DOE Human Genome Program Contractor-Grantee
146. The Need for a Simple Sequence Annotation Standard
Lincoln Stein1, Sean Eddy2, Robin Dowell3
1Cold Spring Harbor Laboratory; 2Department of Genetics, Washington University; 3Biomedical Engineering, Washington University
The pace of human genomic sequencing has outstripped the ability of sequencing centers to annotate and understand the sequence prior to submitting it to the archival databases. Multiple third-party groups have stepped into the breach and are currently annotating the human sequence with a combination of computational and experimental methods. Their analytic tools, data models, and visualization methods are diverse, and it is self-evident that this diversity enhances, rather than diminishes, the value of their work.
The main risk of third-party annotation is that it may fracture knowledge about the genome. Instead of having a convenient one-stop source for genomic annotation, such as Entrez, researchers may have to check multiple Web sites for information about a particular region of interest, download the data in several different formats, and perform a manual integration in order to get the whole picture. Clearly, this is undesirable.
There are several possible approaches to this problem. One is for each of the annotation centers to submit their annotations to a centralized database, such as GenBank. However, this option raises a number of political and technical problems, not the least of which is the long-held tradition of GenBank and its sister databases of allowing only the sequence submitter to modify or comment on a GenBank entry. Another option would be a system which uses Web links to point from the GenBank entry to one or more annotation Web sites. Such a system is available now in the form of the NCBI LinkOut service. However, while this makes it easier for researchers to find third-party annotation sites, it does not solve the problem of data integration.
The solution that we advocate allows sequence annotation to be decentralized among multiple third-party annotators and integrated on an as-needed basis by client-side software. A single server is designated the "reference server." It serves essential structural information about the genomethe physical map which relates one entry to another (where an "entry" is an arbitrary segment of the sequence, such as a sequenced BAC or a contig), the DNA sequence for each entry, and the standard authorship information. Multiple sites then act as third-party "annotation servers." Using a web browser-like application, researchers can interrogate one or more annotation servers to retrieve features in a region of interest. The servers return the results using a standard data format, allowing the sequence browser to integrate the annotations and display them in graphical or tabular form. No attempt is made to automatically resolve contradictions between different third-party annotations. Indeed, it is the ability to facilitate comparison among different centers' annotations that distinguish this proposal. We currently have a working prototype of this system based on ACeDB servers and CGI scripts, and are now generalizing this architecture to support other client and server combinations.
The key development that is necessary for a successful distributed annotation system is the adoption of a standard format to describe sequence features. While almost any one of the existing standards could be adapted for this purpose, certain characteristics are very desirable.1. Handling of multiple levels of relative coordinates
In the ideal world, the genome would be finished to the base pair, and we would be able to unambiguously refer to an annotation based on its position from the top of the chromosome. This will not happen for a very long time. For the conceivable future, the genome will consist of multiple segments of high confidence, related to one another by mapping information of lower confidence. In order to deal with annotations in this dynamic and changeable environment, the format must be able to deal with relative coordinates in which annotations are related to arbitrary hierarchical landmarks. For example, a "clone end" annotation may be related to the start of a contig, an "mRNA" annotation may be related to the clone end, and an "exon" annotation may be related to the start of the mRNA.
2. Easily generated and parsed
4. Functional groupings of annotations
Even if the community does not undertake a formal third-party annotation system for the human genome, the value of a standardized format for the interchange of annotations is immeasurable. Several suitable formats are under development. One is GAME, an XML-based format developed by Suzanna Lewis of the Berkeley Drosophila Genome Project and members of the BioXML interest group. Another is GFF, a tab-delimited format developed by Richard Durbin, Tim Hubbard, and others at the Sanger Centre. Both formats are supported by a handful of Java-based sequence annotation viewers. For our part, we are using a XMLized version of GFF for our ACeDB-based distributed annotation system.
We urge this group to consider the need for a standard format for genome sequence annotation, and to consider architectures that will allow genomic annotations to be developed and interchanged across database and institutional boundaries.
|The online presentation of this publication is a special feature of the Human Genome Project Information Web site.|