Abstract
Centromere (centric) fission, also known as transverse or lateral centric misdivision, has been defined as the splitting of one functional centromere of a metacentric or submetacentric chromosome to produce two derivative centric chromosomes. It has been observed in a range of organisms and has been ascribed an important role in karyotype evolution; however, the underlying mechanisms remain unknown. We have investigated four cases of apparent centric fission in humans. Two cases show a missing chromosome 22 or 18 that is replaced by two centric ring products, a third case shows two chromosome-10-derived telocentric chromosomes, whereas a fourth case involves the formation of two chromosome-18-derived isochromosomes. In all four cases, results of gross cytogenetic and fluorescence in situ hybridisation analyses were consistent with a simple centric fission event. However, detailed molecular analyses provided evidence in support of centromere duplication as a predisposing mechanism for the observed chromosomal breakage in two of the cases. Results for the third case are consistent with direct centric fission not involving centromere pre-duplication as the likely mechanism. Insufficient material has precluded the further study of the fourth case. The data provide the first molecular evidence for centromere pre-duplication as a possible mechanism to explain the classically assumed simple “centric fission” events in clinical cytogenetics, karyotype evolution and speciation.
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Acknowledgements
We thank Robert Robertson and Lesley Ades for patient materials, and Lee Wong and Kerry Fowler for help with quantitative FISH and statistical analyses. J.P. is a Peter Doherty Fellow, and K.H.A.C. a Senior Principal Research Fellow of the National Health and Medical Research Council of Australia.
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Perry, J., Nouri, S., La, P. et al. Molecular distinction between true centric fission and pericentric duplication-fission. Hum Genet 116, 300–310 (2005). https://doi.org/10.1007/s00439-004-1209-4
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DOI: https://doi.org/10.1007/s00439-004-1209-4