Transmission of a Fully Functional Human Neocentromere through Three Generations

Tyler‐Smith, Chris; Gimelli, Giorgio; Giglio, Sabrina; Floridia, Giovanna; Pandya, Arpita; Terzoli, G. L.; Warburton, Peter E.; Earnshaw, William C.; Zuffardi, Orsetta

doi:10.1086/302380

Cited by 111 publications

(82 citation statements)

References 22 publications

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“…Three examples of PD-NC have been described for the human Y chromosome (23)(24)(25). However, our PD-NC4 case differs from these PD-NCY cases in a number of significant ways.…”

Section: Discussionmentioning

confidence: 81%

Human centromere repositioning “in progress”

Amor

Bentley

Ryan

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

197

196

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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 structural͞functional 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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“…Three examples of PD-NC have been described for the human Y chromosome (23)(24)(25). However, our PD-NC4 case differs from these PD-NCY cases in a number of significant ways.…”

Section: Discussionmentioning

confidence: 81%

Human centromere repositioning “in progress”

Amor

Bentley

Ryan

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

197

196

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“…As a consequence, the patient is usually trisomic or tetrasomic for a chromosomal segment and shows an abnormal phenotype, indirectly preventing the transmission of the neocentromere to next generations. Neocentromere appearance not accompanied by the loss of the normal centromere has been reported on chromosome Y (Bukvic et al 1996;Rivera et al 1996;Tyler-Smith et al 1999). In one case, however, the chromosome was unstable (Rivera et al 1996), and in the other two cases, the neocentromere was embedded in the heterochromatic block of Yq.…”

Section: Human Neocentromeresmentioning

confidence: 84%

Recurrent Sites for New Centromere Seeding

et al. 2004

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Using comparative FISH and genomics, we have studied and compared the evolution of chromosome 3 in primates and two human neocentromere cases on the long arm of this chromosome. Our results show that one of the human neocentromere cases maps to the same 3q26 chromosomal region where a new centromere emerged in a common ancestor of the Old World monkeys ∼25-40 million years ago. Similarly, the locus in which a new centromere was seeded in the great apes' ancestor was orthologous to the site in which a new centromere emerged in the New World monkeys' ancestor. These data suggest the recurrent use of longstanding latent centromeres and that there is an inherent potential of these regions to form centromeres. The second human neocentromere case (3q24) revealed unprecedented features. The neocentromere emergence was not accompanied by any chromosomal rearrangement that usually triggers these events. Instead, it involved the functional inactivation of the normal centromere, and was present in an otherwise phenotypically normal individual who transmitted this unusual chromosome to the next generation. We propose that the formation of neocentromeres in humans and the emergence of new centromeres during the course of evolution share a common mechanism

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“…Therefore, the low level of CentO in Cen8 places it at one extreme of a continuum of array sizes in this species. Large CentO arrays fall in the size range of satellite DNA arrays found in other multicellular organisms; for example, the human Y-chromosome alpha satellite array ranges from 400 kb to several megabases in normal men 37 .…”

Section: Discussionmentioning

confidence: 99%

Sequencing of a rice centromere uncovers active genes

Nagaki

Cheng

Ouyang³

et al. 2004

Nat Genet

485

520

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Centromeres are the last frontiers of complex eukaryotic genomes, consisting of highly repetitive sequences that resist mapping, cloning and sequencing. The centromere of rice Chromosome 8 (Cen8) has an unusually low abundance of highly repetitive satellite DNA, which allowed us to determine its sequence. A region of ∼750 kb in Cen8 binds rice CENH3, the centromere-specific H3 histone. CENH3 binding is contained within a larger region that has abundant dimethylation of histone H3 at Lys9 (H3-Lys9), consistent with Cen8 being embedded in heterochromatin. Fourteen predicted and at least four active genes are interspersed in Cen8, along with CENH3 binding sites. The retrotransposons located in and outside of the CENH3 binding domain have similar ages and structural dynamics. These results suggest that Cen8 may represent an intermediate stage in the evolution of centromeres from genic regions, as in human neocentromeres, to fully mature centromeres that accumulate megabases of homogeneous satellite arrays.

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Transmission of a Fully Functional Human Neocentromere through Three Generations

Cited by 111 publications

References 22 publications

Human centromere repositioning “in progress”

Human centromere repositioning “in progress”

Recurrent Sites for New Centromere Seeding

Sequencing of a rice centromere uncovers active genes

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