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Evolution
Human centromere repositioning "in progress"

David J. Amor ^* , Karen Bentley ^*, Jacinta Ryan ^* , Jo Perry ^*, Lee Wong ^*, Howard Slater ^* , and K. H. Andy Choo ^* 

^*Murdoch Children's Research Institute and Department of Paediatrics, and Genetic Health Services Victoria, Royal Children's Hospital, Flemington Road, Victoria 3052, Australia

Edited by Louis M. Kunkel, Harvard Medical School, Boston, MA and approved March 12, 2004 (received for review December 23, 2003)

Centromere repositioning provides a potentially powerful evolutionary force for reproductive isolation and speciation, but the underlying mechanisms remain ill-defined. An attractive model is through the simultaneous inactivation of a normal centromere and the formation of a new centromere at a hitherto noncentromeric chromosomal location with minimal detrimental effect. We report a two-generation family in which the centromeric activity of one chromosome 4 has been relocated to a euchromatic site at 4q21.3 through the epigenetic formation of a neocentromere in otherwise cytogenetically normal and mitotically stable karyotypes. Strong epigenetic inactivation of the original centromere is suggested by retention of 1.3 megabases of centromeric -satellite DNA, absence of detectable molecular alteration in chromosome 4-centromereproximal p- and q-arm sequences, and failure of the inactive centromere to be reactivated through extensive culturing or treatment with histone deacetylase inhibitor trichostatin A. The neocentromere binds functionally essential centromere proteins (CENP-A, CENP-C, CENP-E, CENP-I, BUB1, and HP1), although a moderate reduction in CENP-A binding and sister-chromatid cohesion compared with the typical centromeres suggests possible underlying structural/functional differences. The stable mitotic and meiotic transmissibility of this pseudodicentric-neocentric chromosome in healthy individuals and the ability of the neocentric activity to form in a euchromatic site in preference to a preexisting alphoid domain provide direct evidence for an inherent mechanism of human centromere repositioning and karyotype evolution "in progress." We discuss the wider implication of such a mechanism for meiotic drive and the evolution of primate and other species.

Abbreviations: BAC, bacterial artificial chromosome; FISH, fluorescence in situ hybridization; PD-NC, pseudodicentric-neocentric chromosome; PFGE, pulse-field gel electrophoresis; TSA, trichostatin A; Mb, megabase(s).

To whom correspondence should be addressed. E-mail: andy.choo{at}mcri.edu.au.

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