The chromosome 1 breakpoint region now represents one of the best-supported loci for susceptibility to major mental. Two novel genes are directly disrupted by the chromosome 1 breakpoint, Disrupted-In-Schizophrenia 1 and 2 (DISC1 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 DISC1, DISC2 and neighbouring 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 DISC1 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 DISC1 locus. The method of “annotation anchored genomic sequence aligmnent” 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 DISC1 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.