Human Genetics: Online Resources

Transcription

1 Human Genetics: Online Resources David A Adler, ZymoGenetics, Seattle, Washington, USA There is a large source of information concerning human genetics available on a variety of different Internet sites, via the World Wide Web. Such online resources are now everyday tools in biological research and medicine. Introduction Progress in human genetics today often requires access to vast amounts and varieties of information. The infrastructure for accessing this information is the Internet. Developed originally by the US Department of Defense, the Internet has now become a worldwide digital communications network. During most of the 1980s remote genetic data was available using text-based dumb terminals to communicate with remote databases. These initial query interfaces were often arcane, tedious and certainly not biologist-friendly. Computer technology is now beginning to fulfil the promise of easy-to-use graphical interfaces, delivering text, sound, pictures and videos to the desktop. A large knowledge base of genetics is now readily available to educators, scientists, students and the general public. Online resources in genetics have become everyday tools in biological research and medicine. Unique characteristics of genetic information, including the rate of growth and constantly changing nature of the data, presents special challenges for database repositories and interface designers. Since new data are being generated daily, database repositories must be updated constantly while maintaining a high level of accuracy. Examples of the variety of information includes gene mapping, determination of the position of genes on chromosomes; genomic and expressed sequence tag sequencing; comparative genomics; gene expression profiles in normal and disease states; and human disease features. Adding to the complexity of the content of and access to genetic databases are the ethical issues, particularly concerns about the privacy of an individual s own genetic information and the ownership of parts of the human genome. The Web Given the high rate of data generation, database distribution on physical media, common a few years ago, has become almost totally obsolete. Now the fastest, most reliable, means of distributing database information is via the Internet. Along with the building of the Internet,. Introduction. The Web Introductory article. Using Online Resources Article Contents. National Center for Biotechnology Information. Genome Database (GDB). Genome Consortium (ORNL). Online Mendelian Inheritance in Man (OMIM). Human Genome Project (HGP). Cancer Genome Anatomy Project (CGAP). Future of Online Resources networkprotocols were designed and developed for searching and retrieving information stored on remote computers. Telnet was available to open a terminal session on a remote machine and ftp (file transfer protocol) was the common solution to file transfers, i.e. downloads and uploads. These methods for connecting to remote computers and transferring files, along with basic programs, were sufficient until the volume and diversity of available information, and the number of sites providing information, began growing exponentially. The increasing number of information repositories led to difficulties in finding information. In turn, software systems such as WAIS (Wide Area Information Server; ThinkTechnologies) and Gopher (University of Minnesota) addressed the need for common protocols that provide tools for information searching at many different remote sites. The World Wide Web (WWW) distributed information concept was developed in 1990 at CERN (European Organization for Nuclear Research, High Energy Particle Physics Laboratory) in Geneva. Utilizing hypertext-based documents, a browser provided the ability to navigate the information web with an intuitive and easy-to-learn graphical user interface. Active hypertext words and phrases are highlighted in a displayed document. When the reader selects highlighted text, usually by clicking on the text with the mouse, new information is displayed. This may be a jump to a new section of the document or to a new document. The source of the new document may be a different site from the original server. An important feature of the Web concept is that it is not necessary for the reader to know the locations of linked documents: this information is encoded in Hypertext Markup Language (HTML). The original Web browser developed on the NeXT computer (NeXT was acquired by Apple Computer in 1997) displayed high-quality formatted text with hyperlink words and phrases. This browser, implementation by Tim Behrns-Lee and his group at CERN, demonstrated a novel distributed information navigation tool. However, it was not until the release of Mosaic (a Web browser developed by Marc Andreasson, at the National ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / 1

2 Center for Supercomputing Applications (NCSA) at the University of Illinois, Urbana-Champagne, Illinois, USA), with its intuitive interface and multimedia capabilities, that the WWW began its explosive growth in content. A key element for Mosaic s rapid adoption was that versions were available for most of the common hardware/ operating systems in use in 1993 (MacOS, MS Windows and UNIX/X-Windows), with the graphical interface appearing essentially uniform on all platforms. Use of the WWW now constitutes a major portion of the Internet s traffic flow. The explosion of information on the Web led to a recurrence of the difficulty in finding information. By 1999 Web browsers have become much more sophisticated and a plethora of information-searching tools is now available. Although the Web is known to be changing constantly, with sites appearing and disappearing, the administrators of primary genetic data repositories are well aware of the need for access stability. available help facilities to assist in becoming familiar with using the site. A key to successful inquiry using online resources to human genetic databases, as in science itself, is the clear formulation and statement of the question. Understanding the query combined with familiarity of the various databases and search tools will help in the selection of the appropriate search strategy for the particular question. Common queries of human genetic databases include: Where does a particular gene map in the genome? What genes have been mapped to a particular chromosomal region? Has a gene of interest been cloned? Is the genomic, complementary deoxyribonucleic acid (cdna) or protein sequence known? What are the features of a specific genetic disease? This chapter will introduce a sampling of databases that can be used to investigate these questions. Human genetic databases are emphasized; for more information on mapping, sequence and structure databases see the article on Bioinformatics. Using Online Resources Evidence that computer technology is actually improving is that this section is much shorter than it would have been 10 years ago. Then, descriptions of at least four important networkprotocols would have to be explained along with an equal number of programs for accessing servers using each of the protocols: Telnet, ftp, kermit, Gopher, WAIS, ARCHIE some of these protocols and programs are still in use, often invisibly behind the Web pages appearing on the screen. The widespread acceptance of the Web as a medium for providing access to scientific information, and specifically the Human Genome Project, are driving forces in the development of novel human computer interfaces. Almost all recent genetic data are now accessible using a Web browser. Although Web browsers provide a uniform interface for navigating the Web and locating sites, the interfaces (what appears within the Web browser frame) often differ among sites. Knowing how to exploit all the capabilities of each particular search tool at individual database sites is an essential skill. Appreciating the idiosyncrasies of different search tools allows the sought-after information to be found efficiently. The major Web servers for genetic information typically have extensive help resources. Help pages are invaluable in learning a site s query interface and provide detailed and current descriptions of the data, how it is organized and how to search the database. Often, there are choices for the presentation of results and the user selects the desired display options. It may be useful to open two or more browser windows so that complementary information from multiple websites can be viewed on the screen at the same time. Each of the sites reviewed in this article provides descriptions of the database and the National Center for Biotechnology Information The National Center for Biotechnology Information (NCBI) (USA), a National Institutes of Health (NIH) branch of the National Library of Medicine (NLM), is the reference repository for a number of important genetic databases. Through web-based NCBI s Entrez interface, access is provided to Genbankand Genpept, nucleic acid and protein sequence databases, protein structures, taxonomy, PubMed, OMIM (see below). To interact with the databases, the NCBI has developed and provided search tools within Entrez including: taxonomy and structure components; a BLAST (Basic Local Alignment Search Tool) server for remote sequence similarity searching; and Bankit for electronic sequence submission. The NLM has been a long-time database developer; the search tools at the NCBI are interconnected, providing the ability to jump easily from literature abstracts to sequence and mapping data, to genetic disease information, to protein structures, to taxonomy. Starting points for searches can be author names, keywords, chromosomal locations, OMIM articles and sequence entries. Journal publishers have begun offering electronic access to full-text articles with graphics, many PubMed entries now include links to available electronic journals. An NCBI demonstration project The Human Gene Map 98 exemplifies a wellintegrated knowledge navigator. From the NCBI s starting page, a vast array of biological information can be searched, displayed and downloaded. The home page for the NCBI has a button array across the top for instant access to commonly used services. This page also provides links to background information on the databases maintained at the NCBI and 2 ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group /

3 advice on the use of the various Web-based search tools. Entrez includes access to nucleic acid and protein sequence data; PubMed interface to Medline-indexed literature; a taxonomy browser; protein structure data including graphical display of molecular models; and a genomes browser. The NCBI Web server provides a comprehensive set of views of an extremely large knowledge base; Medline itself is one of the world s largest databases. The DNA sequence database (Genbank/EMBL (European Molecular Biology Laboratory)/DDBJ (DNA Data Bankof Japan)) through much of the 1990s maintained a doubling time of about 18 months. It is a credit to the NCBI bioinformatics staff that they have been able to maintain and improve the information tools while the databases are growing rapidly and the number of users increasing exponentially. A complete discussion of all the services and information available from the NCBI is not possible in this article, so a number of popular features will be discussed here. Two projects, the Online Mendelian Inheritance in Man (OMIM) and Cancer Genome Anatomy Project (CGAP) are discussed below. Genome Database (GDB) The Genome Database (GDB) at Johns Hopkins University has been a central repository for human genome mapping data since Before that, gene mapping informatics was coordinated and maintained at the Human Gene Mapping Library at Yale University. The GDB maintains an extensive database; mapping data from a number of different sources can be searched and displayed. The basic element of the GDB is the genomic segment, which is any defined genomic fragment including genes, amplimers and clones. At present there is not one correct map and therefore the ability to display multiple maps is necessary. A Java-based applet, MapView, was developed to provide an interface for displaying userdefined map views. A variety of queries is possible using the GDB interface, including searching for gene names, chromosome locations, marker names and clone identifiers. Mapview is capable of displaying multiple chromosomes depending on query results. Once a map view is customized to the user s satisfaction, a PostScript file can be generated for printing or creating an illustration. The progress in the Human Genome Project has presented challenges for the maintenance and presentation of human gene mapping data and, as the project has moved from an emphasis on gene mapping to genomic sequencing, the scope of the data has changed along with the needs of the scientific community. The US funding agencies, NIH and the Department of Energy, have decided to transfer responsibility for the maintenance and delivery of human gene mapping data to OakRidge National Laboratories (ORNL). The future of the GDB was uncertain for some time, but alternative funding sources have been obtained, and a new host, the Hospital for SickChildren, Toronto, ensure the continued maintenance and development of this data library. Genome Consortium (ORNL) The Genome Consortium has developed a new database and interface models for accessing gene mapping and sequencing data for human as well as other organisms. ORNL s first attempt at a new genome database interface is the Genome Channel, a Java-based program. Unfortunately, the universal development environment is not quite universal and the first implementation did not work on some platforms. There is now a version 2 of this tool, but still does run on Macintosh or some UNIX systems. To provide universal access to the data, an alternative access interface is now available in the form of the Genome Catalog. The Catalog provides Web-based searching and display of gene mapping and sequence data for many organisms. The interface is easy to use and includes browsing and searching features with the ability to zoom from the cytogenetic map level to genomic sequence and gene prediction models. Online Mendelian Inheritance in Man (OMIM) Victor McKusickpublished his first edition of a catalogue of mendelian inherited human diseases about 40 years ago. McKusickupdated his database almost daily and by the mid-1980s it became apparent that the rate of change and growth of information was outpacing the yearly publication cycle of the print version. McKusickbecame one of the first to provide Internet access to the most current version of his genetic information resource; the electronic version was named Online Mendelian Inheritance in Man or OMIM. OMIM is organized into articles about individual genes and human genetic diseases. Chapters are divided into sections including a text narrative with current knowledge about the locus; descriptions of allelic variants, many of which are disease-causing mutations; references to the literature; and a clinical synopsis of disease features. At the top of each article are linkbuttons to retrieve related information from various other databases, including sequences, protein structures and the Human Gene Mutation Database (at Cardiff). ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / 3

4 Human Genome Project (HGP) The Human Genome Project (HGP) is an international research program designed to construct detailed genetic and physical maps of the human genome, to determine the complete nucleotide sequence of human DNA, to localize the estimated genes within the human genome, and to perform similar analyses on the genomes of several other organisms used extensively in research laboratories as model systems. The Human Genome Organization (HUGO) is an international group established to coordinate individual national efforts. HUGO s mission includes the promotion of research, agreements on ethical uses of genome data and protecting the privacy of individuals. The first phase of the Human Genome Project, beginning in 1990, was to establish the gene map framework. This frameworkwas constructed by localizing and ordering genes and unique DNA fragments to particular sites in the genome (Figure 1). The reference map of anchor markers is a necessary foundation for the methods used for large-scale genomic sequencing. The mapping phase of the project was completed ahead of schedule, and sequencing costs have been reduced considerably in the few intervening years. Although only 10% of the genome was completed by February 1999, the rate of sequence generation is increasing exponentially. The US National Center for Human Genome Research has moved the date for completion of the project to 2003, the year that marks the 50th anniversary of the publication of Watson and Crick s paper on the model for DNA structure and function. Total genome shotgun sequencing was not considered feasible at the time of initiation of the project in 1990, but in the spring of 1998 Celera and Perkin-Elmer announced that a joint venture would be undertaken to produce a completed human genome sequence by The release of the Human Gene Map 98 published in the autumn of 1998, represents the status of the human gene map and a variety of related information on human genetics. Although this Web-based data view is not intended to be updated continuously, it demonstrates a well-integrated interface for examining a variety of human genetic information, from the chromosome to the sequence level. Sequencing of the entire human genome will be completed by 2003; although this will marka major milestone in genetics, much more research will be needed to understand how this genetic encyclopedia directs the biological processes of development and disease. Since only a small fraction of the genome sequence encodes proteins, understanding the role of the bulkof the genome in regulating gene expression and chromosomal functioning will remain to be elucidated. There may well be new genetic codes that emerge, providing the basis for understanding the regulatory roles of the genome. Figure 1 Three views of the human genome: (a) human male (46,XY) metaphase, Giemsa banding method; (b) idiogram panel of human chromosomes; and (c) a small fragment of human genomic sequence. To print the entire three billion base pairs of the human genome, about 700 volumes of 1000 pages each, would be required. 4 ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group /

5 Cancer Genome Anatomy Project (CGAP) The goal of the CGAP, an NIH project, is to achieve a comprehensive molecular characterization of precancerous and malignant cells, and to identify the genes responsible for the establishment and growth of cancer. Project resources and all data are made available to the research community without restrictions. The foundation of CGAP are cdna libraries prepared from many different neoplastic tissue and cell types. There is now a large body of evidence that cancer is associated with alterations of gene expression, and neoplastic progression, like development, involves modulating the repertoire of gene expression in cells. Some of the genes that exhibit changes in gene expression in tumour cells will be involved directly in the aetiology of various cancers. A first step in identifying genes that play a role in the mechanism of tumour initiation and progression is to tally the genes that are differentially regulated in tumour cells. One approach to such analysis is the characterization of cdna libraries from diseased and normal tissue. cdna clones are then randomly picked and subjected to end sequencing. These short messenger ribonucleic acid (mrna) sequence fragments, termed expressed sequence tags (ESTs), may be used to classify a particular cdna clone and, with sufficient numbers of clones from individual libraries, approximations of expression levels of genes can be extrapolated. By comparing EST profiles from a tumour and normal tissue, associations of particular genes with specific disease states can be identified. Expression analysis of a variety of types of tumour and a wide selection of normal tissues can identify candidate genes whose altered expression may be directly involved in particular cancers. There are tools for looking at the CGAP data in several different ways. In addition to sequence-based expression analysis, other methodologies are available to assess the expression profiles of cells. Nucleic acid hybridization can be employed to detect genespecific expression using microarrays in a variety of formats: digital differential display (DDD), electronic Northern blot analysis, and other techniques for assessing gene expression. The main sections of the CGAP website are: gene discovery, a human tumour gene index, descriptions of cdna libraries, Organ Summaries, cdna expression profiles (ESTs, DDD and Serial Analysis of Gene Expression (SAGE)), molecular fingerprinting, Cancer Chromosome Aberration Project (ccap) and Mitelman Chromosomal Aberration Summary; Genetic Annotation Initiative Polymorphism Discovery, and a mouse tumour gene index. In addition to identifying known genes involved in cancer aetiology, another primary goal of the CGAP is to discover new human genes to add to our understanding of the process of cancer and monitoring of the course of the disease. Analysis of CGAP cdna libraries has yielded a substantial number of gene discoveries. Future of Online Resources We are still in the infancy of the information age and can expect a continuing flow of new hardware and software there will be surprises. Although the Web browser is the current almost universal model for accessing the Web, information stored on Web servers will begin to appear in new environments and interfaces. Integration of databases will continue and new ways of looking at information from a variety of sources will allow comparative and complementary views. Much of the informatics development has been directed at the genome researcher and other science professionals; it will also be necessary to provide interfaces for the general public to access genetic information. The future will bring a proliferation of novel interfaces, and the general browser may be joined by navigators tailored to specific areas with features appropriate to particular disciplines. Not only will the contents of a frame change when linking to a new site, but the entire frame and interface will adapt with the information content. The existing heterogeneity among interfaces to different databases is representative of the state of development of computer human interaction. It is not clear what is the best interface, and variety will continue to be desirable to meet the varying needs of different classes of users and varying characteristics of the actual data. In addition, the diversity of interface design is important for the evolution of the technology and, ultimately, to meet the expectations of users for ease of use, accuracy, completeness and timeliness. Further Reading Access Excellence (1992) Introduction The Human Genome Project. Access Excellence. [ Intro_The_Human_Genome.html] Ge néthon (2000) Human Genome Research Centre. Evry, France: Ge néthon. [ The Genome Database (2000) The Genome Database GDB. Toronto: The Hospital for SickChildren. [ Strausberg R (2000) The Cancer Genome Anatomy Project (CGAP). National Cancer Institute. [ McKusickVA (2000) OMIM Online Mendelian Inheritance in Man. National Center for Biotechnology Information. [ National Human Genome Research Institute (2000) Ethical, Legal, and Social Implications (ELSI) Research Program. National Institutes of Health. [ National Human Genome Research Institute (2000) The National Human Genome Research Institute. National Human Genome Research Institute. [ ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / 5

6 Human Genome Management Information System (HGMIS) (2000) Human Genome Project Information. OakRidge National Laboratory. [ Sanger Centre (2000) Human Genome Project. Sanger Centre. [ Swiss Institute of Bioinformatics (SIB) (2000) ExPASy (Expert Protein Analysis System). Geneva: SIB. [ KrawczakM and Cooper DN (1997) The Human Gene Mutation Database. Trends in Genetics 13: [ uwcm/mg/hgmd0.html] [Website maintained at the University of Wales College of Medicine] Mouse Genome Informatics (2000) Mouse Genome Informatics. Bar Harbor, ME: The Jackson Laboratory. [ org/] 6 ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group /