Abstract
A database of mutations in human disease-causing genes has been constructed and named as Keio Mutation Database (KMDB). This KMDB utilizes a database software called MutationView which was designed to compile various mutation data and to provide graphical presentation of data analysis. Currently, the KMDB accommodates mutation data of 38 different genes for 35 different diseases which are involved in eye, heart, ear and brain. These KMDBs are accessible through http://mutview.dmb. med.keio.ac.jp with advanced internet browsers.
INTRODUCTION
We have previously developed the database software, MutationView, as a prototype for distributed database systems (S.Minoshima, S.Mitsuyama, S.Ohno, T.Kawamura and N.Shimizu, manuscript submitted). Using MutationView, we have collected mutation data for human eye disorder genes and constructed an eye disorder-specific database, KMeyeDB (1). Here, we further utilized MutationView for other human diseases involved in heart, ear and brain. Mutation data related to cancer and autoimmunity was also developed separately. These mutation databases were designated KMheartDB, KMearDB, KMbrainDB and KMcancerDB, respectively, and integrated as components of MutationView. Thus, MutationView should be of great use as a central system for a distributed database for locus-specific databases (LSDB) while maintaining the independency of each LSDB.
DATABASE AND SOFTWARE
Database was made for each gene as a set of hierarchical tables according to the format defined for the distributed database software MutationView. MutationView has two different versions, JAVA and HTML. The former provides a dynamic interactive user interface and can be used through advanced browser software with JAVA1.1, while the latter may be used on conventional browsers and is convenient for downloading the data.
To date, we have constructed five separate KMDBs in which a total of 1593 entries of mutations are found for 38 different genes which are involved in 35 distinct diseases collected from 311 literatures (Table 1).
Table 1. Mutation data in the KMDBs and MutationView.
| Category | No. of diseases | No. of genes | No. of mutation entries | No. of literatures compiled |
|---|---|---|---|---|
| Eye | 20 | 17 | 580 | 136 |
| Brain/Nerve | 3 | 5 | 169 | 58 |
| Heart | 4 | 5 | 44 | 13 |
| Ear | 2 | 5 | 20 | 7 |
| Autoimmunity | 2 | 2 | 96 | 14 |
| Cancer-related | 4 | 4 | 684 | 83 |
| Total | 35 | 38 | 1593 | 311 |
Figure 1 upper panel shows the entrance windows of MutationView and five separate KMDBs. Figure 1 lower panel shows ‘Anatomy’ window of the JAVA version of MutationView (left), KMeyeDB (center) and KMheartDB (right). By clicking a certain anatomical part in these windows, a list of genes and/or diseases associated with eye or heart appear (not shown). Clicking one of these genes/diseases, ‘myosin binding protein, cardiac; MYBPC3’ in the KMheartDB creates a ‘Gene structure’ window, displaying mutation data of the gene MYBPC3 (Fig. 2, left background). By clicking ‘About this gene’ button, a window with the same name appears (Fig. 2, left foreground), showing further information from other databases such as OMIM, GDB and HGMD.
Figure 1.
Entrance displays of MutationView and five types of KMDBs. See text for details.
Figure 2.
Gene structure window and mutation details of the MYBPC3 gene in the KMheartDB. See text for details.
In the default of the ‘Gene structure’ window, mutations are displayed along the genomic structure of the gene. Various types of mutations are listed in the ‘Symbol table’ (Fig. 3, upper right) which pops-up through the help menu. Each mutation symbol on the X-axis locates exactly on the mutation site. The height of each bar represents the case number of mutation that appeared in the literature. Clicking the mutation symbol ‘1091-2A→G’ for example (blue arrow) opens a new window for the details of mutation (Fig. 2, upper right), including the change in nucleotide sequence and its consequences such as alterations of amino acid, splicing signal and restriction site. In a case that the mutation is a large deletion and complicated chromosome translocation, schematic diagrams of the mutation are presented (Fig. 3, bottom, left and right). By clicking the ‘Zoom-in’ button of the ‘Gene structure’ window, the X-axis can be changed from the genomic structure to even the nucleotide sequence (data not shown).
Figure 3.
Classified view of gene mutations in the choroideremia shown in the KMeyeDB. Mutations are classified according to mutation type, particularly chromosome translocation (red arrow) and large deletion (blue arrow).
A variety of information can be shown on the Y-axis. These include mutation frequency, mutation type, symptoms, ethnic origin, hereditary pattern, onset age, and so on. By clicking the ‘Classify menu’ button, ‘Classify’ window pops-up (Fig. 4, upper right). Selecting the ‘Mutation type’ and then clicking the ‘Classify’ button displays a re-classified view in the gene structure window (Fig. 3, upper left).
Figure 4.
Classified view of the Parkin gene mutations and PCR primer information in the KMbrainDB. Mutations are classified according to ethnic origin and the PCR primer information is displayed for the mutation indicated by an arrow. See text for details.
Figure 4 displays a result of re-classification of Parkin gene (PARK2) (2) mutations according to ‘Ethnic origin’. Probe information such as PCR primers can be displayed in the ‘Gene structure’ window by switching ‘View type’ menu (Fig. 4, left). Clicking the ‘PCR primer name’ (indicated by an arrow) creates a new window, displaying detailed information such as primer sequences and reaction conditions (Fig. 4, bottom right).
ACCESSIBILITY AND AVAILABILITY
Since MutationView and the KMDBs employ the JAVA1.1 interpreter for their full function, advanced internet browsing software is required. These requirements depend on the types of terminal computers:
• For Macintosh: Internet Explorer 3.0/4.0/4.5 + MRJ2.0/2.1.
• For Windows95/98/NT: Netscape Communicator 4.03 AWT1.1, Netscape Communicator 4.05 Preview Release 1 (AWT1.1.5), Netscape Communicator 4.06 or later, Internet Explorer 3.0 with SDK for Java 1.5 or Internet Explore 4.0 or later.
• For Solaris 2.4 or later of SparcWorkstation: Netscape 4.04 JavaAWT1.1 Preview Release 2 (CDE or Open Windows), Netscape Communicator 4.05 Preview Release 1 (AWT1.1.5) (Open Windows), or Netscape Communicator 4.06 or later (Open Windows).
MutationView and the KMDBs are located at Keio University School of Medicine and are accessible via http://mutview.dmb. med.keio.ac.jp . The user ID and password are issued after receiving applications through the same URL. The software MutationView is available to all interested research groups under the conditions that users participate actively in the establishment of a world-wide distributed database system for disease gene mutations. For inquiries, contact Shinsei Minoshima (mino@dmb.med.keio.ac.jp ) or Nobuyoshi Shimizu (shimizu@ dmb.med.keio.ac.jp ).
Acknowledgments
ACKNOWLEDGEMENTS
We thank Chi Co., Ltd for their extensive collaboration. This work was supported in part by a fund for the ‘Research for the Future’ Program from the Japan Society for the Promotion of Science (JSPS) and a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Science, Sports and Culture of Japan. The figure of the human body in Figure 1 lower left window was used with publisher’s permission from ‘Cystic Fibrosis’ authored by Michael J. Welsh and Alan E. Smith in Nikkei Science (1996) Vol. 26, p. 92.
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