International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)

A29. Sequence and Functional Comparison in the Beckwith-Wiedemann Imprinting Cluster Region between Human and Mouse: Implications for a Novel Imprinting Center and Extended Imprinting

Martina Paulsen1, Osman El-Maarri1, Sabine Engemann1, Martin Strödicke1, Olivia Franck1, Karen Davies3, Natasha Lane3, Wolf Reik3, and Jörn Walter
1 Max-Planck-Institut für molekulare Genetik, Ihnestr. 73, D-14195 Berlin, Germany
2 Laboratory of Developmental Genetics and Imprinting, The Babraham Institute, Cambridge CB2 4AT, United Kingdom

In human and mouse most imprinted genes are arranged in chromosomal clusters. This linked organization suggests coordinated mechanisms controlling imprinted expression. To gain insight into the functional and structural conservation of such a region we have sequenced 800 kb of the mouse imprinting cluster on distal chromosome 7 and compared it to the orthologous Beckwith-Wiedemann gene cluster on human chromosome 11p15.5. This comparative analysis of a major imprinting cluster revealed a highly conserved arrangement of 12 orthologous genes identified(1,2). The most striking similarity was found in the 3` part of the KCNQ1 / Kcnq1 genes in large stretches of mostly non-coding sequences. The conserved region, which most likely constitutes a second imprinting centre, includes the recently identified KCNQ1OT1 / Kcnq1ot1 antisense transcripts, flanked by a strikingly conserved cluster of LINE / Line elements and a CpG island which we show to carry a maternal germline methylation imprint. Besides this highly conserved structures and synthenic organisation several important differences were discovered which will help to understand the complex regulation in this disease associated region. First some genes apparently escape imprinting in both organisms whereas others exhibit tissue and species specific imprinting. Second the human sequence is significantly enlarged compared to the mouse, mostly due to the insertions of two large repetitive clusters. Third, two of the orthologous gene pairs Tssc4/TSSC4 and Ltrpc5/LTRPC5 showed apparent differences in imprinting between human and mouse, whereas others like Tssc6/TSSC6 were not imprinted in either organism. Fourth at least in the mouse the previous confines of the imprinting domain have to be reconsidered as the newly identified gene Obph1, is imprinted in mouse placenta and lies outside of the previously defined imprinting cluster. Fifth, whereas all imprinted

genes within the cluster contain CpG islands the non-imprinted like Ltrpc5, Tssc6, Cars and Tssc5 do not suggesting that CpG islands are key features of imprinted domains. Together our studies show that the control of imprinting in the cluster appears to be a highly dynamic process under fast evolutionary adaptation. They also demonstrate the extreme usefullness of a comparative approach to elucidate important structural and functional elements.


1) Paulsen et al., Human Molecular Genetics 9, 1829-1841 (2000).

2) Engemann et al., submitted.


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