Bioinformatics Advance Access originally published online on September 9, 2004
Bioinformatics 2005 21(3):408-409; doi:10.1093/bioinformatics/bti017
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Bioinformatics vol. 21 issue 3 © Oxford University Press 2005; all rights reserved.
Human–Mouse Gene Searcher: a tool to assist discovery of malformation-associated genes by using phenotype databases
1 Institute of Child Health 30 Guilford Street, London WC1N 1EH, UK
2 School of Computing Science, Middlesex University London, UK
3 Bioinformatics, Medical School, University of Edinburgh London, EH8 9XD, UK
*To whom correspondence should be addressed.
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Abstract |
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 TOP Abstract INTRODUCTIONSYSTEM AND METHODSREFERENCE |
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An open-access World Wide Web application has been developed which enables the cross-linking of anatomical data on the phenotypic manifestations of human and mouse malformation syndromes to data on gene function and/or expression patterns in the mouse GXD database. Ultimately, the system has been designed to assist biologists in the process of discovering hitherto unidentified malformation genes. More specifically, it facilitates search from the phenotypic level.
Availability: The application and further information is available at http://genetics.ich.ucl.ac.uk/linksearchtool
Contact: i.bradford{at}ich.ucl.ac.uk
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INTRODUCTION |
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TOPAbstractINTRODUCTIONSYSTEM AND METHODSREFERENCE |
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The goal of all genetic studies is to relate phenotypes to genotypes. For genes important in embryonic development, the first clues about their function frequently come from naturally occurring mutants with an abnormal developmental phenotype. The organism that has been studied in greatest detail here is the human, with Clinical Dysmorphology being the study of abnormal physical development. There are now over 3000 reported non-chromosomal dysmorphic syndromes, of which 2200 appear to have a single-gene aetiology. These syndromes have been fully catalogued and indexed by their clinical and physical abnormalities in the London Dysmorphology Database (LDDB) (Winter and Baraitser, 1996). Of the 2200 single-gene syndromes, those genes causing approximately 370 have been found and a further 220 conditions have been mapped; this leaves a further 75% of these genes to be found.
Cross-linking related data on human and mouse malformation syndromes to data on gene function and/or expression patterns should provide a useful tool to assist in the process of malformation-gene identification, by allowing an expert user to initiate search from phenotype data. We have produced the Human–Mouse Gene Searcher (HMGS) for this purpose; it comprises a web-based search tool together with a supporting suite of curation and data-manipulation tools. The search tool is available at http://genetics.ich.ucl.ac.uk/linksearchtool
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SYSTEM AND METHODS |
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TOPAbstractINTRODUCTIONSYSTEM AND METHODSREFERENCE |
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HMGS enables a user to perform searches on the mouse Gene Expression Database (GXD; Ringwald et al., 1999) using a specifically developed interface that allows search keys to be defined from a human clinical feature list. Searches can be made using either the ‘Gene Expression’ or the ‘Alleles and Phenotypes’ sections of GXD. Both use a list of human clinical features as an initial set of search terms which, in turn, map to GXD search criteria through a series of curated links. The client program is a web-browser that allows users to select up to five search terms from a list of human clinical features derived from LDDB (Fig. 1). These features are then resolved to mouse terms (mouse phenotypes or mouse anatomy depending on the search type) that are used to query GXD directly. The GXD responses are returned to the HMGS client and displayed to the user. Crucial to this process is the mapping between the human clinical features of LDDB and the appropriate mouse-phenotype and mouse-anatomy terms. This is achieved by a database of links curated by domain experts.
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Phenotype search
For phenotype-based searches, human features (HF) are mapped to a set of terms used in the GXD, called ‘The Phenotype Ontology’ (The Mammalian Phenotype Ontology, 2004, http://www.informatics.jax.org/searches/MP_form.shtml) or ‘mouse phenotypes’ (MP)—GXD use these mammalian phenotype terms to annotate mutant mice. These mapping links are not part of the visible client interface nor are they accessible to the user, but are created using a purpose-built link curation tool and stored in a database as a ‘lookup’ system. The lookups resolve the HF to MP terms that are then used to query GXD. The results are returned and refined using set algebra before being returned for display on the client search interface.
Anatomy search
For anatomy-based searches, human features have been mapped to mouse anatomy terms from the Edinburgh Mouse Anatomy Database (Bard et al., 1998) which GXD uses to classify gene expression. To make these links, a further dedicated tool has been developed that is similar to the phenotype tool, except that an HF is grouped with developmental stages and structures. A group may contain more than one structure and be present at more than one developmental stage. An anatomy-based search proceeds from an HF to the appropriate mouse terms stored in a look-up table that is used to query the GXD. The process for resolving the links and the set algebra is similar to that for the feature-phenotype links.
CONCLUSION
We have developed the Human–Mouse Gene Searcher, a user-friendly, Internet-based tool that aims to assist an expert user in the process of malformation gene identification. To this end, it allows a biologist to search the ‘Alleles and Phenotype’ and ‘Gene Expression’ sections of the GXD by initiating search from phenotypes, using a series of expertly curated phenotype mappings.
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Acknowledgments |
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We thank Action Medical Research for support (grant no. SP3859).
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Footnotes |
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Deceased. 
Received on June 29, 2004; revised on August 23, 2004; accepted on September 2, 2004
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REFERENCE |
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TOPAbstractINTRODUCTIONSYSTEM AND METHODSREFERENCE |
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Bard, J.B.L., Kaufman, M.H., Dubreuil, C., Brune, R.M., Burger, A., Baldock, R.A., Davidson, D.R. (1998) An internet-accessible database of mouse developmental anatomy based on a systematic nomenclature. Mech. Dev., 74, 111–120[CrossRef][ISI][Medline].
Ringwald, M., Mangan, M.E., Eppig, J.T., Kadin, J.A., Richardson, J.E. (1999) GXD: a Gene Expression Database for the laboratory mouse. Nucleic Acids Res., 27, 106–112
Winter, R. and Baraitser, M. (1996) LDDB, London Dysmorphology Database, Mothercare Unit of Genetics and Fetal Medicine (now Clinical and Molecular Genetics). , London Institute of Child Health.
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