LA 70803 USA

Ultraconserved elements (UCEs) have become popular markers in phylogenomic studies because of their cost effectiveness and their potential to resolve problematic phylogenetic relationships. Although UCE datasets typically contain a much larger number of loci and sites than more traditional datasets of PCR-amplified, single-copy, protein coding genes, a fraction of UCE sites are expected to be part of a nearly invariant core, and the relative performance of UCE datasets versus protein coding gene datasets is poorly understood. Here we use phylogenetic informativeness (PI) to compare the resolving power of multi-locus and UCE datasets in a sample of percomorph fishes with sequenced genomes (genome-enabled). We compare three data sets: UCE core regions, flanking sequence adjacent to the UCE core and a set of ten protein coding genes commonly used in fish systematics. We found the net informativeness of UCE core and flank regions to be roughly ten-fold and 100-fold more informative than that of the protein coding genes. On a per locus basis UCEs and protein coding genes exhibited similar levels of phylogenetic informativeness. Our results suggest that UCEs offer enormous potential for resolving relationships across the percomorph tree of life. (C) 2015 Elsevier Inc. All rights reserved.

关键词： Ultraconserved elements Next-generation sequencing non-coding dna Phylogenomics Molecular evolution Phylogenetic informativeness

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Unravelling cis-Regulatory Elements in the Genome of the Smallest Photosynthetic Eukaryote: Phylogenetic Footprinting in Ostreococcus

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JOURNAL OF MOLECULAR EVOLUTION 2009年第3期69卷 249-259页

作者： Piganeau, Gwenael Vandepoele, Klaas Gourbiere, Sebastien Van de Peer, Yves Moreau, Herve Observ Oceanol LOB UMR7621 CNRS F-66651 Banyuls Sur Mer France Univ Paris 06 UMR 7621 Lab Arago F-66651 Banyuls Sur Mer France VIB Dept Plant Syst Biol B-9052 Ghent Belgium Univ Ghent Dept Mol Genet B-9052 Ghent Belgium Univ Perpignan UMR 5244 Lab Biol & Ecol Tropicale & Mediterraneenne F-66860 Perpignan France

We used a phylogenetic footprinting approach, adapted to high levels of divergence, to estimate the level of constraint in intergenic regions of the extremely gene dense Ostreococcus algae genomes (Chlorophyta, Prasinophyceae). We first benchmarked our method against the Saccharomyces sensu stricto genome data and found that the proportion of conserved non-coding sites was consistent with those obtained with methods using calibration by the neutral substitution rate. We then applied our method to the complete genomes of Ostreococcus tauri and O. lucimarinus, which are the most divergent species from the same genus sequenced so far. We found that 77% of intergenic regions in Ostreococcus still contain some phylogenetic footprints, as compared to 88% for Saccharomyces, corresponding to an average rate of constraint on intergenic region of 17% and 30%, respectively. A comparison with some known functional cis-regulatory elements enabled us to investigate whether some transcriptional regulatory pathways were conserved throughout the green lineage. Strikingly, the size of the phylogenetic footprints depends on gene orientation of neighboring genes, and appears to be genus-specific. In Ostreococcus, 5' intergenic regions contain four times more conserved sites than 3' intergenic regions, whereas in yeast a higher frequency of constrained sites in intergenic regions between genes on the same dna strand suggests a higher frequency of bidirectional regulatory elements. The phylogenetic footprinting approach can be used despite high levels of divergence in the ultrasmall Ostreococcus algae, to decipher structure of constrained regulatory motifs, and identify putative regulatory pathways conserved within the green lineage.

关键词： Phylogenetic footprinting non-coding dna cis-regulatory elements Saccharomyces Ostreococcus

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The Most Deeply Conserved noncoding Sequences in Plants Serve Similar Functions to Those in Vertebrates Despite Large Differences in Evolutionary Rates

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PLANT CELL 2014年第3期26卷 946-961页

作者： Burgess, Diane Freeling, Michael Univ Calif Berkeley Dept Plant & Microbial Biol Berkeley CA 94720 USA

In vertebrates, conserved noncoding elements (CNEs) are functionally constrained sequences that can show striking conservation over >400 million years of evolutionary distance and frequently are located megabases away from target developmental genes. Conserved noncoding sequences (CNSs) in plants are much shorter, and it has been difficult to detect conservation among distantly related genomes. In this article, we show not only that CNS sequences can be detected throughout the eudicot clade of flowering plants, but also that a subset of 37 CNSs can be found in all flowering plants (diverging similar to 170 million years ago). These CNSs are functionally similar to vertebrate CNEs, being highly associated with transcription factor and development genes and enriched in transcription factor binding sites. Some of the most highly conserved sequences occur in genes encoding RNA binding proteins, particularly the RNA splicing-associated SR genes. Differences in sequence conservation between plants and animals are likely to reflect differences in the biology of the organisms, with plants being much more able to tolerate genomic deletions and whole-genome duplication events due, in part, to their far greater fecundity compared with vertebrates.

关键词： non-coding dna PLANT dna PLANT genomes EUDICOTYLEDONES TRANSCRIPTION factors

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