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community databases. For example, all of The mission of the three centers is to pro- convulsive threshold screen, has identified two the mutants are being registered with the vide the scientific community with new new mutant alleles in the Kcnq2 , whose Mouse Genome Informatics (MGI) database mouse models for understanding gene func- human homolog is mutated in a form of at JAX (www.informatics.jax.org), which is tion in the nervous system. To date, over 100 human epilepsy. Finally, the Neuromuta- the primary community database for the new mouse mutants relevant to neurological genesis Program of the TMGC, using tail sus- laboratory mouse3.Integrating the data disorders in humans have been generated by pension and open-field behavioral screens, allows researchers to get a comprehensive these centers. The mutants include mice with has identified several distinct anxiety/depres- overview of the connections between , defects in balance, blindness, susceptibility to sion or emotional behavior mutants, four of alleles and phenotypes in the mouse. In the seizures and abnormalities in circadian which are localized to mouse 7 longer term, the extensive strain-specific and rhythm, open field behavior, pain responses and one to mouse chromosome 15. The dis- mutant phenotypic data produced by each and hearing. These mutant lines can be used covery of the mutant genes that give rise to center will provide great synergy with other as models to study disorders of neural func- these and other mutant phenotypes is another databases of mouse phenotypic data such as tion. For example, the Center for Functional powerful strategy for the functional annota- the Mouse Phenome Database at JAX Genomics at Northwestern University discov- tion of the genome. (http://aretha.jax.org/pub-cgi/phenome/mpd- ered a new mutant named ‘overtime’ that 1. Russell, W.L. et al. Proc. Natl. Acad. Sci. USA 76, cgi?rtn = docs/home) and the gene expres- defines a clock locus that maps to a region of 5818–5819 (1979). sion profiling of BXD recombinant inbred mouse chromosome 14 where there are no 2. Noveroske, J.K., Weber, J.S. & Justice, M.J. Mamm. Genome 11, 478–483 (2000). strains at the University of Tennessee known circadian genes. The Neuroscience 3. Bult, C.J. et al. Nucleic Acids Res. 32, D476–D481 (http://nervenet.org). Mutagenesis Facility at JAX, using an electro- (2004).

WebQTL: rapid exploratory analysis of gene http://www.nature.com/natureneuroscience expression and genetic networks for brain and behavior

Elissa J Chesler, Lu Lu, Jintao Wang, Robert W Williams & Kenneth F Manly

Brain mRNA expression is modulated by exploits sophisticated gene mapping meth- (RI) strains. The two progenitor strains, B numerous genetic factors and often varies ods2,3 to rapidly perform whole-genome and D, have both been sequenced and are substantially between strains of mice that analysis at many levels—from differences in known to differ at roughly 1.8 million single- have been reared in a standard laboratory NR2B mRNA levels to differences in open- nucleotide polymorphisms (SNPs) across the environment. Examples include members of field activity levels. mouse genome. This amounts to an average the NMDA receptor family that are critical in WebQTL has three major applications: of one SNP every 1,500 base pairs. Each of © 2004 Nature Publishing Group learning and memory, and genes involved in exploring variation in gene expression using the BXD strains is a unique ‘mosaic’ of chro- synaptic vesicle trafficking. Molecular varia- a panel of more than 30 recombinant inbred mosomal segments inherited from either the tion of this type is often heritable and is pro- strains and several different tissues (for B or D progenitor strain4.About 34 BXD duced by genetic polymorphisms at many example, forebrain, cerebellum, hematopoi- strains are available from The Jackson locations across the genome. Differences in etic stem cells); mapping upstream gene loci Laboratory, and an additional 45 strains will both alleles and mRNA levels will often pro- that modulate transcript levels; and studying soon be available from The University of duce significant behavioral, pharmacological networks of genetic correlations among Tennessee. A wide range of phenotypes seen and neuroanatomical variants1.Over the past ∼100,000 transcript assays and 650 published in the BXD reference population are also several years, with support from the NIH phenotypes. Additional features include incorporated in WebQTL (see WebQTL’s Human Brain Project, we have assembled a tools for the simultaneous analysis of groups Published Phenotypes database). WebQTL suite of databases and web-based analysis of traits, custom annotation of Affymetrix also includes high-density marker maps software called WebQTL (www.webqtl.org). probes and probe sets, and external based on 779 microsatellites5 and SNPs. By WebQTL is a freely accessible system that links to the Machine testing the association of genetic markers (http://genereg.ornl.gov/gotm), the Gene with variation in transcript levels and other Expression Atlas (http://expression.gnf.org), traits, WebQTL maps the quantitative trait All authors are at the Center for Genomics and NCBI (www.ncbi.nlm.nih.gov) and the loci (QTLs) that are likely to contain modu- Bioinformatics, University of Tennessee Health Genome Browser (http://genome.ucsc.edu). lators of these complex phenotypes. The Science Center, 855 Monroe Avenue, Memphis, The integration of diverse data types pro- value of this BXD reference population to the Tennessee 38163, USA. Elissa J. Chesler, Lu Lu vides a powerful resource for exploratory research community grows multiplicatively and Robert W. Williams are in the Department of systems biology. as additional phenotypes are collected and Anatomy and Neurobiology, and Kenneth F. Manly Data in WebQTL have been acquired from integrated into WebQTL. and Jintao Wang are in the Department of two common progenitor strains, C57BL/6J The gene encoding the NMDA NR2B Pathology and Laboratory Medicine. (B) and DBA/2J (D), their F1 hybrid, and a receptor subunit Grin2b provides an example e-mail: [email protected] set of different BXD recombinant inbred of the type of analysis possible using

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Figure 1 A map of quantitative trait loci on 6 and 8 regulating the expression of the ionotropic glutamate receptor gene Grin2b. All mouse chromosomes, with the exception of chromosome Y, are plotted along the x-axis. The orange triangle is the transcript location; the solid blue trace is the likelihood ratio statistic for association of the phenotype with genotype across the genome. The horizontal lines indicate permutation significance thresholds for significant (P < 0.05, blue) and suggestive (P < 0.67, green) loci. Yellow bars indicate the most likely location of QTL peaks by bootstrap analysis.

WebQTL. The abundance of Grin2b mRNA ety, maze learning, neuron cell numbers, may simultaneously influence expression of transcript in several forebrain data sets varies hippocampal and cerebellar volumes and several critical components of synaptic approximately two-fold across 35 strains. adult neurogenesis. Similarly, hundreds of receptor cycling. Several members of this Half of the variation in expression is herita- transcripts with expression differences that extended family of genes also have known ble; and this makes it practical to map the covary with Grin2b expression can be relations to alcohol-related phenotypes6. responsible QTLs. Grin2b has two major extracted. These include Mpdz,which This example is just one of many query paths QTLs, one on chromosome 8 (Fig. 1), and encodes a involved in the clustering that can be navigated rapidly in WebQTL to another on chromosome 6 near the tran- and endocytosis of NMDA receptors; Ag1g1, generate and test hypotheses using this refer- script itself—probably associated with one or which encodes an adaptor protein complex ence set of RI strains. more of the 556 SNPs in this gene. The QTL that is part of the clathrin coated pit; Inpp4a, 1. Brem, R.B., Yvert, G., Clinton, R. & Kruglyak, L. on chromosome 8 is particularly intriguing, which is involved in the cycling of clathrin to Science 296, 752–755 (2002). http://www.nature.com/natureneuroscience but it would be a project in its own right to the Golgi; and Nfm, which encodes a neuro- 2. Chesler, E.J. et al. Neuroinformatics 1, 343–357 discover the single correct gene associated filament protein. At least five members of the (2003). ∼ 3. Wang, J., Williams, R.W. & Manly, K.F. with this QTL among 50 candidates. kinesin family of motor , essential for Neuroinformatics 1, 299–308 (2003). WebQTL allows hundreds of covariates transport of the endocytic vesicle through 4. Taylor, B.A. et al. Mamm. Genome 10, 335–348 with high correlations to Grin2b to be rapidly the axoplasm, also have expression levels that (1999). extracted, analyzed and graphed. These correlate positively with Grin2b.What is 5. Williams, R.W., Gu, J., Qi, S. & Lu, L. Genome Biol. 2, 0046.1–0046.18 (2001). include many ethanol-related phenotypes, as intriguing about this example is that genetic 6. Fehr, C., Shirley, R.L., Belknap, J K., Crabbe, J.C. & well as measures of locomotor activity, anxi- variation underlying receptor expression Buck, K.J. J. Neurosci. 22, 3730–3738 (2002).

Neurodatabase.org: networking the microelectrode © 2004 Nature Publishing Group Daniel Gardner Electrophysiological signals report activity The Laboratory of Neuroinformatics, sup- accompanied by descriptive metadata. Users of single neurons, neuronal arrays and ported by the Human Brain Project of the can acquire actual datasets, supplied by multi- networks. Our understanding of neural cod- US National Institutes of Health (NIH), ple laboratories, recorded with different tech- ing, information transmission and brain has developed neurodatabase.org—a freely niques from different preparations, all in a processes would be aided if such data could accessible database to aid sharing of neuro- common format and annotated compatibly, be made available for further analyses that physiological data. This resource acquires, for extended analyses. Additional user tools, could integrate and compare findings from organizes, annotates, archives, delivers and such as Bruxton DataGlobe, under develop- individual laboratories, and test multiple displays single- and multi-unit neuronal data ment as a joint academic–corporate effort, hypotheses. Such analyses require access to from mammalian cerebral cortex1.The data- will ease reanalysis of shared data by permit- actual sets of digitized data themselves, base is presently populated with somatosen- ting data upload from within data acquisi- rather than to printed views of the data sory recordings, with planned expansion to tion applications, and data download directly through static journal figures1.However,data data from other regions. It is available to any to standard acquisition routines. sharing of this sort requires agreement on user with a contemporary Java-enabled net- Effective use and re-use of shared data techniques, formats and ownership, as well as worked computer. requires methods for selecting specific methods for classification and selection. The underlying data model in the database datasets from among others in a repository. provides standards for data archiving, The neurodatabase.org QueryTool allows description and exchange. Java-based tools searching by data-descriptive metadata Daniel Gardner is at the Laboratory of dynamically reflect this data model and terms, specified by the submitters, from mul- Neuroinformatics, Department of Physiology, Weill support multiplatform assembly, upload, tiple hierarchies of controlled vocabularies. Medical College of Cornell University, New York, annotation, search and acquisition. They also For example, data from particular cortical New York 10021, USA. provide views of XML-wrapped data on user- regions can be sought by either general e-mail: [email protected] controlled, expanded or contracted time scales, terms, such as “somatosensory” or more spe-

486 VOLUME 7 | NUMBER 5 | MAY 2004 NATURE NEUROSCIENCE