The Mouse Genome Database (MGD): integration nexus for the laboratory mouse.

The Mouse Genome Database (MGD) is the community database resource for the laboratory mouse, a key model organism for interpreting the human genome and for understanding human biology and disease (http://www.informatics.jax.org). MGD provides standard nomenclature and consensus map positions for mouse genes and genetic markers; it provides a curated set of mammalian homology records, user-defined chromosomal maps, experimental data sets and the definitive mouse \u27gene to sequence\u27 reference set for the research community. The integration and standardization of these data sets facilitates the transition between mouse DNA sequence, gene and phenotype annotations. A recent focus on allele and phenotype representations enhances the ability of MGD to organize and present data for exploring the relationship between genotype and phenotype. This link between the genome and the biology of the mouse is especially important as phenotype information grows from large mutagenesis projects and genotype information grows from large-scale sequencing projects

A Behavioral Comparison of Four Inbred Strains of Mice

Isogenic, or inbred, mouse strains are currently the experimental subjects of choice in laboratory studies focused on genetics, pharmacology, and psychological issues. Understanding phenotypic differences in isogenic strains is important in order to interpret experimental results obtained from inbred mouse strains. Four commonly used inbred strains, C57BL/6NHsd (C57), DBA/2NHsd (DBA), 129S2/SvHsd (129), and Balb/cAnHsd (Balb/c), are investigated in this study using four different behavioral tasks that measure locomotor activity and cognitive behavior (Morris Water Maze (MWM), T-maze, and operant autoshaping procedures). In the locomotor activity task 129 mice showed significantly less horizontal ambulation than any other strain, while differences in rearing was seen between all strains, with C57 mice producing the most, and 129 showing the least rearing. Thigmotaxia was seen the most in the 129 strain, less so with the Balb/c and DBA strains, and the least in the C57 mice. In the MWM learning across strains was noted but there was no difference between the strains. In the T-maze the Balb/c strain showed the shortest latency to enter an arm, while the 129 strain showed the longest. As expected they also showed the lowest accuracy and the highest percent time-outs compared to all the other strains. In the autoshaping procedure little difference between the strains was observed. Balb/c mice trended graphically towards higher rates however there was no difference with regard to number of contingent responses or number per strain to reach a criterion of 10 or more contingent reinforcers. Finally, locomotor activity was measured again at the end of the study. The activity results were still similar, although the C57 strain showed a decrease in horizontal ambulation as compared to DBA and Balb/c strains; however, the 129 strain still showed the least activity. These results indicate that there are significant differences in locomotor behavior and cognitive processes in these strains that should be considered when interpreting results from studies using these inbred mouse strains

Comparative and molecular characterisation of a schizophrenia susceptibility locus

A substantial genetic contribution to the aetiology of schizophrenia and other major mental illnesses has been convincingly and repeatedly established by family, twin and adoption studies. However, phenotypic and genetic heterogeneity have severely hampered linkage and association studies, and consequently the molecular basis of the genetic contribution remains undefined. The use of cytogenetic abnormalities to identify disease loci is a well established technique that overcomes many of the problems of linkage and association studies. A balanced t(l;l I)(q42;q14) translocation segregates in a large Scottish family (LOD = 7.1) with schizophrenia and related psychiatric disorders. At least three independent studies have also identified the 1q42 region of the genome as a susceptibility locus for major mental illness. The chromosome 1 breakpoint region now represents one of the best-supported loci for susceptibility to major mental illness. Two novel genes are directly disrupted by the chromosome 1 breakpoint, Disrupted-In-Schizophrenia 1 and 2 (DISCI and DISC2). The central hypothesis of this work is that genes directly disrupted by, or near to the chromosome 1 breakpoint contribute a significant susceptibility to major mental illness. This thesis set out to characterise DISCI, DISC2 and neighboring genes through comparative sequence analysis. Specifically, the research aimed to better define the locus, the genes, their functions and regulatory sequences, to evaluate the functional consequences of the translocation and how these may relate to the t(1;11) phenotype.Human genomic sequence over the breakpoint region was assembled. The DISCI region of the Fugu rubripes genome was cloned and 45 kb of contiguous genomic sequence generated. The orthologous region of the mouse and chicken genomes was identified and characterised. A pipeline for preliminary genomic annotation and subsequent comparative genomic analysis was developed using the cystic fibrosis locus as a model, and subsequently applied to the DISCI locus. The method of "annotation anchored global sequence alignment" substantially increased the sensitivity in detection of biologically relevant conserved sequence motifs. Comparative genomic analysis, RT-PCR and cDNA clone identification were used to construct a transcriptional map of the Fugu genomic region and refine the human transcription map. Conservation of synteny between 0.7 Mb of the human genome and 45 kb of the Fugu genome was demonstrated, with one boundary of synteny being clearly defined. The region of conserved synteny contained the genes Egg Laying Nine-1 (EGLN1), Translin Associated factor X (TRAX) and DISCI in both species.EGLN1 was found to be a member of a previously undescribed gene family. The mouse and human members were identified and characterised. In addition, evolutionary evidence for a novel mechanism of host - pathogen interactions was discovered. TRAX and its homologue Translin were tentatively identified as members of a nucleic acid helicase family of proteins, providing a mechanistic basis for their known biological roles, and suggesting previously undescribed functional aspects of these proteins. DISCI was found to be rapidly evolving in both genomic structure and protein sequence, although three N-terminal motifs and blocks of coiled coil forming potential in the C-terminal half of the protein are conserved features, suggesting a general structure and function for the protein. Neither the antisense transcript DISC2 nor the intergenic splicing of TRAX to DISCI are conserved in Fugu.The work presented in this thesis has substantially enhanced understanding of the chromosome 1 breakpoint locus both at the genomic and encoded protein level. Two novel gene families have been defined and characterised, allowing a more complete evaluation of their functional candidacy in the aetiology of major mental illness. The sequence and clone resources resulting from this work also form the basis for protein functional studies and future characterisation of the locus in animal models