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The Encyclopedia of DNA Elements (ENCODE) Data Coordinating Center has developed the ENCODE Portal database and website as the source for the data and metadata generated by the ENCODE Consortium. Two principles have motivated the design. First, experimental protocols, analytical procedures and the data themselves should be made publicly accessible through a coherent, web-based search and download interface. Second, the same interface should serve carefully curated metadata that record the provenance of the data and justify its interpretation in biological terms. Since its initial release in 2013 and in response to recommendations from consortium members and the wider community of scientists who use the Portal to access ENCODE data, the Portal has been regularly updated to better reflect these design principles. Here we report on these updates, including results from new experiments, uniformly-processed data from other projects, new visualization tools and more comprehensive metadata to describe experiments and analyses. Additionally, the Portal is now home to meta(data) from related projects including Genomics of Gene Regulation, Roadmap Epigenome Project, Model organism ENCODE (modENCODE) and modERN. The Portal now makes available over 13000 datasets and their accompanying metadata and can be accessed at: https://www.encodeproject.org/.

Launched in 2001 to showcase the draft human genome assembly, the UCSC Genome Browser database (http://genome.ucsc.edu) and associated tools continue to grow, providing a comprehensive resource of genome assemblies and annotations to scientists and students worldwide. Highlights of the past year include the release of a browser for the first new human genome reference assembly in 4 years in December 2013 (GRCh38, UCSC hg38), a watershed comparative genomics annotation (100-species multiple alignment and conservation) and a novel distribution mechanism for the browser (GBiB: Genome Browser in a Box). We created browsers for new species (Chinese hamster, elephant shark, minke whale), 'mined the web' for DNA sequences and expanded the browser display with stacked color graphs and region highlighting. As our user community increasingly adopts the UCSC track hub and assembly hub representations for sharing large-scale genomic annotation data sets and genome sequencing projects, our menu of public data hubs has tripled.

The University of California Santa Cruz Genome Browser (http://genome.ucsc.edu) offers online public access to a growing database of genomic sequence and annotations for a wide variety of organisms. The Browser is an integrated tool set for visualizing, comparing, analyzing and sharing both publicly available and user-generated genomic data sets. In the past year, the local database has been updated with four new species assemblies, and we anticipate another four will be released by the end of 2011. Further, a large number of annotation tracks have been either added, updated by contributors, or remapped to the latest human reference genome. Among these are new phenotype and disease annotations, UCSC genes, and a major dbSNP update, which required new visualization methods. Growing beyond the local database, this year we have introduced ‘track data hubs’, which allow the Genome Browser to provide access to remotely located sets of annotations. This feature is designed to significantly extend the number and variety of annotation tracks that are publicly available for visualization and analysis from within our site. We have also introduced several usability features including track search and a context-sensitive menu of options available with a right-click anywhere on the Browser's image.

The Encyclopedia of DNA Elements (ENCODE) Consortium is entering its 5th year of production-level effort generating high-quality whole-genome functional annotations of the human genome. The past year has brought the ENCODE compendium of functional elements to critical mass, with a diverse set of 27 biochemical assays now covering 200 distinct human cell types. Within the mouse genome, which has been under study by ENCODE groups for the past 2 years, 37 cell types have been assayed. Over 2000 individual experiments have been completed and submitted to the Data Coordination Center for public use. UCSC makes this data available on the quality-reviewed public Genome Browser (http://genome.ucsc.edu) and on an early-access Preview Browser (http://genome-preview.ucsc.edu). Visual browsing, data mining and download of raw and processed data files are all supported. An ENCODE portal (http://encodeproject.org) provides specialized tools and information about the ENCODE data sets.

The University of California, Santa Cruz (UCSC) Genome Browser website (http://genome.ucsc.edu/) provides a large database of publicly available sequence and annotation data along with an integrated tool set for examining and comparing the genomes of organisms, aligning sequence to genomes, and displaying and sharing users' own annotation data. As of September 2009, genomic sequence and a basic set of annotation 'tracks' are provided for 47 organisms, including 14 mammals, 10 non-mammal vertebrates, 3 invertebrate deuterostomes, 13 insects, 6 worms and a yeast. New data highlights this year include an updated human genome browser, a 44-species multiple sequence alignment track, improved variation and phenotype tracks and 16 new genome-wide ENCODE tracks. New features include drag-and-zoom navigation, a Wiki track for user-added annotations, new custom track formats for large datasets (bigBed and bigWig), a new multiple alignment output tool, links to variation and protein structure tools, in silico PCR utility enhancements, and improved track configuration tools.

The Encyclopedia of DNA Elements (ENCODE) Data Coordinating Center (DCC) is responsible for organizing, describing and providing access to the diverse data generated by the ENCODE project. The description of these data, known as metadata, includes the biological sample used as input, the protocols and assays performed on these samples, the data files generated from the results and the computational methods used to analyze the data. Here, we outline the principles and philosophy used to define the ENCODE metadata in order to create a metadata standard that can be applied to diverse assays and multiple genomic projects. In addition, we present how the data are validated and used by the ENCODE DCC in creating the ENCODE Portal (https://www.encodeproject.org/). Database URL: www.encodeproject.org.

The University of California Santa Cruz (UCSC) Genome Browser (http://genome.ucsc.edu) offers online public access to a growing database of genomic sequence and annotations for a large collection of organisms, primarily vertebrates, with an emphasis on the human and mouse genomes. The Browser's web-based tools provide an integrated environment for visualizing, comparing, analysing and sharing both publicly available and user-generated genomic data sets. As of September 2013, the database contained genomic sequence and a basic set of annotation 'tracks' for ∼90 organisms. Significant new annotations include a 60-species multiple alignment conservation track on the mouse, updated UCSC Genes tracks for human and mouse, and several new sets of variation and ENCODE data. New software tools include a Variant Annotation Integrator that returns predicted functional effects of a set of variants uploaded as a custom track, an extension to UCSC Genes that displays haplotype alleles for protein-coding genes and an expansion of data hubs that includes the capability to display remotely hosted user-provided assembly sequence in addition to annotation data. To improve European access, we have added a Genome Browser mirror (http://genome-euro.ucsc.edu) hosted at Bielefeld University in Germany.

The Encyclopedia of DNA Elements (ENCODE), http://encodeproject.org, has completed its fifth year of scientific collaboration to create a comprehensive catalog of functional elements in the human genome, and its third year of investigations in the mouse genome. Since the last report in this journal, the ENCODE human data repertoire has grown by 898 new experiments (totaling 2886), accompanied by a major integrative analysis. In the mouse genome, results from 404 new experiments became available this year, increasing the total to 583, collected during the course of the project. The University of California, Santa Cruz, makes this data available on the public Genome Browser http://genome.ucsc.edu for visual browsing and data mining. Download of raw and processed data files are all supported. The ENCODE portal provides specialized tools and information about the ENCODE data sets.

The mission of the Encyclopedia of DNA Elements (ENCODE) Project is to enable the scientific and medical communities to interpret the human genome sequence and apply it to understand human biology and improve health. The ENCODE Consortium is integrating multiple technologies and approaches in a collective effort to discover and define the functional elements encoded in the human genome, including genes, transcripts, and transcriptional regulatory regions, together with their attendant chromatin states and DNA methylation patterns. In the process, standards to ensure high-quality data have been implemented, and novel algorithms have been developed to facilitate analysis. Data and derived results are made available through a freely accessible database. Here we provide an overview of the project and the resources it is generating and illustrate the application of ENCODE data to interpret the human genome., National Human Genome Research Institute (U.S.), National Institutes of Health (U.S.)

The Encyclopedia of DNA Elements (ENCODE) project is an international consortium of investigators funded to analyze the human genome with the goal of producing a comprehensive catalog of functional elements. The ENCODE Data Coordination Center at The University of California, Santa Cruz (UCSC) is the primary repository for experimental results generated by ENCODE investigators. These results are captured in the UCSC Genome Bioinformatics database and download server for visualization and data mining via the UCSC Genome Browser and companion tools (Rhead et al. The UCSC Genome Browser Database: update 2010, in this issue). The ENCODE web portal at UCSC (http://encodeproject.org or http://genome.ucsc.edu/ENCODE) provides information about the ENCODE data and convenient links for access.

The UCSC Genome Browser Database (GBD, http://genome.ucsc.edu) is a publicly available collection of genome assembly sequence data and integrated annotations for a large number of organisms, including extensive comparative-genomic resources. In the past year, 13 new genome assemblies have been added, including two important primate species, orangutan and marmoset, bringing the total to 46 assemblies for 24 different vertebrates and 39 assemblies for 22 different invertebrate animals. The GBD datasets may be viewed graphically with the UCSC Genome Browser, which uses a coordinate-based display system allowing users to juxtapose a wide variety of data. These data include all mRNAs from GenBank mapped to all organisms, RefSeq alignments, gene predictions, regulatory elements, gene expression data, repeats, SNPs and other variation data, as well as pairwise and multiple-genome alignments. A variety of other bioinformatics tools are also provided, including BLAT, the Table Browser, the Gene Sorter, the Proteome Browser, VisiGene and Genome Graphs.

With the sequencing of the chimpanzee genome (Chimpanzee Sequencing and Analysis Consortium 2005), detailed analysis of the genetic determinants of our humanity has begun. In pursuit of the fastest evolving regions of the human genome, it has been observed that single-base substitutions in the top scoring regions were dramatically biased in favor of changes from AT to GC base pairs (Pollard et al. 2006a, b). In the top four fastest evolving regions, there were 33 cases of an AT pair being replaced by a GC pair, but only one case of a GC being replaced by an AT. Thus, bases that pair with two hydrogen bonds (“weak”) were replaced by bases that pair with three (“strong”). This substitution bias is particularly surprising given that overall numbers of strong-to-weak and weak-to-strong mutations are roughly equal in the human genome (Eyre-Walker 1999; Maki 2002; Lipatov et al. 2006). The force that has biased substitutions in recent human evolution may be related to the pressures that have shaped isochores, areas of warm-blooded vertebrate genomes as large as ∼300 kb with strikingly greater or lesser proportions of G+C than surrounding areas (Bernardi et al. 1985; Bernardi 2000). Three main theories have been proposed to explain the existence of isochores (Eyre-Walker and Hurst 2001). The first involves variation in mutation rates (Sueoka 1988; Wolfe et al. 1989; Fryxell and Zuckerkandl 2000) in different areas of a genome. Under this model, initial mutations vary in the proportion of G+C at different locations, and this imbalance is carried forward as a substitution bias by neutral evolution. The second theory is that natural selection (Bernardi and Bernardi 1986; Eyre-Walker 1999) for GC alleles has driven the formation and maintenance of isochores. Variability in G+C content might be evolutionarily advantageous, since G+C% is known to be correlated with (Lercher et al. 2003) and positively affect (Kudla et al. 2006) gene expression. G+C% may also be related to thermal stability. A third model that could lead to widespread variation in G+C content involves biased gene conversion (BGC) (Eyre-Walker 1993). BGC is a recombination-driven process that results in the biased fixation of GC alleles due to a biochemical bias in the DNA repair mechanism (Brown and Jiricny 1988; Webster and Smith 2004) acting on short stretches of hetero-duplexed DNA during crossing-over. BGC acts much like a selection pressure (Nagylaki 1983), providing a general mechanism for increased G+C, although it remains to be demonstrated (theoretically or experimentally) how BGC could lead to very large increases in substitution rate. Correlation between recombination rates and G+C content in a number of species supports the BGC hypothesis (Brown and Jiricny 1988; Birdsell 2002; Meunier and Duret 2004). The three models to explain bias in G+C give rise to different predictions regarding patterns of bias in polymorphisms and fixed substitutions (Eyre-Walker and Hurst 2001). If mutation bias is at work, then single nucleotide polymorphisms (SNPs) should show a similar pattern of bias as substitutions (Eyre-Walker and Hurst 2001; Lercher et al. 2003). But if higher G+C is the result of a selection pressure, there should be a more pronounced bias in substitutions than in SNPs (Lercher et al. 2002; Schmegner et al. 2007). Distinguishing between natural selection and BGC-mediated increases in G+C can be more difficult (Duret 2002; Meunier and Duret 2004). If natural selection is the source, then substitution bias may be different between areas of low and high conservation. However, if BGC is the cause of bias, then genomic G+C would be correlated with historical recombination rates or hot spots (Kong et al. 2002). To the extent that regional recombination rates remain constant (Myers et al. 2005), biased substitutions might be correlated with measures of current recombination. This study has been undertaken to document the characteristics of biased substitution patterns across the human and chimp genomes. We examine nucleotide bias in human SNPs and fixed chimp–human differences in an effort to characterize the roles of mutation bias, natural selection, and BGC in the observed patterns of substitution bias in the last 6 million years of human evolution.