Unsupervised pattern discovery in human chromatin structure through genomic segmentation
22 Sep 2013-Vol. 9, Iss: 5, pp 813
TL;DR: An integrative method is developed to identify patterns from multiple experiments simultaneously while taking full advantage of high-resolution data, discovering joint patterns across different assay types, and yields a model which elucidates the relationship between assay observations and functional elements in the genome.
Abstract: Sequence census methods like ChIP-seq now produce an unprecedented amount of genome-anchored data. We have developed an integrative method to identify patterns from multiple experiments simultaneously while taking full advantage of high-resolution data, discovering joint patterns across different assay types. We apply this method to ENCODE chromatin data for the human chronic myeloid leukemia cell line K562, including ChIP-seq data on covalent histone modifications and transcription factor binding, and DNase-seq and FAIRE-seq readouts of open chromatin. In an unsupervised fashion, we identify patterns associated with transcription start sites, gene ends, enhancers, CTCF elements, and repressed regions. The method yields a model which elucidates the relationship between assay observations and functional elements in the genome. This model identifies sequences likely to affect transcription, and we verify these predictions in laboratory experiments. We have made software and an integrative genome browser track freely available (noble.gs.washington.edu/proj/segway/).
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TL;DR: The Encyclopedia of DNA Elements project provides new insights into the organization and regulation of the authors' genes and genome, and is an expansive resource of functional annotations for biomedical research.
Abstract: The human genome encodes the blueprint of life, but the function of the vast majority of its nearly three billion bases is unknown. The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure and histone modification. These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. Many discovered candidate regulatory elements are physically associated with one another and with expressed genes, providing new insights into the mechanisms of gene regulation. The newly identified elements also show a statistical correspondence to sequence variants linked to human disease, and can thereby guide interpretation of this variation. Overall, the project provides new insights into the organization and regulation of our genes and genome, and is an expansive resource of functional annotations for biomedical research.
13,548 citations
Journal Article•
TL;DR: The Encyclopedia of DNA Elements project provides new insights into the organization and regulation of the authors' genes and genome, and is an expansive resource of functional annotations for biomedical research.
Abstract: The human genome encodes the blueprint of life, but the function of the vast majority of its nearly three billion bases is unknown. The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure and histone modification. These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. Many discovered candidate regulatory elements are physically associated with one another and with expressed genes, providing new insights into the mechanisms of gene regulation. The newly identified elements also show a statistical correspondence to sequence variants linked to human disease, and can thereby guide interpretation of this variation. Overall, the project provides new insights into the organization and regulation of our genes and genome, and is an expansive resource of functional annotations for biomedical research.
8,106 citations
TL;DR: The ability of CADD to prioritize functional, deleterious and pathogenic variants across many functional categories, effect sizes and genetic architectures is unmatched by any current single-annotation method.
Abstract: Our capacity to sequence human genomes has exceeded our ability to interpret genetic variation. Current genomic annotations tend to exploit a single information type (e.g. conservation) and/or are restricted in scope (e.g. to missense changes). Here, we describe Combined Annotation Dependent Depletion (CADD), a framework that objectively integrates many diverse annotations into a single, quantitative score. We implement CADD as a support vector machine trained to differentiate 14.7 million high-frequency human derived alleles from 14.7 million simulated variants. We pre-compute “C-scores” for all 8.6 billion possible human single nucleotide variants and enable scoring of short insertions/deletions. C-scores correlate with allelic diversity, annotations of functionality, pathogenicity, disease severity, experimentally measured regulatory effects, and complex trait associations, and highly rank known pathogenic variants within individual genomes. The ability of CADD to prioritize functional, deleterious, and pathogenic variants across many functional categories, effect sizes and genetic architectures is unmatched by any current annotation.
4,956 citations
University of Copenhagen1, University Hospital Regensburg2, University of Birmingham3, University of North Carolina at Chapel Hill4, Harvard University5, Aarhus University6, University of Edinburgh7, Lawrence Berkeley National Laboratory8, European Bioinformatics Institute9, Karolinska Institutet10, VU University Medical Center11
TL;DR: It is shown that enhancers share properties with CpG-poor messenger RNA promoters but produce bidirectional, exosome-sensitive, relatively short unspliced RNAs, the generation of which is strongly related to enhancer activity.
Abstract: Enhancers control the correct temporal and cell-type-specific activation of gene expression in multicellular eukaryotes. Knowing their properties, regulatory activity and targets is crucial to understand the regulation of differentiation and homeostasis. Here we use the FANTOM5 panel of samples, covering the majority of human tissues and cell types, to produce an atlas of active, in vivo-transcribed enhancers. We show that enhancers share properties with CpG-poor messenger RNA promoters but produce bidirectional, exosome-sensitive, relatively short unspliced RNAs, the generation of which is strongly related to enhancer activity. The atlas is used to compare regulatory programs between different cells at unprecedented depth, to identify disease-associated regulatory single nucleotide polymorphisms, and to classify cell-type-specific and ubiquitous enhancers. We further explore the utility of enhancer redundancy, which explains gene expression strength rather than expression patterns. The online FANTOM5 enhancer atlas represents a unique resource for studies on cell-type-specific enhancers and gene regulation.
2,260 citations
TL;DR: An overview of machine learning applications for the analysis of genome sequencing data sets, including the annotation of sequence elements and epigenetic, proteomic or metabolomic data is provided.
Abstract: The field of machine learning, which aims to develop computer algorithms that improve with experience, holds promise to enable computers to assist humans in the analysis of large, complex data sets. Here, we provide an overview of machine learning applications for the analysis of genome sequencing data sets, including the annotation of sequence elements and epigenetic, proteomic or metabolomic data. We present considerations and recurrent challenges in the application of supervised, semi-supervised and unsupervised machine learning methods, as well as of generative and discriminative modelling approaches. We provide general guidelines to assist in the selection of these machine learning methods and their practical application for the analysis of genetic and genomic data sets.
1,317 citations
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49,597 citations
TL;DR: The upper bound is obtained for a specific probabilistic nonsequential decoding algorithm which is shown to be asymptotically optimum for rates above R_{0} and whose performance bears certain similarities to that of sequential decoding algorithms.
Abstract: The probability of error in decoding an optimal convolutional code transmitted over a memoryless channel is bounded from above and below as a function of the constraint length of the code. For all but pathological channels the bounds are asymptotically (exponentially) tight for rates above R_{0} , the computational cutoff rate of sequential decoding. As a function of constraint length the performance of optimal convolutional codes is shown to be superior to that of block codes of the same length, the relative improvement increasing with rate. The upper bound is obtained for a specific probabilistic nonsequential decoding algorithm which is shown to be asymptotically optimum for rates above R_{0} and whose performance bears certain similarities to that of sequential decoding algorithms.
6,804 citations
25 Jun 2006
TL;DR: It is shown that a deep connection exists between ROC space and PR space, such that a curve dominates in R OC space if and only if it dominates in PR space.
Abstract: Receiver Operator Characteristic (ROC) curves are commonly used to present results for binary decision problems in machine learning. However, when dealing with highly skewed datasets, Precision-Recall (PR) curves give a more informative picture of an algorithm's performance. We show that a deep connection exists between ROC space and PR space, such that a curve dominates in ROC space if and only if it dominates in PR space. A corollary is the notion of an achievable PR curve, which has properties much like the convex hull in ROC space; we show an efficient algorithm for computing this curve. Finally, we also note differences in the two types of curves are significant for algorithm design. For example, in PR space it is incorrect to linearly interpolate between points. Furthermore, algorithms that optimize the area under the ROC curve are not guaranteed to optimize the area under the PR curve.
5,063 citations
TL;DR: A comprehensive search for conserved elements in vertebrate genomes is conducted, using genome-wide multiple alignments of five vertebrate species (human, mouse, rat, chicken, and Fugu rubripes), using a two-state phylogenetic hidden Markov model (phylo-HMM).
Abstract: We have conducted a comprehensive search for conserved elements in vertebrate genomes, using genome-wide multiple alignments of five vertebrate species (human, mouse, rat, chicken, and Fugu rubripes). Parallel searches have been performed with multiple alignments of four insect species (three species of Drosophila and Anopheles gambiae), two species of Caenorhabditis, and seven species of Saccharomyces. Conserved elements were identified with a computer program called phastCons, which is based on a two-state phylogenetic hidden Markov model (phylo-HMM). PhastCons works by fitting a phylo-HMM to the data by maximum likelihood, subject to constraints designed to calibrate the model across species groups, and then predicting conserved elements based on this model. The predicted elements cover roughly 3%-8% of the human genome (depending on the details of the calibration procedure) and substantially higher fractions of the more compact Drosophila melanogaster (37%-53%), Caenorhabditis elegans (18%-37%), and Saccharaomyces cerevisiae (47%-68%) genomes. From yeasts to vertebrates, in order of increasing genome size and general biological complexity, increasing fractions of conserved bases are found to lie outside of the exons of known protein-coding genes. In all groups, the most highly conserved elements (HCEs), by log-odds score, are hundreds or thousands of bases long. These elements share certain properties with ultraconserved elements, but they tend to be longer and less perfectly conserved, and they overlap genes of somewhat different functional categories. In vertebrates, HCEs are associated with the 3' UTRs of regulatory genes, stable gene deserts, and megabase-sized regions rich in moderately conserved noncoding sequences. Noncoding HCEs also show strong statistical evidence of an enrichment for RNA secondary structure.
3,719 citations
TL;DR: Find Individual Motif Occurrences (FIMO), a software tool for scanning DNA or protein sequences with motifs described as position-specific scoring matrices, and provides output in a variety of formats, including HTML, XML and several Santa Cruz Genome Browser formats.
Abstract: Summary: A motif is a short DNA or protein sequence that contributes to the biological function of the sequence in which it resides. Over the past several decades, many computational methods have been described for identifying, characterizing and searching with sequence motifs. Critical to nearly any motif-based sequence analysis pipeline is the ability to scan a sequence database for occurrences of a given motif described by a position-specific frequency matrix. Results: We describe Find Individual Motif Occurrences (FIMO), a software tool for scanning DNA or protein sequences with motifs described as position-specific scoring matrices. The program computes a log-likelihood ratio score for each position in a given sequence database, uses established dynamic programming methods to convert this score to a P-value and then applies false discovery rate analysis to estimate a q-value for each position in the given sequence. FIMO provides output in a variety of formats, including HTML, XML and several Santa Cruz Genome Browser formats. The program is efficient, allowing for the scanning of DNA sequences at a rate of 3.5 Mb/s on a single CPU. Availability and Implementation: FIMO is part of the MEME Suite software toolkit. A web server and source code are available at
3,266 citations