Sequence and functional comparison in the Beckwith-Wiedemann region: implications for a novel imprinting centre and extended imprinting

The clustered organization of most imprinted genes in mammals suggests coor dinated genetic and epigenetic control mechanisms. Comparisons between huma n and mouse will help in elucidating these mechanisms by identifying struct ural and functional similarities. Previously we reported on such a comparis on in the central part of the mouse imprinting cluster on distal chromosome 7 with the homologous Beckwith-Wiedemann syndrome (BWS) gene cluster on hu man chromosome 11p15.5, Here we focus on the adjacent sequences of 0.5 Mb i ncluding the KCNQ1/Kcnq1 and CDKN1C/Cdkn1c genes, which are implicated in B WS, and on one of the proposed boundary regions of the imprinting cluster. As in the previously analysed central region, this part of the cluster exhi bits a highly conserved arrangement and structure of genes. The most striki ng similarity is found in the 3' part of the KCNQ1/Kcnq1 genes in large str etches of mostly non-coding sequences. The conserved region includes the re cently identified KCNQ1OT1/Kcnq1ot1 antisense transcripts, flanked by a str ikingly conserved cluster of LINE/Line elements and a CpG island which we s how to carry a maternal germline methylation imprint. This region is likely to be the proposed second imprinting centre (IC2) in the BWS cluster. We a lso identified several novel genes inside and outside the previously propos ed boundaries of the imprinting cluster. One of the genes outside the clust er, Obph1, is imprinted in mouse placenta indicating that at least in extra -embryonic tissues the imprinting cluster extends into a larger domain.