Sequence and comparative analysis of the mouse 1-megabase region orthologous to the human 11p15 imprinted domain

A major barrier to conceptual advances in understanding the mechanisms and regulation of imprinting of a genomic region is our relatively poor underst anding of the overall organization of genes and of the potentially importan t cis-acting regulatory sequences that lie in the nonexonic segments that m ake up 97% of the genome. Interspecies sequence comparison offers an effect ive approach to identify sequence from conserved functional elements. In th is article we describe the successful use of this approach in comparing a s imilar to1-Mb imprinted genomic domain on mouse chromosome 7 to its ortholo gous region on human 11p15.5. Within the region, we identified 112 exons of known genes as well as a novel gene identified uniquely in the mouse regio n, termed Msuit, that was found to be imprinted. In addition to these codin g elements, we identified 33 CpG islands and 49 orthologous nonexonic, noni sland sequences that met our criteria as being conserved, and making up 4.1 % of the total sequence. These conserved noncoding sequence elements were g enerally clustered near imprinted genes and the majority were between Igf2 and H19 or within Kvlqt1. Finally, the location of CpG islands provided evi dence that suggested a two-island rule for imprinted genes. This study prov ides the first global view of the architecture of an entire imprinted domai n and provides candidate sequence elements for subsequent functional analys es.