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 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 alpha-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.
Amor
David J
DJ
Murdoch Children's Research Institute and Department of Paediatrics, Genetic Health Services Victoria, Royal Children's Hospital, Flemington Road, Victoria 3052, Australia.
Bentley
Karen
K
Ryan
Jacinta
J
Perry
Jo
J
Wong
Lee
L
Slater
Howard
H
Choo
K H Andy
KH
D001324:Autoantigens / Q000378:metabolism; D002461:Cell Line, Transformed; D002503:Centromere; D000076247:Centromere Protein A; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D022202:Chromosomes, Artificial, Bacterial; D016521:Electrophoresis, Gel, Pulsed-Field; D005455:Fluorescent Antibody Technique; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D011485:Protein Binding
D001324:Autoantigens; C000619700:CENPA protein, human; D000076247:Centromere Protein A; D002868:Chromosomal Proteins, Non-Histone; D006877:Hydroxamic Acids; C012589:trichostatin A