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Stable dicentric X chromosomes with two functional centromeres

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    It has long been speculated, from cytogenetic observation of primary constrictions, that when the two centromeres of a dicentric chromosome are close then they may both be active. That is, orientation of the respective kinetochores on each chromatid to opposite spindle poles is possible so that the dicentric can evade the “fusion-breakage-bridge” cycle of Barbara McClintock and segregate efficiently. Thus, for example, Robertsonian translocation chromosomes usually have two active centromeres. Conversely, it is suggested that widely spaced centromeres of a dicentric may misalign on the spindle, since the chromatin between them can twist; the dicentric is thus forced to somehow undergo inactivation of one of the centromeres for efficient segregation to be possible. Until now it has not been possible to extrapolate from cytogenetic observations of dicentric chromosomes to centromere distances in terms of megabases of DNA. The recent letter to Nature Genetics by Sullivan and Willard now addresses this problem nicely. These authors describe experiments with a variety of dicentric (dic)X chromosomes, in which the extent of the X short arm chromatin between centromeres is defined, varying from 4 to 34 Mb. Sullivan and Willard used antibodies to CENP-C and E, specific to active centromeres. They found that, in the four dic(X)s with the shortest intercentromeric distances (4-12 Mb), these proteins were present at both centromeres in 67-87% of cells. Excitingly, however, dic(X) chromosomes with greater intercentromeric distances, for example, the cited case of 34 Mb, showed only a single CENP positive centromere in 100% of cells; they were thus functionally monocentric. The authors attempted to correlate these findings with stability of chromosome segregation at anaphase. They therefore monitored movement of the respective dicentric and control chromosomes using a technique involving enriching for anaphase and telophase cells. As expected, controls and functionally monocentric X chromosomes showed no evidence of anaphase lag, that is, they segregated efficiently. However, in two of three functionally dicentric X cell lines the dic(X) was shown at the spindle midzone in anaphase, or between two newly formed daughter cells in telophase, in approximately 25% of cells, as illustrated in the elegantly presented figures. It is not clear why the above unstable segregation was not seen in the third functionally dicentric X cell line tested, or why the two cell lines showing high degrees of anaphase lag did not eventually lose the dic(X) completely. Sullivan and Willard suggest that there are other mechanisms involved in ensuring the stability of dicentric chromosomes. Behaviour of the dic(X)s at cell division did not, moreover, correlate with the presence of mosaicism in the karyotype, although it was not made clear whether this mosaicism applied to the original patients’ karyotypes or to those of the cell lines derived from these patients (mosaicism in cell lines being subject to distortion by clonal expansion). The authors, therefore, propose that the mosaicism associated with dic(X) cases reflects chromosome loss at the time of dicentric formation and not subsequent instability and ongoing clonal evolution. Their inference may be somewhat of a conceptual leap, but this caveat should not detract from what is otherwise an elegant and concisely described piece of work.

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