Human Molecular Genetics

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Human Molecular Genetics, 2000, Vol. 9, No. 12 1829-1841
© 2000 Oxford University Press

Sequence conservation and variability of imprinting in the Beckwith–Wiedemann syndrome gene cluster in human and mouse

Martina Paulsen^1,2, Osman El-Maarri^,1,+, Sabine Engemann^+,1, Martin Strödicke^+,1, Olivia Franck¹, Karen Davies³, Richard Reinhardt¹, Wolf Reik³ and Jörn Walter^,1,§

¹Max-Planck-Institut für Molekulare Genetik, Ihnestraße 73, D-14195 Berlin, Germany, ²University of Cambridge, Department of Anatomy, Downing Street, Cambridge CB2 3DY, UK and ³Laboratory of Developmental Genetics and Imprinting, The Babraham Institute, Cambridge CB2 4AT, UK

In human and mouse most imprinted genes are arranged in chromosomal clusters. This linked organization suggests coordinated mechanisms controlling imprinted expression. We have sequenced 250 kb in the centre of the mouse imprinting cluster on distal chromosome 7 and compared it with the orthologous Beckwith–Wiedemann gene cluster on human chromosome 11p15.5. This first comparative imprinting cluster analysis revealed a high structural and functional conservation of the six orthologous genes identified. However, several striking differences were also discovered. First, compared with the mouse the human sequence is ~40% longer, mostly due to insertions of two large repetitive clusters. One of these clusters encompasses an additional gene coding for a homologue of the ribosomal protein L26. Second, pronounced blocks of unique direct repeats characteristic of imprinted genes were only found in the human sequence. 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. Together these results suggest a significant functional and structural variability in the centre of the imprinting cluster. Some genes escape imprinting in both organisms whereas others exhibit tissue- and species-specific imprinting. Hence the control of imprinting in the cluster appears to be a highly dynamic process under fast evolutionary adaptation. Intriguingly, whereas imprinted genes within the cluster contain CpG islands the non-imprinted Ltrpc5 and Tssc6/TSSC6 do not. This and additional comparisons with other imprinted and non-imprinted regions suggest that CpG islands are key features of imprinted domains.

⁺ These authors contributed equally to this work

^§ To whom correspondence should be addressed. Tel: +49 30 84131274; Fax: +49 30 84131385; Email: walter@molgen.mpg.de

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