Human Centromere Repositioning "In Progress"

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 hith...

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Published in:Proceedings of the National Academy of Sciences - PNAS Vol. 101; no. 17; pp. 6542 - 6547
Main Authors: Amor, David J., Bentley, Karen, Ryan, Jacinta, Perry, Jo, Wong, Lee, Slater, Howard, K. H. Andy Choo, Kunkel, Louis M.
Format: Journal Article
Language:English
Published: United States National Academy of Sciences 27-04-2004
National Acad Sciences
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Summary: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 α-satellite DNA, absence of detectable molecular alteration in chromosome 4-centromere-proximal 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.
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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@mcri.edu.au.
This paper was submitted directly (Track II) to the PNAS office.
Edited by Louis M. Kunkel, Harvard Medical School, Boston, MA
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0308637101