Ancora: a web resource for exploring highly conserved noncoding elements and their association with developmental regulatory genes
© Engström et al.; licensee BioMed Central Ltd. 2008
Received: 12 October 2007
Accepted: 15 February 2008
Published: 15 February 2008
Metazoan genomes contain arrays of highly conserved noncoding elements (HCNEs) that span developmental regulatory genes and define regulatory domains. We describe Ancora http://ancora.genereg.net, a web resource that provides data and tools for exploring genomic organization of HCNEs for multiple genomes. Ancora includes a genome browser that shows HCNE locations and features novel HCNE density plots as a powerful tool to discover developmental regulatory genes and distinguish their regulatory elements and domains.
Comparisons of metazoan genome sequences have revealed an abundance of genomic segments that are highly conserved across large evolutionary distances even though they do not encode proteins and do not tend to be near transcription start sites. For example, 256 non-exonic segments longer than 200 bp were found to be perfectly conserved between human, mouse and rat genomes; 140 of these were more than 10 kb away from any known gene . Using less stringent criteria for length and sequence similarity, other investigators have found thousands of non-exonic segments in the human genome that are conserved in organisms as distant as fugu [2, 3] and shark .
Several lines of evidence indicate that these highly conserved noncoding elements (HCNEs) play a fundamental role in regulating animal development and constraining genome evolution. In vertebrates, insects and worms, HCNEs tend to cluster in the vicinity of developmental regulatory genes [1–7]. Through experiments in transgenic animals in which cloned HCNEs are tested for the ability to drive transcription of a reporter gene, many HCNE sequences have shown the ability to induce part of the embryonic expression pattern of a developmental regulatory gene located in the genomic neighborhood of the endogenous HCNE [3, 8–11]. These experiments have associated HCNEs and developmental genes separated by considerable genomic distances, up to 800 kb in human , suggesting that many HCNEs act as long-range regulatory elements. Hundreds of HCNEs have now been characterized as developmental enhancers in transgenic mice, frogs or zebrafish, and the list is growing rapidly [10, 12–14].
The emerging model for explaining these observations is that an array of HCNEs defines a region of regulatory inputs of its target gene(s), and that the full complement of those inputs results in the expression pattern of the gene [3, 8–11]. If this notion that HCNE arrays constitute regulatory domains is correct, chromosomal rearrangements within HCNE arrays should be selected against in evolution [15–17]. Accordingly, large HCNE arrays have been found to correspond to the largest and most deeply conserved blocks of synteny across vertebrates  and across insects . In addition to HCNE arrays and their target genes, many of these synteny blocks contain unrelated (bystander) genes that do not appear to be regulated by the HCNEs, although they can be situated between HCNEs and target genes, as well as contain HCNEs in their introns. Kikuta et al.  termed these synteny blocks 'genomic regulatory blocks' (GRBs) and demonstrated that, for some GRBs, it is possible to distinguish bystander from target genes by comparing mammalian genome sequences with those of teleost fish (such as fugu and zebrafish). This is facilitated by a whole-genome duplication event that occurred in the teleost lineage  and caused each GRB to be present in two copies, thereby allowing some bystander genes to be disentangled from HCNE arrays during the subsequent rediploidization .
Despite a rising interest in HCNEs in the genomics and evo-devo community, there has been a lack of resources that provide information about HCNEs and allow researchers to explore the distribution of HCNEs along chromosomes. Here, we describe Ancora , a web resource consisting of: a genome browser where HCNE locations and HCNE density plots can be viewed over different genomes, with a number of adjustable parameters; data files that allow users to easily view HCNE locations and densities in the UCSC Genome Browser ; and a service that allows users to view HCNE data in the Ensembl browser  through the distributed annotation system (DAS) protocol for sharing sequence annotations . We demonstrate how Ancora can be used to discover developmental regulatory genes and distinguish their chromosomal regulatory domains that correspond to the GRBs described above. The visualization of these regulatory domains is the most powerful and novel function of Ancora. We anticipate that Ancora will be particularly useful for assigning distal regulatory elements to their target genes, and for the discovery of hitherto unknown developmental regulatory genes, including noncoding RNAs.
A comprehensive HCNE database
Counts for selected HCNE sets
Criteria for HCNE detection
Number of HCNEs detected in indicated comparison
Minimum size (bp)
Human vs mouse
Human vs chicken
Human vs zebrafish
Zebrafish vs Tetraodon
80% over 30 columns
90% over 30 columns
96% over 30 columns
70% over 50 columns
80% over 50 columns
90% over 50 columns
95% over 50 columns
98% over 50 columns
90% over 50 columns
95% over 50 columns
Exploring HCNEs and GRBs with the Ancora genome browser
To put HCNEs in context, the browser also shows gene annotation from NCBI , Ensembl , the UCSC Genome Browser , Mouse Genome Informatics , the Zebrafish Information Network , FlyBase  and miRBase , as well as a selection of other annotation tracks from UCSC. The user can click on gene models to bring up detailed gene information pages from the original data sources. By default, the HCNEs are colored by the chromosome they align to in the other genome. This simplifies the identification of conserved HCNE arrays: a stretch of HCNEs in the same color suggests a conserved array. To visualize the tendency of HCNE arrays to correspond to large synteny blocks, we have included tracks showing human-zebrafish synteny blocks and Drosophila synteny blocks from recent analyses [6, 18]. (The human-zebrafish synteny blocks should be interpreted with caution, however, because of artifacts in the underlying zebrafish genome assembly - in particular artificial segmental duplications, which may appear as overlapping synteny blocks on the human genome.) The user can move between the vertebrate genomes that the genome browser displays by clicking on HCNEs and synteny blocks, which link aligned regions from the different genomes. Ancora also provides links that bring up the same region in other major genome browsers (Ensembl, UCSC and FlyBase) and the VISTA browser, which is useful for detailed examination of sequence conservation .
GBrowse extensions in Ancora
Unique information revealed by HCNE density plots
We compute HCNE densities as the percentage of bases covered by HCNEs within a window of a given size. Because the genome browser computes HCNE densities on demand, the window size can be set by the user. The algorithm that computes the densities moves a window across the displayed chromosomal segment in steps of a size that is adapted to the size of the displayed segment. If the user zooms in to single-base resolution, densities are computed for every base shown. At lower resolutions, the step size is at least one step per pixel and ten steps per window. In our experience, this is more than sufficient for detecting peaks of interest. At resolutions where several density values are computed for each pixel, the plot shows the maximum density value per pixel, so that peaks are not omitted. By default, the browser displays overlaid density curves for HCNEs detected at three different sequence identity thresholds (Figure 2a). This allows users to easily locate regions with the most strongly conserved HCNEs and simultaneously delineate other HCNE-dense regions. The default window size for vertebrate genomes is 300 kb. It is important to note that this large window size leads to slopes of GRB signals extending outside the actual HCNE-spanned regions. To estimate the edges better, the user should consult synteny and HCNE location tracks, or decrease the window size in density plots. Despite this side effect, large window sizes are more appropriate for outlining GRB distribution along chromosomes, as well as for the determination of most likely target genes. It should also be noted that extremely high densities of HCNEs detected at the most stringent identity thresholds (high red density peaks) can originate from (rare) cross-species contamination of genome sequences. Users of the Ancora genome browser can identify such contamination as high HCNE densities coming from near-identical sequence segments confined to a single compared species. For example, much of Xenopus tropicalis scaffold 7291 is composed of fragments of near-identity to human chromosome 5, even though these regions have no HCNEs conserved in mouse, chicken or fish.
Discovering genes that encode developmental regulators
Since there is a strong association between HCNE arrays and developmental regulatory genes [1–7], it is likely that most regions of high HCNE-density contain at least one developmental regulatory gene, even in cases where no such gene has been annotated. Inspection of HCNE density can thus be used to formulate hypotheses about gene function and identify likely target genes of putative enhancer activity of HCNEs. In a study from 2004, Sandelin et al.  identified HCNEs conserved among human, mouse and fugu, and closely inspected the 50 most HCNE-rich regions for the presence of developmental regulatory genes. They found 41 of these regions to contain a gene known to be involved in embryonic development. Of the remaining nine regions, seven contained a gene known to be a transcription factor or predicted as such based on homology. In a recent study, one of these transcription factor genes (FLJ20321) was recognized as a homolog of the Drosophila gene castor and found to be upregulated in cell differentiation , confirming the prediction from HCNE density. Sandelin et al. focused on the 50 HCNE-densest regions they detected in the human genome. Inspection of other HCNE-dense regions has revealed that several coincide with microRNA gene loci , a class of regulators implicated in multiple aspects of development . We predict that many additional HCNE-dense regions will be found to contain developmental regulators. By plotting HCNE densities along entire chromosomes, the Ancora genome browser makes it easy to survey genomes for HCNE-dense regions (Figure 4). HCNE density curves from multiple pairwise genome comparisons can be shown simultaneously, so that users can identify regions rich in HCNEs that are specific to a subset of species, or shared across many species, if so desired. By zooming in, the user can investigate these regions in detail by inspecting the genome annotation available in Ancora as well as annotation in the other genome browsers to which direct links are provided. As a demonstration of the immediate utility of Ancora, we identified 129 genomic regions in the human genome in which the density of human-zebrafish HCNEs (70% identity over 50 columns) surpassed 0.5% and, using the principles outlined here, identified putative target genes in 120 of these regions (Additional data file 1). The regions in which no target gene could be assigned are prime candidates for discovery of novel genes or non-coding RNA involved in developmental regulation.
Detecting and interpreting duplicated GRBs
Distinguishing chromosomal regulatory domains
Viewing HCNEs and density plots in other genome browsers
HCNE locations and precomputed density curves are available for download in the 'bed' and 'wig' formats used for UCSC Genome Browser custom tracks . It is not necessary to download the .bed and .wig files to use them as custom tracks in the UCSC Genome Browser: the user can simply copy the URLs for track files of interest from the Ancora downloads section and paste them into the 'add custom tracks' form on the UCSC Genome Browser web site.
The Ensembl browser can display sequence annotations provided over the web through DAS, a method for data exchange . Much of the Ancora data are available through DAS. Ancora provides an interface where the user can add HCNE tracks to Ensembl ContigView. Tracks added in this way are stored as part of the user's Ensembl preferences. Users who are familiar with DAS can also retrieve data directly from the DAS server. For example, the URL given in reference  provides a list of available tracks.
Comparison to other tools
While the genome browsers at UCSC and Ensembl provide rich and diverse annotation sets including information about sequence conservation, they do not distinguish coding from noncoding conserved elements. To our knowledge, the Ancora genome browser is the first tool that makes it easy to visualize HCNE distributions on large genomic regions, up to whole chromosomes, and the browser is tailored to show data in a flexible manner at this level.
The ECR Browser  and VISTA Browser  allow detailed inspection of sequence conservation profiles across many genomes, highlight conserved elements in a user-customizable manner and distinguish noncoding from coding conservation. In the ECR Browser, one drawback is that thresholds for detection of conserved elements are uniform across all comparisons shown, irrespective of evolutionary distance. In contrast, Ancora and VISTA browsers can show results for multiple different thresholds simultaneously. A limitation of both the ECR and VISTA browsers is that they are not designed for visualizing the distribution of conserved elements on segments larger than a few megabases. The VISTA Browser can only display regions up to 5 Mb in size and the ECR Browser's display of large regions is difficult to interpret because conserved elements are drawn close together. In contrast, the HCNE density plots in Ancora make it possible to view and intuitively interpret HCNE content at any scale. Ancora is therefore better suited for exploring conservation genome-wide and discovering regulatory domains at loci not known beforehand, while the ECR and VISTA browsers provide more functionality for close examination of sequence-level conservation profiles.
The CONDOR database  holds information on about 6,800 HCNEs from about 120 blocks of conserved synteny between human and fugu and provides a graphical interface to view the distribution of HCNEs in those regions. While there are several similarities between Ancora and CONDOR, Ancora has the advantage of providing HCNE data for entire genomes. Another difference between the two resources is that the Ancora HCNE sets are not as stringently defined in terms of conservation as those in CONDOR, where HCNEs are required to be conserved among four diverged vertebrates. In Ancora, we have chosen to provide a range of HCNE data sets from different pairwise comparisons and with different similarity thresholds (Figure 1 and Table 1), so that users can choose to look at the data appropriate for their questions. A valuable section of CONDOR provides developmental expression patterns for about 100 HCNEs that have been investigated by reporter assays in zebrafish. We are preparing to link similar data to Ancora.
Ancora is a new web resource that provides data and tools for exploring HCNEs and their association with developmental regulatory genes. Built upon a database of HCNEs conserved between various metazoan genomes, Ancora provides a genome browser for visualizing the distribution of those elements on chromosomes in the context of other types of annotation integrated from different sources. One of the novel features of Ancora is the possibility to display highly customizable plots of HCNE density along chromosomes. HCNE density plots are qualitatively different from conservation profiles available in other genome browsers [21, 22, 30, 34]: they clearly reveal regions of extensive noncoding conservation and highlight larger chromosomal regulatory domains (GRBs) that have been maintained in evolution. The GRBs typically coincide with loci of developmental regulatory genes, for which HCNEs appear to act as enhancers [3, 8–12]. Consequently, we anticipate that Ancora will be highly useful for discovering developmental regulatory genes and their distal cis-regulatory elements. We have illustrated how Ancora can be used to define the chromosomal regulatory domains of those genes and distinguish genes that appear to be functionally associated with HCNEs from unrelated 'bystander' genes within the same GRB. The HCNE data in Ancora are also available for download and can easily be displayed in the popular general-purpose genome browsers at UCSC  and Ensembl .
Additional data files
The following additional data are available with the online version of this paper. Human genomic regions in which the density (in a 300 kb sliding window) of human-zebrafish HCNEs (70% identity over 50 columns) surpassed 0.5% and putative target genes in 120 of these regions.
distributed annotation system
genomic regulatory block
highly conserved noncoding element.
This work was supported by the Functional Genomics Programme (FUGE) of the Research Council of Norway, Bergen Research Foundation (Bergen Forskningsstiftelse, BFS), and a core grant from the Sars Centre. We thank Ying Sheng, Xianjun Dong and Altuna Akalin for comments on the genome browser.
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