(RI) strains. The two progenitor strains, B and D, have both been sequenced and are known to differ at roughly 1.8 million single- nucleotide polymorphisms (SNPs) across the mouse genome. This amounts to an average of one SNP every 1,500 base pairs. Each of the BXD strains is a unique ‘mosaic’ of chro- mosomal segments inherited from either the B or D progenitor strain 4 . About 34 BXD strains are available from The Jackson Laboratory, and an additional 45 strains will soon be available from The University of Tennessee. A wide range of phenotypes seen in the BXD reference population are also incorporated in WebQTL (see WebQTL’s Published Phenotypes database). WebQTL also includes high-density marker maps based on 779 microsatellites 5 and SNPs. By testing the association of genetic markers with variation in transcript levels and other traits, WebQTL maps the quantitative trait loci (QTLs) that are likely to contain modu- lators of these complex phenotypes. The value of this BXD reference population to the research community grows multiplicatively as additional phenotypes are collected and integrated into WebQTL. The gene encoding the NMDA NR2B receptor subunit Grin2b provides an example of the type of analysis possible using exploits sophisticated gene mapping meth- ods 2,3 to rapidly perform whole-genome analysis at many levels—from differences in NR2B mRNA levels to differences in open- field activity levels. WebQTL has three major applications: exploring variation in gene expression using a panel of more than 30 recombinant inbred strains and several different tissues (for example, forebrain, cerebellum, hematopoi- etic stem cells); mapping upstream gene loci that modulate transcript levels; and studying networks of genetic correlations among ∼100,000 transcript assays and 650 published phenotypes. Additional features include tools for the simultaneous analysis of groups of traits, custom annotation of Affymetrix probes and probe sets, and external links to the Gene Ontology Machine (http://genereg.ornl.gov/gotm), the Gene Expression Atlas (http://expression.gnf.org), NCBI (www.ncbi.nlm.nih.gov) and the Genome Browser (http://genome.ucsc.edu). The integration of diverse data types pro- vides a powerful resource for exploratory systems biology. Data in WebQTL have been acquired from two common progenitor strains, C57BL/6J (B) and DBA/2J (D), their F1 hybrid, and a set of different BXD recombinant inbred Brain mRNA expression is modulated by numerous genetic factors and often varies substantially between strains of mice that have been reared in a standard laboratory environment. Examples include members of the NMDA receptor family that are critical in learning and memory, and genes involved in synaptic vesicle trafficking. Molecular varia- tion of this type is often heritable and is pro- duced by genetic polymorphisms at many locations across the genome. Differences in both alleles and mRNA levels will often pro- duce significant behavioral, pharmacological and neuroanatomical variants 1 . Over the past several years, with support from the NIH Human Brain Project, we have assembled a suite of databases and web-based analysis software called WebQTL (www.webqtl.org). WebQTL is a freely accessible system that community databases. For example, all of the mutants are being registered with the Mouse Genome Informatics (MGI) database at JAX (www.informatics.jax.org), which is the primary community database for the laboratory mouse 3 . Integrating the data allows researchers to get a comprehensive overview of the connections between genes, alleles and phenotypes in the mouse. In the longer term, the extensive strain-specific and mutant phenotypic data produced by each center will provide great synergy with other databases of mouse phenotypic data such as the Mouse Phenome Database at JAX (http://aretha.jax.org/pub-cgi/phenome/mpd- cgi?rtn = docs/home) and the gene expres- sion profiling of BXD recombinant inbred strains at the University of Tennessee (http://nervenet.org). convulsive threshold screen, has identified two new mutant alleles in the Kcnq2 gene, whose human homolog is mutated in a form of human epilepsy. Finally, the Neuromuta- genesis Program of the TMGC, using tail sus- pension and open-field behavioral screens, has identified several distinct anxiety/depres- sion or emotional behavior mutants, four of which are localized to mouse chromosome 7 and one to mouse chromosome 15. The dis- covery of the mutant genes that give rise to these and other mutant phenotypes is another powerful strategy for the functional annota- tion of the genome. 1. Russell, W.L. et al. Proc. Natl. Acad. Sci. USA 76, 5818–5819 (1979). 2. Noveroske, J.K., Weber, J.S. & Justice, M.J. Mamm. Genome 11, 478–483 (2000). 3. Bult, C.J. et al. Nucleic Acids Res. 32, D476–D481 (2004). The mission of the three centers is to pro- vide the scientific community with new mouse models for understanding gene func- tion in the nervous system. To date, over 100 new mouse mutants relevant to neurological disorders in humans have been generated by these centers. The mutants include mice with defects in balance, blindness, susceptibility to seizures and abnormalities in circadian rhythm, open field behavior, pain responses and hearing. These mutant lines can be used as models to study disorders of neural func- tion. For example, the Center for Functional Genomics at Northwestern University discov- ered a new mutant named ‘overtime’ that defines a clock locus that maps to a region of mouse chromosome 14 where there are no known circadian genes. The Neuroscience Mutagenesis Facility at JAX, using an electro- WebQTL: rapid exploratory analysis of gene expression and genetic networks for brain and behavior Elissa J Chesler, Lu Lu, Jintao Wang, Robert W Williams & Kenneth F Manly NATURE NEUROSCIENCE VOLUME 7 | NUMBER 5 | MAY 2004 485 DATABASES S CALING U P N EUROSCIENCE All authors are at the Center for Genomics and Bioinformatics, University of Tennessee Health Science Center, 855 Monroe Avenue, Memphis, Tennessee 38163, USA. Elissa J. Chesler, Lu Lu and Robert W. Williams are in the Department of Anatomy and Neurobiology, and Kenneth F. Manly and Jintao Wang are in the Department of Pathology and Laboratory Medicine. e-mail: echesler@utmem.edu © 2004 Nature Publishing Group http://www.nature.com/natureneuroscience