Human Centromere Repositioning "In Progress"

• 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
• Subjects: Autoantigens - metabolism; Biological Sciences; Cell Line, Transformed; Cell lines; Centromere; Centromere Protein A; Centromeres; Chromosomal Proteins, Non-Histone - metabolism; Chromosomes; Chromosomes, Artificial, Bacterial; Daughter cells; DNA; Electrophoresis, Gel, Pulsed-Field; Epigenetics; Evolution; Fluorescence in situ hybridization; Fluorescent Antibody Technique; Genetic Linkage; Genotype; Humans; Hydroxamic Acids - pharmacology; In Situ Hybridization, Fluorescence; Karyotype; Karyotyping; Kinetochores; Protein Binding; Reproduction
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0308637101

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.