Genomic structure and localisation within a linkage hotspot of Disrupted In Schizophrenia 1, a gene disrupted by a translocation segregating with schizophrenia

Two overlapping and antiparallel genes on chromosome 1, Disrupted In Schizo phrenia 1 and 2 (DISC1 and DISC2), are disrupted by a (1;11)(q42.1;q14.3) t ranslocation which segregates with schizophrenia through at least four gene rations of a large Scottish family. Consequently, these genes are worthy of further investigation as candidate genes potentially involved in the aetio logy of major psychiatric illness. We have constructed a contiguous clone m ap of PACs and cosmids extending across at least 400 kb of the chromosome 1 translocation breakpoint region and this has provided the basis for examin ation of the genomic structure of DISC1. The gene consists of thirteen exon s, estimated to extend across at least 300 kb of DNA. The antisense gene DI SC2 overlaps with exon 9. Exon 11 contains an alternative splice site that removes 66 nucleotides from the open reading frame. The final intron of DIS C1 belongs to the rare AT-AC class of introns. We have also mapped marker D IS251 in close proximity to DISC1, localising the gene within a critical re gion identified by several independent studies. Information regarding the s tructure of the DISC1 gene will facilitate assessment of its involvement in the aetiology of major mental illness in psychotic individuals unrelated t o carriers of the translocation.