International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA



9.15am – 9.30am


Yang S2, Murphy TK2, Hadley D4, Farias M2, Kapfhamer D2, Ungar L1, Kim J3, Bucan M1

1 Penn Center for Bioinformatics, University of Pennsylvania, Philadelphia, United States, 2 Department of Genetics/SOM, University of Pennsylvania, Philadelphia, United States, 3 Department of Computer and Information Sciences/SEAS, University of Pennsylvania, Philadelphia, United States, 4 Department of Biology/SAS, University of Pennsylvania, Philadelphia, United States

The goal of our studies is to use the neuronal synapse, the key functional unit in cell-cell communication in the brain, as a model for a comparative and integrative approach to pathway building and to address the relevance of this pathway to human disease.  We have developed SynapseDB - a database of components (genes/proteins) that are the functional building blocks of a synapse (genomic sequence, multi-species conserved sequences, expression and mutant phenotypes).  Phylogenomic analyses of gene and protein sequences for several large gene families (synaptotagmins, syntaxins, rab proteins) revealed variable rates of evolutionary changes in different gene families, "species-specific" paralogs and evolutionary dynamics of non-coding regions.  Specifically, while coding regions of closely related paralogs showed slow rates of sequence changes as measured by per-gene ratios of Ka/Ks, non-coding regions showed high levels of sequence changes. 

We have also investigated Rab3a, a small GTPase involved in synaptic vesicle trafficking, in more detail.  To address the molecular mechanisms underlying behavioral phenotypes in two alleles (loss-of-function and dominant-negative allele), we carried out transcriptome analysis by the microarray and Q-PCR analysis of RNA isolated from the cortex and hippocampus of wild type and mutant mice (C57BL/6J - N4 generation). These experiments identified a set of differentially expressed genes (wild type vs, mutant) and only one differentially expressed gene (Rabphilin – a Rab3A effector) in common between the two alleles.  The most striking result was the detection of over 20 differentially expressed genes (129/Sv vs. C57BL/6J) located in the 129/Sv-derived chromosomal region surrounding the Rab3A-/- gene.  Our results illustrate the challenges of molecular and behavioral comparison of mutants that arise on different genetic backgrounds.

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