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Human Molecular Genetics, 2000, Vol. 9, No. 19 2879-2884
© 2000 Oxford University Press

Interchromosomal repeat array interactions between chromosomes 4 and 10: a model for subtelomeric plasticity

Petra G.M. van Overveld1, Richard J.F.L. Lemmers1, Giancarlo Deidda1,2, Lodewijk Sandkuijl1, George W. Padberg3, Rune R. Frants1 and Silvère M. van der Maarel1,+

1Department of Human and Clinical Genetics, Leiden University Medical Center, Wassenaarseweg 72, PO Box 9502, 2333 AL Leiden, The Netherlands, 2National Research Council, Rome, Italy and 3Department of Neurology, University of Nijmegen, Nijmegen, The Netherlands

Chromosomal rearrangements occur more frequently in subtelomeric domains than in other regions of the genome and are often associated with human pathology. To further elucidate the plasticity of subtelomeric domains, we examined the 3.3 kb D4Z4 repeat array on chromosome 4 and its homologue on chromosome 10 in 208 Dutch blood donors by pulsed field gel electrophoresis. These subtelomeric repeats are known to rearrange and partial deletions of this polymorphic array on chromosome 4 are associated with facioscapulohumeral muscular dystrophy (FSHD), an autosomal dominant myopathy. Our results show that mitotic rearrangements occur frequently as 3% of individuals display somatic mosaicism for a repeat expansion or contraction explaining the high variability of subtelomeric repeat array sizes. Translocated 4-type repeat arrays on chromosome 10 and the reverse configuration of 10-type repeat arrays on chromosome 4 are observed in 21% of individuals. The translocated repeat arrays on chromosome 4 tend to be more heterogeneous than 4-type repeats on chromosome 10. The repeat length on chromosome 4 is on average larger than on chromosome 10. But on both chromosomes we observe a multi-modal repeat length distribution with equidistant peaks at intervals of 65 kb, possibly reflecting a higher-order chromatin structure. Interestingly, in as many as six random blood donors (3%) we identified FSHD-sized 4-type repeat arrays. Assuming that these individuals are clinically unaffected, these results imply an incomplete penetrance in the upper range of FSHD alleles. Overall, the observed dynamic characteristics of these homologous domains may serve as a model for subtelomeric plasticity.

+ To whom correspondence should be addressed. Tel: +31 71 527 6107; Fax: +31 71 527 6075; Email: maarel@lumc.nl


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